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2021 Year in Review: Advances in Dual Immunotherapy Cancer Treatments

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Dual immunotherapy for cancer has been one of the most successful modes of treatment researched and developed in recent years, with many new studies having been completed this past year. Immunotherapy has been used in the past for oncological treatments with monotherapy and in combination with chemotherapy; these new studies provide data on the success of combinations of various monoclonal antibodies for treatment of solid tumors.

These major research advances have been compiled from presentations at the 2021 American Society of Clinical Oncology and 2021 European Society for Medical Oncology annual meetings, in addition to manuscripts published in key journals. This year in review summarizes data on these important and innovative therapies.

The material is divided into 2 sections:

  1. Pivotal Data from Phase 3 Trials
  2. Early Clinical Development: Phase 1-2 Trials

The studies presented cover advances in dual immunotherapy of renal carcinoma, non–small-cell lung cancer, mesothelioma, head and neck squamous-cell carcinoma, cutaneous melanoma, neuroendocrine neoplasms, uveal melanoma, hepatocellular carcinoma, and colorectal cancer.

Various combinations of nivolumab, ipilimumab, durvalumab, tremelimumab, relatlimab, pembrolizumab, tiragolumab, and atezolizumab are presented as dual immunotherapies.

We hope these summaries provide you with an update on the groundbreaking research that has been reported over the past year.

Pivotal Data from Phase 3 Trials

5-Year Follow-Up for First-Line Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma: CheckMate-214

Durable efficacy benefits have been found in long-term follow-up of nivolumab plus ipilimumab in treatment for patients with advanced renal-cell carcinoma.

CheckMate-214 was a phase 3, randomized, controlled trial, conducted between 2014 and 2016 in which 1096 patients with advanced or metastatic renal-cell carcinoma (RCC) with a clear-cell component were treated first-line with either nivolumab (NIVO), an anti–PD-1 immune checkpoint inhibitor, plus ipilimumab (IPI), an anti–cytotoxic T-lymphocyte antigen-4 antibody, followed by maintenance therapy with NIVO, or sunitinib, a tyrosine kinase inhibitor.1 One group of patients was administered NIVO 3 mg/kg intravenously (IV) plus IPI 1 mg/kg IV every 3 weeks for 4 doses; they then received NIVO 3 mg/kg every 2 weeks. The other group was treated with sunitinib 50 mg orally once daily for 4 weeks, then off for 2 weeks.1 Both regimens were continued until disease progression or unacceptable toxicity occurred.

The original CheckMate-214 study demonstrated the overall survival (OS) benefit of NIVO plus IPI over sunitinib for the first-line treatment of intermediate- or poor-risk advanced clear-cell RCC.1 The 12-month OS of intermediate- and poor-risk patients treated with NIVO plus IPI was 80% (95% confidence interval [CI], 76-84) compared with treatment with sunitinib, which was 72% (95% CI, 67-76).1 Objective response rate (ORR) was 42% (95% CI, 37-47) for NIVO plus IPI and 27% (95% CI, 22-31) for sunitinib. Median progression-free survival (PFS) for NIVO plus IPI was 11.6 months (95% CI, 8.7-15.5); for sunitinib, it was 8.4 months (95% CI, 7.0-10.8).1

In the intention-to-treat patients, the 12-month OS was 83% (95% CI, 80-86) and 77% (95% CI, 74-81) for NIVO plus IPI and sunitinib, respectively. ORR was 39% (95% CI, 35-43) for NIVO plus IPI and 32% (95% CI, 28-36) for sunitinib. Median PFS was 12.4 months for NIVO plus IPI and 12.3 months for sunitinib, which was not a significant difference (P = .85).1

In a 5-year follow-up study, investigators examined both conditional survival, which is used to predict the sustained benefit of treatment (the probability of a patient staying alive, progression-free, or in response for 2 years after annual landmark timepoints) and the actual 5-year follow-up data.2 At the 5-year follow-up, 34 (6%) patients in the NIVO plus IPI cohort and 9 (2%) in the sunitinib cohort had continued their therapy.2

In the intent-to-treat and intermediate- and poor-risk patients, superior OS, PFS, ORR, and complete response (CR) were maintained for NIVO plus IPI compared with sunitinib.2 At 5 years, the OS was 48% for the NIVO plus IPI group compared with 37% for the sunitinib group. In the intermediate/poor risk cohort, the median OS was 47.0 months (95% CI, 35.4-57.4) for NIVO plus IPI compared with 26.6 months (95% CI, 22.1-33.5) for the sunitinib group, with 43% OS versus 31% for the NIVO plus IPI and sunitinib groups, respectively.2

There were more patients with ongoing responses in the NIVO plus IPI group than in the sunitinib group.2 At 5 years, the PFS was 30% for the NIVO plus IPI group compared with 14% for the sunitinib group. In the intermediate/poor risk cohort, the median PFS was 11.6 months (95% CI, 8.4-16.54) for NIVO plus IPI versus 8.3 months (95% CI, 7.0-10.45) for the sunitinib group, with 31% PFS compared with 11% for the NIVO plus IPI and sunitinib groups, respectively.2

The incidence of treatment-related adverse events (TRAEs) remained consistent with prior reports; the incidence of grade 3/4 TRAEs continued to be lower with NIVO plus IPI (48%) than with sunitinib (64%).2 In addition, health-related quality of life was better with NIVO plus IPI than with sunitinib, which was also true in the original study.1,2

The researchers concluded that there are durable clinical benefits with first-line treatment for advanced RCC with NIVO plus IPI compared with sunitinib, and that most patients who are alive or in partial response or CR at 3 years will also be alive or in partial response or CR at 5 years with this treatment.2

References

  1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277-1290.
  2. Motzer RJ, Tannir NM, McDermott DF, et al. Conditional survival and 5-year follow-up in CheckMate 214: first-line nivolumab plus ipilimumab versus sunitinib in advanced renal cell carcinoma. Presented at: 2021 ESMO Virtual Congress; September 16-21, 2021. Abstract 661P.

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Four-Year Follow-Up Data for First-Line Nivolumab Combined with Ipilimumab in NSCLC: CheckMate-227

After more than 4 years of follow-up, patients with advanced NSCLC treated with nivolumab plus ipilimumab maintained overall survival rates.

In the phase 3 CheckMate-227 study (Part 1a) of nivolumab (NIVO; an anti–PD-1 antibody) plus ipilimumab (IPI; an anti-cytotoxic T-lymphocyte antigen-4 antibody),1 adults (N = 1739)1 with treatment-naïve stage IV/recurrent non–small-cell lung cancer (NSCLC), who had no known EGFR/ALK alterations and European Cooperative Oncology Group performance status ≤1,2 received either NIVO (3 mg/kg every 2 weeks) plus IPI (1 mg/kg every 6 weeks) or chemotherapy (Part 1a).1,2

The primary measure of efficacy was overall survival (OS) with NIVO plus IPI versus chemotherapy in patients with PD-L1 ≥1%.2 Safety outcomes were management and timing of immune-mediated adverse events.1

At the primary analysis, with a median follow-up of 29.3 months, the median OS was 17.1 months (95% confidence interval [CI], 15.0-20.1) for patients with PD-L1 ≥1% treated with NIVO plus IPI and 14.9% (95% CI, 12.7-16.7) for those treated with chemotherapy alone (hazard ratio [HR], 0.79; 95% CI, 0.67-0.94; P = .0066).3

Based on CheckMate-227, NIVO plus IPI was approved in the United States for adults with metastatic NSCLC who express PD-L1 ≥1% with no EGFR or ALK mutations for first-line treatment.1

At the American Society of Clinical Oncology 2021 Annual Meeting, researchers presented extended 4-year follow-up data for the CheckMate-227 trial. With a median follow-up of 54.8 months, the OS for patients with PD-L1 ≥1% was 29% for NIVO plus IPI compared with 18% for chemotherapy (HR, 0.76; 95% CI, 0.65-0.90).1 For the group of patients with PD-L1 ≥50%, at 4 years, the OS rate was 37% for NIVO plus IPI compared with 20% for chemotherapy.1

At 2 years, the progression-free survival (PFS) rate for patients with PD-L1 ≥1% was 22% and 7% for the NIVO plus IPI and chemotherapy-alone groups, respectively. In this study, the PFS rate at 4 years was 14% for patients who received NIVO plus IPI, compared with 4% for those who received chemotherapy alone.1 For the PD-L1 ≥50% group, the 4-year PFS rates were 20% and 1% for the NIVO plus IPI and chemotherapy-alone groups, respectively.1

At 2 years, for patients with PD-L1 ≥1%, the mean duration of response (DOR) was 50% for the patients treated with NIVO plus IPI compared with 13% for patients treated with chemotherapy. After 4 years, the DOR was 34% for NIVO plus IPI and 7% for chemotherapy.1 The histology of the cancers was divided into squamous and nonsquamous; there was no difference in outcomes between these 2 groups2; the PFS and DOR for both groups at 4 years were improved.1

For the PD-L1 ≥50% group, at the 4-year follow-up, 40% of the NIVO plus IPI group remained in response and 3% of the chemotherapy group remained in response.1

Analysis of safety revealed that treatment-related adverse events (TRAEs) that caused patients to discontinue treatment occurred in 18% of patients treated with NIVO plus IPI and 9% of those treated with chemotherapy.1 Safety data also showed that the most common TRAE that was immune-mediated with NIVO plus IPI was rash (19%).1 Other immune-mediated adverse events were transaminitis, adrenal insufficiency, pneumonitis, and diarrhea.1 These occurred ≤6 months after treatment was started and resolved ≤3 months after; they were generally treated with systemic corticosteroids.1 The most common TRAE that led to patients discontinuing treatment with NIVO plus IPI was pneumonitis (3.6%).1 Despite discontinuing NIVO plus IPI, patients with TRAEs still had long-term OS (44%).1 There were no new treatment-associated deaths reported at the 4-year follow-up.1

The investigators found that after 4 years of follow-up, patients with advanced NSCLC maintained long-term OS and better PFS when treated with NIVO plus IPI than those treated with chemotherapy alone, irrespective of histology or PD-L1 expression.1,2

References

  1. Paz-Ares LG, Ramalingam SS, Ciuleanu TE, et al. First-line nivolumab plus ipilimumab in advanced non-small cell lung cancer: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial. J Thorac Oncol. Published online October 11, 2021. 2021;S1556-0864(21)03207-X.
  2. Paz-Ares LG, Ciuleanu TE, Lee JS, et al. Nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for advanced non-small cell lung cancer (NSCLC): 4-year update from CheckMate 227. J Clin Oncol. 2021;39(suppl_15):9016-9016.
  3. Hellman MD, Paz-Ares L, Bernabe Caro R. Nivolumab plus ipilimumab in advanced non–small-cell lung cancer. N Engl J Med. 2019;381:2020-2031.

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First-Line Nivolumab plus Ipilimumab in Unresectable Malignant Pleural Mesothelioma: 3-Year Update from CheckMate-743

The phase 3 CheckMate-743 trial demonstrated survival improvement over 3 years with first-line nivolumab plus ipilimumab for patients with unresectable malignant pleural mesothelioma.

The prognosis has been generally poor for patients with malignant pleural mesothelioma (MPM), as it is an aggressive disease and usually unresectable at the time of diagnosis.1 Chemotherapy had been the only available treatment, but long-term survival was poor with that treatment.1 When bevacizumab was added to the regimen, survival improved, but this option has not been widely used.1 Nivolumab (NIVO), an anti–PD-L1 antibody, plus ipilimumab (IPI), an anti-cytotoxic T-lymphocyte-4 antibody, have been shown to produce durable overall survival (OS) for treatment of melanoma, renal-cell carcinoma, and non–small-cell lung cancer.1 Therefore, the investigators hypothesized that NIVO plus IPI when added to chemotherapy would improve the efficacy and safety of treatment for unresectable MPM.1

Patients (N = 605) in the CheckMate-743 study were randomized to receive NIVO 3 mg/kg intravenously (IV) every 2 weeks plus IPI IV 1 mg/kg every 6 weeks or chemotherapy (cisplatin or carboplatin plus pemetrexed).1 The primary end point was OS. Treatment was continued until unacceptable toxicity, disease progression, or 2 years of immunotherapy.1

The median OS was 18.1 months (95% confidence interval [CI], 16.8-21.4) in the NIVO plus IPI group, compared with 14.1 months (95% CI, 12.4-16.2) in the chemotherapy group.1,2 The 1-year OS was 68% (95% CI, 62.3-72.8) and 58% (95% CI, 51.7-63.2) for NIVO plus IPI and chemotherapy, respectively. At 2 years, OS was 41% (95% CI, 35.1-46.5) and 27% (95% CI, 21.9-32.4) for NIVO plus IPI and chemotherapy, respectively.1

In this 3-year update, the OS in all randomized patients was 23.2% (95% CI, 18.4-28.2) for the NIVO plus IPI group compared with 15.4% (95% CI, 11.5-19.9) for the chemotherapy group.2,3 The OS was also evaluated by histology; the 3-year OS in patients with epithelioid histology was 24% in the NIVO plus IPI group compared with 15% in the chemotherapy group; for the non-epithelioid histology, the OS was 22% compared with 4%, respectively.2

The progression-free survival at 3 years was 14% for the NIVO plus IPI group compared with 1% for the chemotherapy group.2 The percentage of patients in response, measured by overall response rate/duration of response, was 28% for the NIVO plus IPI group compared with 0% for the chemotherapy group at the 3-year follow-up.

The exploratory analysis in this study evaluated OS by several other factors, including the 4-gene inflammatory signature score, which correlated with improved survival benefit with NIVO plus IPI. OS was also better with NIVO plus IPI than chemotherapy across all lung immune prognostic index scores. Tumor mutational burden did not correlate with better survival.3

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 30% of the patients treated with NIVO plus IPI and in 32% of those treated with chemotherapy. Serious TRAEs occurred in 21% of the NIVO plus IPI group and in 8% of the chemotherapy group.1 Grade 3/4 serious TRAEs occurred in 15% of patients in the NIVO plus IPI group and in 6% of patients in the chemotherapy group.1 Deaths due to disease progression occurred in 61% of the NIVO plus IPI group and in 70% of the chemotherapy group.1

In the NIVO plus IPI group, discontinuation of therapy occurred due to disease progression (61%) and drug toxicity (20%).1 In the patients treated with chemotherapy, disease progression led to discontinuation of therapy in 16% of patients and drug toxicity led to 8% stopping therapy.1

The 3-year update on TRAEs demonstrated that safety was consistent with the past report, with no change in the overall rate of TRAEs.2 At 3 years, the efficacy in patients who discontinued NIVO plus IPI due to TRAEs was 37% as measured by OS. Of the responders who discontinued treatment secondary to TRAEs, 34% maintained their responses for ≥3 years after the discontinuation.2

In conclusion, first-line NIVO plus IPI as treatment for unresectable MPM has been shown to produce sustained survival improvement over 3 years. These data confirm NIVO plus IPI as the standard of care for treatment of unresectable MPM.2,3

References

  1. Baas P, Scherpereel A, Nowak AK, et al. First-line nivolumab plus ipilimumab in unresectable malignant pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. [Published correction appears in Lancet. 2021;397:670]. Lancet. 2021;397:375-386.
  2. Peters S, Scherpereel A, Cornelissen R, et al. LBA65-First-line nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) in patients (pts) with unresectable malignant pleural mesothelioma (MPM): 3-year update from CheckMate 743. Presented at: ESMO Congress 2021; September 16-21, 2021.
  3. Peters S, Scherpereel A, Cornelissen R, et al. LBA65-First-line nivolumab (NIVO) plus ipilimumab (IPI) vs chemotherapy (chemo) in patients (pts) with unresectable malignant pleural mesothelioma (MPM): 3-year update from CheckMate 743. Ann Oncol. 2021;32(suppl_5):S1283-S1346.

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First-Line Nivolumab plus Ipilimumab Combined with 2 Cycles of Chemotherapy in Patients with Stage IV/Recurrent NSCLC: 2-Year Update of CheckMate-9LA

Nivolumab plus ipilimumab combined with 2 cycles of chemotherapy for the treatment of advanced NSCLC demonstrates durable efficacy compared with 4 cycles of chemotherapy alone in a 2-year follow-up study.

Long-term outcomes for patients with advanced non–small-cell lung cancer (NSCLC) are often poor, despite the advent of new therapies or combinations of therapies. Anti–PD-L1 drugs, such as pembrolizumab, nivolumab (NIVO; plus ipilimumab [IPI]), and atezolizumab have improved outcomes.1 Therefore, the investigators of CheckMate-9LA examined whether dual immunotherapy combined with a limited course of 2 cycles of chemotherapy could control disease early in the disease process and provide durable survival benefit while lessening the adverse events associated with chemotherapy alone.1,2

The CheckMate-9LA study was a randomized, international, phase 3 trial with patients (N = 719) who had histologically confirmed squamous or nonsquamous stage IV or recurrent NSCLC and had not received prior systemic anticancer treatment for advanced/metastatic disease.1 Patients received either chemotherapy alone (every 3 weeks for 4 cycles) or NIVO 360 mg intravenously (IV) every 3 weeks plus IPI 1 mg/kg IV every 6 weeks plus platinum doublet chemotherapy (either carboplatin plus paclitaxel for squamous histology or carboplatin plus pemetrexed or cisplatin plus pemetrexed for nonsquamous) every 3 weeks limited to 2 cycles.1

The primary end point was overall survival (OS), and the secondary end points were progression-free survival (PFS) and objective response rate (ORR). Therapy continued until disease progression, unacceptable toxicity, or 2 years (end of protocol).1

In the initial prespecified interim analysis with a minimum follow-up of 8.1 months, the primary end points were met, showing statistically significant improvements in addition to a manageable safety profile.2 The median OS was 14.1 months (95% confidence interval [CI], 13.2-16.2) in the NIVO plus IPI plus limited chemotherapy group compared with 10.7 months (95% CI, 9.5-12.4) in the chemotherapy group (hazard ratio [HR], 0.69; 96.71% CI, 0.55-0.87; P = .00065). The median PFS was 6.8 months (95% CI, 5.6-7.7) in the NIVO plus IPI group compared with 5.0 months (95% CI, 4.3-5.6) in the chemotherapy group (HR, 0.70; 97.48% CI, 0.57-0.86; P = .00012).1

ORR was reported in 37.7% (95% CI, 32.7-42.9) of patients in the NIVO plus IPI plus limited chemotherapy group compared with 25.1% (95% CI, 20.7-30.0) of patients in the chemotherapy-alone group (P = .00030).1

The 2-year follow-up study investigated the continued efficacy with the regimen of NIVO plus IPI plus chemotherapy and the PFS after the next line of therapy (PFS2), to determine the impact of that therapy. In addition, an analysis of treatment-related adverse events (TRAEs) by treatment cycle and outcomes of patients who discontinued treatment secondary to TRAEs was performed.2

With a minimum follow-up of 24.4 months, the OS at 2 years was 38% for the NIVO plus IPI plus chemotherapy group compared with 26% for the chemotherapy-alone group (HR, 0.72; 95% CI, 0.61-0.86), including across key subgroups (by PD-L1 expression levels and histology).2 The PFS at 2 years was 20% for the NIVO plus IPI plus limited chemotherapy group compared with 8% for the chemotherapy-alone group.2 The ORR was 38% for the NIVO plus IPI plus limited chemotherapy group versus 25.4% in the chemotherapy-alone group.2

The median PFS2 was 13.9 months in the NIVO plus IPI plus limited chemotherapy group and 8.7 months in the chemotherapy-alone group (in all randomized patients) (HR, 0.66; 95% CI, 0.56-0.78).2 The 1-year PFS2 rate was 55% in the NIVO plus IPI plus limited chemotherapy group and 37% months in the chemotherapy-alone group; the 2-year PFS2 rate was 35% in the NIVO plus IPI plus limited chemotherapy group and 21% in the chemotherapy-alone group. When evaluated by subgroups (PD-L1 expression and histology), PFS2 was also better in the NIVO plus IPI plus limited chemotherapy group compared with the chemotherapy-alone group.2

At 2 years, safety data were consistent with the original 1-year data. TRAEs of any grade occurred in 92% of the NIVO plus IPI plus chemotherapy group and in 88% of the chemotherapy-alone group. Grade 3/4 TRAEs occurred in 48% of the NIVO plus IPI plus chemotherapy group compared with 38% in the chemotherapy-alone group.2 The onset of grade 1/2 TRAEs was similar between the 2 treatment groups in respective cycles. The onset of most of the grade 3/4 TRAEs occurred in the first 2 cycles in the NIVO plus IPI plus chemotherapy group (during the course of platinum-doublet chemotherapy) compared with cycles 7 to 8 in the chemotherapy-alone group.2

In the post-hoc analysis of the patients who discontinued therapy (NIVO plus IPI plus limited chemotherapy) secondary to TRAEs, the median duration of treatment was 4.4 months. The median OS was 27.5 months with a 2-year OS rate of 54%. Median PFS was 5.1 months; 1-year PFS rate was 44%; ORR was 51% (responses maintained for median of 14.5 months [95% CI, 2.86-not reached] after treatment discontinuation).2 These patients remained treatment-free for a median of 11.9 months (95% CI, 3.8-21), with a 48% chance of being treatment-free at 1 year.2

The researchers concluded that NIVO plus IPI in combination with 2 cycles of chemotherapy continued to show durable efficacy compared with 4 cycles of chemotherapy alone for first-line treatment of advanced NSCLC. This was found to be true across histologies and regardless of PD-L1 expression.2

References

  1. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. [Published correction appears in Lancet Oncol. 2021;22:e92.] Lancet Oncol. 2021;22:198-211.
  2. Reck M, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. ESMO Open. 2021;6:100273.

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Nivolumab plus Ipilimumab as First-Line Therapy in Patients with Advanced Melanoma: 6.5-Year Update from CheckMate-067

In a 6.5-year update of CheckMate-067, durable improvements in overall survival, progression-free survival, and objective response rate were observed with nivolumab plus ipilimumab over nivolumab alone as first-line therapy in patients with advanced melanoma, with no new safety signals.

In the phase 3 CheckMate-067 trial, a durable and sustained clinical benefit was achieved with nivolumab (NIVO) plus ipilimumab (IPI) and NIVO alone compared with IPI at the 5-year mark of follow-up. Overall survival (OS) rates for NIVO plus IPI, NIVO alone, and IPI alone were 52%, 44%, and 26%, respectively. Progression-free survival (PFS) rates for NIVO plus IPI, NIVO alone, and IPI alone were 36%, 29%, and 8%, respectively.1 At the American Society of Clinical Oncology 2021 Annual Meeting, the investigators reported 6.5-year efficacy and safety outcomes.2

Eligible patients with previously untreated unresectable stage III or IV melanoma were randomly assigned in a 1:1:1 ratio and stratified by PD-L1 status, BRAF mutation status, and metastasis stage. Patients received NIVO 1 mg/kg plus IPI 3 mg/kg every 3 weeks for 4 doses followed by NIVO 3 mg/kg every 2 weeks (n = 314), NIVO 3 mg/kg every 2 weeks plus placebo (n = 316), or IPI 3 mg/kg every 3 weeks for 4 doses plus placebo (n = 315) until progression or unacceptable toxicity. Co-primary end points were PFS and OS with NIVO plus IPI or NIVO alone compared with IPI alone. Secondary end points included objective response rate (ORR), descriptive efficacy assessments of NIVO plus IPI compared with NIVO alone, and safety.

With a minimum follow-up of 6.5 years, median OS was 72.1 months with NIVO plus IPI, 36.9 months with NIVO alone, and 19.9 months with IPI alone. The median time from randomization to subsequent systemic therapy was not reached (NR; 95% confidence interval [CI], 59.6-NR) with NIVO plus IPI, 25.2 months (95% CI, 16.0-43.2) with NIVO alone, and 8.0 months (95% CI, 6.5-8.7) with IPI alone. For NIVO plus IPI, NIVO alone, and IPI alone, 36%, 49%, and 66% of patients, respectively, received any subsequent systemic therapy.

The median treatment-free interval (excluding patients who discontinued follow-up before starting subsequent systemic therapy) was 27.6 months (0-83.0 months) for NIVO plus IPI, 2.3 months (0.2-81.6 months) for NIVO alone, and 1.9 months (0.1-81.9 months) for IPI alone. Of the patients who were still alive and in follow-up, 81% of the NIVO plus IPI group, 74% of the NIVO-alone group, and 43% of the IPI-alone group were off treatment and never received subsequent systemic therapy.

Grade 3/4 treatment-related adverse events were reported in all groups: 59% of the NIVO plus IPI group, 24% of the NIVO group, and 28% of the IPI group. Since the primary analysis, no new safety signals were observed, and no additional treatment-related deaths occurred.

This 6.5-year analysis is the longest follow-up from a phase 3 melanoma trial investigating checkpoint inhibitor combination therapy. The results show durable improved outcomes with NIVO plus IPI and NIVO alone compared with IPI alone in patients with advanced melanoma, with improvement in OS, PFS, and ORR with NIVO plus IPI compared with treatment with NIVO alone.

References

  1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381:1535-1546.
  2. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. Presented at: American Society of Clinical Oncology Annual Meeting 2021; June 4-8, 2021. Abstract 9506.

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Nivolumab plus Ipilimumab versus the EXTREME Regimen for Treatment of Recurrent/Metastatic Squamous-Cell Carcinoma of the Head and Neck: CheckMate-651

Nivolumab plus ipilimumab demonstrated clinical benefit in the treatment of head and neck recurrent/metastatic squamous-cell carcinoma.

Recurrent/metastatic squamous-cell carcinoma of the head and neck (R/M SCCHN) has a history of poor prognosis, significant morbidity, and decreased quality of life. The EXTREME regimen (cetuximab, cisplatin/carboplatin, and fluorouracil [5-FU]) resulted in improved overall survival (OS), but the responses are not durable. Treatment with the combination of nivolumab (NIVO) plus ipilimumab (IPI) has resulted in improved OS and durable responses in several cancers, including non–small-cell lung cancer, metastatic melanoma, renal-cell carcinoma, and mesothelioma. Based on this history of success with dual immunotherapy, the combination of NIVO plus IPI was evaluated versus the EXTREME regimen for first-line treatment of platinum-eligible R/M SCCHN in the phase 3 CheckMate-651 clinical trial.1

Eligible patients (N = 947) with R/M SCCHN, including the oral cavity, oropharynx, hypopharynx, or larynx, who had no prior treatment for recurrent/metastatic disease, and had a European Cooperative Oncology Group performance status of 0-1 were included in the study. Patients were randomized into 2 groups: one group received NIVO 3 mg/kg every 2 weeks plus IPI 1 mg/kg every 6 weeks; the other cohort was administered the EXTREME regimen (cetuximab plus cisplatin/carboplatin plus 5-FU every 3 weeks for 6 cycles, followed by cetuximab alone every week). Therapy was continued until disease progression, unacceptable toxicity, or 2 years of NIVO plus IPI.1

The dual primary end points were OS in the all-randomized (intent-to-treat) population and OS in patients whose tumors expressed PD-L1 combined positive score (CPS) ≥20. Secondary end points included OS in patients with PD-L1–expressing tumors at different cutoff values, progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR) in all patients and in those with PD-L1–expressing tumors. Exploratory end points were PFS, ORR/DOR in patients with PD-L1 CPS ≥1, patient-reported outcomes, and safety.1

The median OS for the NIVO plus IPI cohort was 13.9 months (95% confidence interval [CI], 12.1-15.8) compared with 13.5 months for the EXTREME cohort (95% CI, 12.6-15.2) for all patients.1 In all patients, PFS for the NIVO plus IPI group was 3.3 months (95% CI, 2.8-4.2) and 6.7 months (95% CI, 5.8-7.0) for the EXTREME group. ORRs were 24% and 37% for NIVO plus IPI and EXTREME, respectively; complete response (CR) was 7% and 5% for the 2 groups, respectively; the median DOR was 16.6 months for NIVO plus IPI and 5.9 months for EXTREME.1

In patients with PD-L1 CPS ≥20, the median OS was 17.6 months (95% CI, 13.8-22) for the NIVO plus IPI cohort and 14.6 months (95% CI, 12.3-16) for the EXTREME cohort.1 Efficacy in the PD-L1 CPS ≥20 patient group had similar comparative results. The median PFS was 5.4 months (95% CI, 3.1-6.9) for the NIVO plus IPI group and 7.0 months (95% CI, 5.6-8.7) for the EXTREME group. ORR was 34% for the NIVO plus IPI group and 36% for the EXTREME patients. CR was observed in 12% of the NIVO plus IPI cohort and 7% for the EXTREME cohort. The median DOR was 32.6 months (95% CI, 12.1-not reached) and 7.0 months (95% CI, 5.6-10.1) in the NIVO plus IPI and EXTREME groups, respectively.1

In the PD-L1 CPS ≥1 population, median OS was 15.7 months (95% CI, 13.7-18.8) and 13.2 months (95% CI, 11.1-14.6) for the NIVO plus IPI group and the EXTREME group, respectively. PFS was 4.2 months (95% CI, 2.9-5.4) for the NIVO plus IPI group and 6.1 months (95% CI, 5.6-7.0) for the EXTREME cohort. The NIVO plus IPI group demonstrated a 28% ORR compared with 36% ORR in the EXTREME group. DOR was 18.3 months (95% CI, 10.9-32.6) and 6.0 months (95% CI, 5.6-7.6) for the NIVO plus IPI group and the EXTREME group, respectively.1

Patient-reported outcomes included time to symptom deterioration (TTSD) and overall self-rated health status. The median TTSD for the patients treated with NIVO plus IPI was 16.7 months compared with 7.6 months in the EXTREME patient cohort. Measured by the EuroQol five-dimension visual analog scale, the health status of the patients on NIVO plus IPI was better (mean change from baseline of + 20) than that reported by the patients on the EXTREME regimen (mean change from baseline of –8 to +2).1

In the NIVO plus IPI group, any-grade treatment-related adverse events (TRAEs) occurred in 72% of patients and grade 3/4 TRAEs occurred in 28% of patients compared with 98% any-grade TRAEs and 71% grade 3/4 TRAEs in the EXTREME group.1 The immune-mediated adverse events >1% in the NIVO plus IPI group were hypothyroidism/thyroiditis, rash, hyperthyroidism, diarrhea, and hepatitis. Treatment-related deaths in the EXTREME group were caused by sepsis (5 patients), pneumonia (2 patients), and acute respiratory syndrome (1 patient).1

Although NIVO plus IPI showed a clear, positive trend toward OS in patients whose tumors express PD-L1 with a CPS ≥20, the study did not meet its primary end points. The safety profile of NIVO plus IPI in this trial was consistent with previously reported studies in solid tumors.1

Reference

  1. Argiris A, Harrington K, Tahara M, et al. LBA36 - Nivolumab + ipilimumab vs EXTREME regimen as first-line treatment for recurrent/metastatic squamous cell carcinoma of the head and neck: final results of CheckMate 651. Presented at: ESMO Congress 2021; September 16-21, 2021. Abstract LBA36.

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Durvalumab Alone or in Combination with Tremelimumab and Chemotherapy versus Chemotherapy Alone as First-Line Treatment for Metastatic NSCLC: POSEIDON Study

Durvalumab plus standard-of-care chemotherapy and durvalumab with tremelimumab plus standard-of-care chemotherapy were both associated with better progression-free survival compared with standard-of-care chemotherapy alone in the treatment of metastatic NSCLC.

The treatment for advanced non–small-cell lung cancer (NSCLC) has improved greatly over the past years. PD-1/PD-L1 inhibitors as monotherapy and combined with chemotherapy have both been instrumental in this; however, there is still a need for better therapy.

The POSEIDON trial is an international, multicenter phase 3 study of first-line treatment of patients with NSCLC whose tumors do not have EGFR mutations or ALK fusions (N = 1013). Patients in this trial were treated with durvalumab (DURV) plus tremelimumab (TREM) plus standard-of-care (SOC) chemotherapy, DURV monotherapy plus SOC chemotherapy, or SOC chemotherapy alone.1-3 Patients were randomized 1:1:1 to receive either DURV 1500 mg every 4 weeks plus chemotherapy every 3 weeks for 4 cycles and then maintenance DURV 1500 mg every 4 weeks plus pemetrexed, or DURV 1500 mg plus TREM 75 mg plus chemotherapy every 3 weeks for 4 cycles and then maintenance DURV 1500 mg every 4 weeks plus TREM 75 mg at week 16 and pemetrexed, or platinum-based chemotherapy every 3 weeks for up to 6 cycles, then maintenance pemetrexed. SOC chemotherapy consisted of abraxane plus carboplatin for NSCLC with squamous and nonsquamous histologies, gemcitabine plus cisplatin or carboplatin for squamous patients only, and pemetrexed plus cisplatin or carboplatin for nonsquamous patients only. The therapies were each continued until disease progression.1-3 The patients were stratified by PD-L1 expression, disease stage, and histology.2

The primary end points were progression-free survival (PFS) and overall survival (OS) for DURV plus chemotherapy compared with chemotherapy alone. The secondary end points were PFS and OS for DURV plus TREM plus chemotherapy compared with chemotherapy alone.1-3 The objective response rate (ORR), duration of response (DOR), best objective response, and 1-year PFS were additional outcome measures investigated, in addition to safety, tolerability, and health-related quality of life.2,3

The median PFS for DURV plus chemotherapy was 5.5 months (95% confidence interval [CI], 4.7-6.5) compared with 4.8 months for chemotherapy alone (95% CI, 4.6-5.8) and 6.2 months for DURV plus TREM plus chemotherapy (95% CI, 5.0-6.5).

The 1-year PFS rates were 24.4% (95% CI, 19.7-29.5) for DURV plus chemotherapy compared with 13.1% (95% CI, 9.3-17.6) for chemotherapy alone, and 26.6% (95% CI, 21.7-31.7) for DURV plus TREM plus chemotherapy.2,3

The median OS was 13.3 months (95% CI, 11.4-11.7) for DURV plus chemotherapy and 11.7 months (95% CI, 10.5-13.1) with chemotherapy alone (hazard ratio [HR], 0.86; 95% CI, 0.72-1.02; P = .07581 [not statistically significant]).3 However, for DURV plus TREM plus chemotherapy, median OS was 14.0 months (95% CI, 11.7-16.1) compared with 11.7 months for chemotherapy alone (HR, 0.77; 95% CI, 0.65-0.92; P = .00304).3

The 2-year OS rates were 29.6% (95% CI, 24.8-34.6) for DURV plus chemotherapy, 22.1% (95% CI, 17.8-26.8) for chemotherapy alone, and 32.9% (95% CI, 27.9-37.9) for DURV plus TREM plus chemotherapy.2,3

ORRs were 41.5% for DURV plus chemotherapy, 38.8% for DURV plus TREM plus chemotherapy, and 24.4% for chemotherapy alone.3 The DOR was 7.0 months (95% CI, 5.7-9.9) for DURV plus chemotherapy, 9.5 months (95% CI, 7.2-not estimable) for DURV plus TREM plus chemotherapy, and 5.1 months (95% CI, 4.4-6.0) for chemotherapy alone.3 This response was maintained at 12 months in 38.9% of the DURV plus chemotherapy group, 49.7% of the DURV plus TREM plus chemotherapy group, and 21.4% of the chemotherapy-alone group.3

All-grade, all-cause adverse events (AEs) occurred in 96.1% of the DURV plus chemotherapy group (54.8% grade 3/4), 97.3% of the DURV plus TREM plus chemotherapy group (53.3% grade 3/4), and 96.1% of the chemotherapy-alone group (51.7% grade 3/4). Serious AEs occurred in 40.1%, 44.2%, and 35.1% of the DURV plus chemotherapy group, DURV plus TREM plus chemotherapy group, and chemotherapy-alone group, respectively.3

Treatment-related AEs (TRAEs) occurred in 88.6% of patients treated with DURV plus chemotherapy, 92.7% of patients on DURV plus TREM plus chemotherapy, and 89.5% of patients on chemotherapy alone.3 Of the TRAEs, 44.6%, 51.8%, and 44.4% were grade 3/4 in the DURV plus chemotherapy, DURV plus TREM plus chemotherapy, and chemotherapy-alone groups, respectively.2,3

Serious TRAEs occurred in 19.5%, 27.6%, and 17.7% of patients administered DURV plus chemotherapy, DURV plus TREM plus chemotherapy, and chemotherapy alone, respectively.3 Treatment was stopped because of TRAEs in 14.1% of patients on DURV plus chemotherapy, 15.5% on DURV plus TREM plus chemotherapy, and 9.9% on chemotherapy alone,2 with death reported from TRAEs in 2.1%, 3.3%, and 2.4% of patients in those groups, respectively.3

The researchers concluded that both DURV plus chemotherapy with TREM and without TREM showed improvement in PFS when compared with chemotherapy alone for treatment of metastatic NSCLC.2,3 In addition, DURV with TREM plus chemotherapy led to a statistically significant increase in OS compared with chemotherapy alone.2 They also proposed that DURV plus TREM plus chemotherapy may be a new first-line therapy for NSCLC.2

References

  1. ClinicalTrials.gov. A phase III, randomized, multi-center, open-label, comparative global study to determine the efficacy of durvalumab or durvalumab and tremelimumab in combination with platinum-based chemotherapy for first-line treatment in patients with metastatic non small-cell lung cancer (NSCLC) (POSEIDON). ClinicalTrials.gov identifier NCT03164616. Updated October 29, 2021. https://clinicaltrials.gov/ct2/show/NCT03164616. Accessed November 6, 2021.
  2. Johnson ML, Cho BC, Luft A, et al. Durvalumab ± tremelimumab + chemotherapy as first-line treatment for mNSCLC: results from the phase 3 POSEIDON study. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer Virtual; September 8-14, 2021. Abstract PL02.01.
  3. Mauro G. Durvalumab combo, with or without tremelimumab, improves PFS in NSCLC. Target Oncol. 2021;21:74.

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Relatlimab plus Nivolumab versus Nivolumab Alone in First-Line Advanced Melanoma: Primary Results from RELATIVITY-047

First-line treatment with relatlimab plus nivolumab demonstrated a statistically significant progression-free survival benefit compared with nivolumab monotherapy in patients with advanced melanoma.

Many tumor types, including melanoma, have an upregulated immune checkpoint pathway involving lymphocyte-activation gene-3 (LAG-3) that inhibits T-cell activity. Relatlimab (RELA) is a human IgG4 anti–LAG-3 antibody that can restore the effector function of T-cells. RELA plus nivolumab (NIVO), an anti–PD-1 drug, may be able to augment antitumor immune responses by modulating synergistic immune checkpoint pathways. RELATIVITY-047 was a global, randomized, double-blind, phase 2/3 study evaluating a novel immune checkpoint inhibitor combination of RELA plus NIVO as a fixed-dose combination first-line treatment in advanced melanoma.1

Patients with advanced melanoma (N = 714) who had not been previously treated were randomized to RELA 160 mg plus NIVO 480 mg intravenously (IV) every 4 weeks (n = 355) or NIVO alone 480 mg IV every 4 weeks (n = 359). The patients were divided into cohorts by LAG-3 expression, PD-1 expression, BRAF mutation status, and stage. The primary end point was progression-free survival (PFS). Secondary end points were overall survival and objective response rate. Additional objectives were PFS in subgroups: LAG-3 (≥1% compared with <1%), BRAF (mutation positive compared with mutation wild-type), and American Joint Committee on Cancer M stage.1

The median PFS in the group receiving RELA plus NIVO was 10.1 months (95% confidence interval [CI], 6.4-15.7) and 4.6 months (95% CI, 3.4-5.6) in the NIVO monotherapy group (hazard ratio, 0.75; 95% CI, 0.62-0.92; P = .0055).1,2 The PFS at 12 months was 47.7% (95% CI, 41.8-53.2) for the RELA plus NIVO cohort and 36.0% (95% CI, 30.5-41.6) for NIVO alone.1,2 This benefit was also shown in the PFS rates in the subgroups.1

In the combination RELA plus NIVO group, the incidence of grade 3/4 treatment-related adverse events (TRAEs) was 18.9% compared with 9.7% in the NIVO monotherapy group. TRAEs of any grade led to discontinuation of therapy in 14.6% of the patients in the RELA plus NIVO group and 6.7% of those in the NIVO group. In addition, there were 3 treatment-related deaths with RELA plus NIVO and 2 with NIVO alone.1

In conclusion, first-line therapy of advanced melanoma with combination RELA plus NIVO demonstrated a benefit in PFS that was statistically significant compared with that of NIVO alone. This combination therapy was well-tolerated with manageable adverse events. This was the first phase 3 study of a novel fixed-dose combination to demonstrate a clinically meaningful benefit by dual inhibition of the LAG-3 and PD-1 pathways.1

References

  1. Lipson EJ, Tawbi AHH, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). J Clin Oncol. 2021;39(suppl_15):9503-9503.
  2. 2. Hodi FS, Tawbi HA, Lipson EJ, et al. Relatlimab (RELA) + nivolumab (NIVO) vs. NIVO in previously untreated metastatic or unresectable melanoma: additional efficacy in RELATIVITY-047. Presented at: 2021 ESMO Congress; September 16-21, 2021. Abstract 10360.

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Early Clinical Development: Phase 1-2 Trials

COAST: An Open-Label, Randomized, Phase 2 Platform Study of Durvalumab Alone or in Combination with Novel Agents in Patients with Locally Advanced, Unresectable, Stage III NSCLC

Durvalumab plus either oleclumab or monalizumab improved overall response rate, progression-free survival, and 10-month progression-free survival in locally advanced, unresectable, stage III NSCLC.

Durvalumab plus either oleclumab or monalizumab improved overall response rate, progression-free survival, and 10-month progression-free survival in locally advanced, unresectable, stage III NSCLC.

Previously, the PACIFIC trial showed that durvalumab (DURV) could become the standard-of-care treatment for patients with non–small-cell lung cancer (NSCLC) after treatment with concurrent chemoradiotherapy (cCRT) with no progression.1,2 The investigators of the COAST trial hypothesized that combination therapy with DURV plus another immunologically active monoclonal antibody would improve outcomes even further.

COAST was a phase 2 trial in which DURV alone or combined with either oleclumab (OLE) or monalizumab (MONA) was evaluated as consolidation therapy for locally advanced, unresectable, stage III NSCLC.2,3 OLE is an anti-CD73 antibody and MONA is an anti-NKG2A antibody. The expression of CD73 and NKG2A is induced by radiotherapy, thereby inhibiting antitumor immune responses. Therefore, it was hypothesized that inhibiting CD73 and NKG2A, by OLE and MONA, respectively, would be effective in antitumor activity.2

The patients studied had their tumor stage histologically and cytologically confirmed. They had a European Cooperative Oncology Group performance status score of 0/1 and had not progressed after cCRT. They were randomized to either DURV 1500 mg intravenously (IV) every 4 weeks alone or combined with OLE 3000 mg IV every 2 weeks for 2 cycles and then every 4 weeks, or MONA 750 mg IV every 2 weeks for up to 12 months, and stratified by histology.2,3

The primary end point of the study was overall response rate (ORR).3 Secondary end points were progression-free survival (PFS), safety, duration of response (DOR), disease control rate (DCR), overall survival, pharmacokinetics, and immunogenicity.2

There were 186 patients in this study; 66 were administered DURV alone, 59 received DURV plus OLE, and 61 received DURV plus MONA. Median follow-up was 11.5 months.3 ORR was 17.9% for DURV alone (95% confidence interval [CI], 9.6-29.2), 30.0% for DURV plus OLE (95% CI, 18.8-43.2), and 35.5% for DURV plus MONA (95% CI, 23.7-48.7).2 The median DOR for DURV alone was not reached (95% CI, 2.3 months-not applicable), 12.9 months for DURV plus OLE (95% CI, 6.7-not applicable), and not reached for DURV plus MONA (95% CI, 9.0 months-not applicable). The DCR was 58.2% for DURV alone (95% CI, 45.5-70.2), 81.7% for DURV plus OLE (95% CI, 69.6-90.5), and 77.4% for DURV plus MONA (95% CI, 65-87.1).2 DURV plus OLE and DURV plus MONA significantly improved PFS compared with DURV alone.3 The median PFS for DURV alone was 6.3 months, not reached for DURV plus OLE, and 15.1 months for DURV plus MONA.2

The incidence of all treatment-related adverse events (TRAEs) was 98.5% for DURV, 96.6% for DURV plus OLE, and 100% for DURV plus MONA.2 The incidence of grade ≥3 TRAEs (all cause) was 39.4%, 40.7%, and 27.9% with DURV, DURV plus OLE, and DURV plus MONA, respectively.2,3 Adverse events leading to treatment discontinuation occurred in 16.7%, 15.3%, and 14.8% of patients in DURV, DURV plus OLE, and DURV plus MONA, respectively.2

Pneumonia (5.9%) and decreased lymphocyte count (3.2%) were the most common grade 3/4 TRAEs. They were both more common with DURV and DURV plus OLE than with DURV plus MONA. The combined rates of pneumonitis and radiation pneumonitis of any grade were 21.2% with DURV, 28.8% with DURV plus OLE, and 21.3% with DURV plus MONA, with grade 3 events in 3.0%, 3.4%, and 1.6%, respectively.3

The researchers concluded that the combinations of DURV plus OLE and DURV plus MONA provide clinical benefit in treatment of patients with unresectable stage III NSCLC who have not progressed after cCRT. Both combinations increased ORR and improved PFS when compared with DURV alone. The safety of these combinations was manageable.2

References

  1. Faivre-Finn C, Vicente D, Kurata T, et al. Four-year survival with durvalumab after chemoradiotherapy in stage III NSCLC-an update from the PACIFIC trial. J Thorac Oncol. 2021;16:860-867.
  2. Martinez-Marti A, Majem M, Barlesi F, et al. COAST: an open-label, phase 2, multidrug platform study of durvalumab alone or in combination with novel agents in patients with locally advanced, unresectable, stage III NSCLC. Presented at: ESMO Congress 2021; September 16-21, 2021. Abstract LBA42.
  3. Martinez-Marti A, Majem M, Barlesi F, et al. LBA42 - COAST: an open-label, randomised, phase II platform study of durvalumab alone or in combination with novel agents in patients with locally advanced, unresectable, stage III NSCLC. ESMO Open. 2021;32(suppl_5):S1283-S1346.

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Phase 2 Basket Trial of Ipilimumab plus Nivolumab in Patients with High-Grade Neuroendocrine Neoplasms

Ipilimumab plus nivolumab is beneficial in the treatment of patients with high-grade nonpancreatic neuroendocrine neoplasms.

In the SWOG S1609 Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART) trial, dual checkpoint inhibitor therapy with anti–PD-1 and anti–cytotoxic T-lymphocyte antigen-4 was shown to be successful in treating patients with all grades of nonpancreatic neuroendocrine neoplasms (NENs); the overall response rate (ORR) was 44%.1

A recent prospective study was performed on 19 patients from National Clinical Trial Network institutions between October 2018 and August 2019 with high-grade NENs.1 The patients were treated with ipilimumab (IPI) intravenously (IV) 1 mg/kg every 6 weeks plus nivolumab (NIVO) IV 240 mg every 2 weeks until deterioration of symptoms, disease progression, a delay in treatment past 56 days, or toxicity.1 The dosing was chosen based on the CheckMate-227 trial, for its balance between efficacy and toxicity.1

The primary clinical end point of the study was ORR. Secondary end points were progression-free survival (PFS), overall survival (OS), and toxicity.1

Five of the patients had partial responses (ORR, 26%; 95% confidence interval [CI], 11%-45%; P = .002); 1 patient had stable disease for >6 months; therefore, the clinical benefit rate was 32%.1 The overall 6-month PFS was 32%; the median PFS was 2.0 months with ongoing responses and a median OS of 8.9 months. Of the 5 responders, the duration of response was between 8 and 31 months.1

Adverse events (AEs) were seen in 84% of the patients in the study (fatigue, 36%; rash, 26%); 37% had a grade 3/4 AE (rash, 15%; nausea, lipase elevation, elevation of alkaline phosphatase, 5% each). Of the immune-mediated toxicities, rash was the most common (26%); aspartate aminotransferase was elevated in 21% of patients, and alanine aminotransferase elevation in 15%.1 Rash was the most common immune-related grade 3/4 AE (15%) and elevation of lipase occurred in 10% of patients. No patients needed to permanently stop their treatment secondary to toxicity, and there were no deaths in the study as a result of AEs.1

With this prospective study, the investigators concluded that low-dose IPI plus NIVO benefits patients with high-grade NENs, regardless of the primary site of the tumor.1 In addition, there were no significant safety concerns.1

Reference

  1. Patel SP, Mayerson E, Chae YK, et al. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: high-grade neuroendocrine neoplasm cohort. Cancer. 2021;127:3194-3201.

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Efficacy of Ipilimumab plus Nivolumab for the Treatment of Refractory High-Grade Neuroendocrine Neoplasms

Ipilimumab plus nivolumab could be considered as salvage therapy in patients with refractory, highly aggressive, high-grade neuroendocrine neoplasms.

Dual checkpoint inhibitor therapy with anti–PD-1 and anti–cytotoxic T-lymphocyte–associated protein therapies has been successful in treating patients with high-grade neuroendocrine neoplasms (NENs); the response rates have been between 9% and 44%.1

A retrospective study was performed on 34 patients with high-grade NENs at the Moffitt Cancer Center and Mayo Clinic, who were treated with ipilimumab (IPI) plus nivolumab (NIVO) between September 2017 and July 2020.1 Prior to the treatment with IPI plus NIVO, the patients had received an average of 2 lines of therapy, ≥1 of which was cytotoxic chemotherapy.1 The types of NENs were poorly differentiated neuroendocrine carcinomas in 79.4% of the patients and well-differentiated high-grade neuroendocrine tumors in 20.7%. Pancreas was the most common primary site (29.4%); other primary sites were colon, uterus, anorectum, esophagus, cervix, stomach, and small intestine; some were unknown primary sites.1

The primary end point was objective response rate.1 Five (14.7%) patients showed a best partial response; 9 (26.5%) patients had stable disease; and 17 (50%) had progressive disease, resulting in a disease control rate of 41.2%. Three patients had clinical progression, and therefore did not continue treatment. Median progression-free survival was 1 month (95% confidence interval [CI], 0.45-1.55); median overall survival (OS) from the time of treatment initiation was 5.0 months (95% CI, 3.42-6.59) and median OS from diagnosis was 14.0 months (95% CI, 1.49-26.51). The median duration of treatment was 1 month (range, 0-10 months).1 There were 30 patients who discontinued the treatment for progression (26) or toxicity (4), and 12 (35%) patients who had grade 3 or 4 treatment-related toxicities, including liver transaminitis, elevated blood bilirubin, arthralgia, myalgia, peripheral sensory neuropathy, lower extremity edema, confusion, diarrhea, encephalopathy, acute kidney injury, rhabdomyolysis, myocarditis, and colitis.1

The investigators concluded that IPI plus NIVO was modestly active as salvage therapy in aggressive high-grade NENs that have been heavily pretreated and have progressed on prior cytotoxic chemotherapy.1

Reference

  1. Al-Toubah TE, Gile J, Strosberg JR, Halfdanarson TR. Efficacy of ipilimumab and nivolumab in patients with high-grade neuroendocrine neoplasms. J Clin Oncol. 2021;39(suppl_3):370-370.

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Nivolumab plus Relatlimab in the Neoadjuvant and Adjuvant Settings for Patients with Resectable Clinical Stage III Melanoma

Neoadjuvant and adjuvant treatment with nivolumab plus relatlimab for resectable stage III melanoma achieved high pathologic complete response and major pathologic response rates.

Previous studies have shown that reaching a pathologic complete response (pCR) using neoadjuvant therapy in patients with clinical stage III melanoma has correlated with improved relapse-free survival (RFS) and overall survival (OS). Balancing a favorable pCR with rates of toxicity has been a challenge with these therapies. Neoadjuvant therapy with high- or low-dose ipilimumab plus nivolumab (NIVO) has led to a pCR of 30% to 40%; however, the grade 3/4 toxicity rate for this combination is 20% to 90%. Based on data and experience with treating metastatic melanoma with NIVO plus relatlimab (RELA), which demonstrated low toxicity rates and high response rates in checkpoint inhibitor-naïve and refractory metastatic melanoma, the investigators hypothesized that neoadjuvant NIVO plus RELA would produce high pCRs with acceptable toxicity in patients with stage III melanoma.1

Patients (N = 30) with either measurable resectable clinical stage III or oligometastatic stage IV melanoma were administered NIVO 480 mg intravenously (IV) plus RELA 160 mg IV on weeks 1 and 5. After completion of neoadjuvant NIVO plus RELA, radiographic response was assessed. The patients then underwent surgery and resected specimens were assessed for pathologic response. Following surgery, they were administered up to 10 doses of NIVO plus RELA; scans were performed every 3 months to monitor for recurrence. The primary objective was the pCR rate. Secondary objectives were safety, radiographic response, event-free survival (EFS), RFS, and OS.1

Patients treated with NIVO plus RELA demonstrated a pCR rate of 59%; near pCR (<10% viable tumor) was 7% for a major pathologic response (MPR). A partial pathologic response (10%-50% viable tumor) was reached in 7% of patients and pathologic near response (≥50% viable tumor) was reached in 27%. The objective response rate was 57%. The 1-year EFS was 90%; the RFS was 93%; and the OS was 95% with a median follow-up of 16.2 months. In addition, the 1-year RFS for MPR was 100% and 80% for non-MPR. Grade 3/4 treatment-related adverse events occurred in 26% of patients during adjuvant therapy, but none occurred during neoadjuvant treatment.1

The researchers concluded that high pCR and MPR were achieved with neoadjuvant and adjuvant therapy with NIVO plus RELA with a favorable toxicity profile in both the neoadjuvant and adjuvant periods. In addition, patients with an MPR had better outcomes compared with patients with non-MPRs.1

Reference

  1. Amaria RN, Postow M, Tetzlaff MT, et al. Neoadjuvant and adjuvant nivolumab (nivo) with anti-LAG3 antibody relatlimab (rela) for patients (pts) with resectable clinical stage III melanoma. J Clin Oncol. 2021;39(suppl_15):9502-9502.

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Phase 2 Study of Nivolumab plus Ipilimumab in Metastatic Uveal Melanoma

Nivolumab plus ipilimumab demonstrates deep and sustained confirmed responses for patients with metastatic uveal melanoma.

Previous studies of single-agent immunotherapy with checkpoint inhibitors (specifically anti–PD-1 agents) have not shown positive response rates in treatment of uveal melanoma.1 These studies on monotherapy with ipilimumab (IPI), tremelimumab, pembrolizumab, and nivolumab (NIVO) showed poor overall survival (OS) of 6.8 months, 12.8 months, 7.6 months, and 7.6 months, respectively.1 Combination therapy with NIVO plus IPI has been studied for the treatment of cutaneous melanoma and showed a higher overall response rate (ORR) than the single agents.

In a phase 2 study of NIVO plus IPI in patients with metastatic uveal melanoma, the investigators hypothesized that dual immunotherapy with checkpoint inhibitors would demonstrate improved clinical outcomes in metastatic uveal melanoma.1

To test this hypothesis, a single-arm, open-label study was performed at a single institution between 2015 and 2018.1 The inclusion criteria for the study were ≥18 years of age, with documented metastatic uveal melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1, and acceptable end-organ function.1 The exclusion criteria included metastatic cancer only in bones, a second primary malignancy within the past 2 years, a history of autoimmune disease, or current therapy with immunotherapies other than those being studied, cytotoxic chemotherapy, immunosuppressive drugs, or chronic systemic corticosteroids other than physiologic replacement doses.1

Patients (N = 35) were administered NIVO 1 mg/kg intravenously (IV) plus IPI 3 mg/kg IV every 3 weeks for 4 doses. Following the initial therapy, treatment was continued with NIVO 3 mg/kg IV every 2 weeks but was changed to 480 mg IV every 4 weeks. This treatment was continued for up to 104 weeks, or until disease progression, toxicity, death, or withdrawal of consent.1 The primary end point was ORR. Progression-free survival (PFS), median OS, and 1-year OS were the secondary end points.1

After a median follow-up of 13.0 months, patients had an ORR of 18% (95% confidence interval [CI], 7.0%-35.5%).1 One patient (3%) had a complete response (CR) and 5 patients (15%) had a partial response (PR).1 Stable disease (SD) was achieved in 33% of the patients; 6 of those patients maintained that response for ≥6 months, and 49% of the patients had disease progression.1 A total of 27 patients had liver metastases; 19% of those had a PR and 11% had SD for ≥6 months. In the other 6 patients who had extrahepatic metastases, 17% had a CR and 50% had SD for ≥6 months.1

There were 2 patients who had received treatment prior to the study with pembrolizumab monotherapy; of these, 1 patient had SD and 1 had disease progression on NIVO plus IPI.1 The patients who responded had a median time to response of 2.7 months. These responders had a median duration of response of 12.1 months with a median treatment duration of 3.9 months.1 For the patients who were responders, the median PFS was 5.5 months (95% CI, 3.4-9.5 months); the median OS was 19.1 months (95% CI, 9.6 months-not reached), and the 1-year OS was 56% (95% CI, 38%-71%).1

There were 29 (83%) patients with a treatment-related adverse event (TRAE). Grade 3/4 TRAEs occurred in 14 (40%) patients. Diarrhea, liver enzyme abnormalities, pruritus, and hypothyroidism were the most common TRAEs of any grade. Adverse events caused 10 patients (29%) to leave the study. There were no treatment-related deaths in the study.1

The researchers concluded that NIVO plus IPI exhibits antitumor activity in metastatic uveal melanoma. This study, combined with the Spanish GEM-1402 study, supports the use of the NIVO plus IPI combination for patients in this setting.1

Reference

  1. Pelster MS, Gruschkus SK, Bassett R, et al. Nivolumab and ipilimumab in metastatic uveal melanoma: results from a single-arm phase II study. J Clin Oncol. 2021;39:599-607.

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Phase 2 Study of the Anti-TIGIT Antibody Tiragolumab plus Atezolizumab versus Placebo plus Atezolizumab as First-Line Treatment in Patients with PD-L1–Selected NSCLC: CITYSCAPE

Treatment for NSCLC using the combination of tiragolumab plus atezolizumab was more effective than treatment with placebo plus atezolizumab.

Tiragolumab (TIRA) is an IgG1/kappa monoclonal antibody that binds T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) and prevents interaction with its ligand.1 In a phase 1 study, it was demonstrated that TIRA alone or in combination with atezolizumab (ATEZO) was safe and effective in treating cancer-immunotherapy-naïve, PD-L1–positive tumors; patients with non–small-cell lung cancer (NSCLC) were included in the study.1,2

Based on results from that study, the researchers of the phase 2 CITYSCAPE study investigated the efficacy and safety of TIRA plus ATEZO compared with placebo plus ATEZO as first-line therapy of NSCLC.2 CITYSCAPE was a prospective, randomized, double-blind trial in patients with locally advanced or metastatic PD-L1–positive NSCLC who had not previously been treated with chemotherapy. The patients (N = 135) were European Cooperative Oncology Group performance status 0-1 and did not have EGFR or ALK mutations.2

Patients were randomized to receive either TIRA 600 mg intravenously (IV) plus ATEZO 1200 mg IV or placebo plus ATEZO 1200 mg IV every 3 weeks.2 The patients were stratified by PD-L1 status, tobacco history, and histology.2

The primary end points were objective response rate (ORR) and progression-free survival (PFS).2 Overall survival, duration of response, and safety were additional end points. The effects of PD-L1 status on ORR and PFS were exploratory end points.2

At a median follow-up of 5.9 months, TIRA plus ATEZO had improved ORR and median PFS (mPFS) compared with placebo plus ATEZO.2 After 6 additional months, improvements in ORR and mPFS were maintained, with an ORR of 37.3% and mPFS of 5.6 months in the TIRA plus ATEZO cohort compared with an ORR of 20.6% and mPFS of 3.9 months in the placebo plus ATEZO cohort.2

Treatment-related adverse events (TRAEs) occurred in 72% of the patients in the placebo plus ATEZO group and in 80.6% in the TIRA plus ATEZO group. Grade ≥3 TRAEs occurred in 19.1% of the patients in the placebo plus ATEZO group and in 14.9% in the TIRA plus ATEZO group. The adverse events that led to withdrawal from treatment occurred in 10.3% of patients in the placebo plus ATEZO group and in 7.5% of patients in the TIRA plus ATEZO group.2

The researchers concluded that therapy with TIRA plus ATEZO demonstrated clinically important improvement in ORR and PFS as first-line treatment in patients with PD-L1–positive NSCLC compared with placebo plus ATEZO.2

References

  1. Bendell JC, Bedard P, Bang Y-J, et al. Phase Ia/Ib dose-escalation study of the anti-TIGIT antibody tiragolumab as a single agent and in combination with atezolizumab in patients with advanced solid tumors. Presented at: 2020 AACR Virtual Annual Meeting; June 22-24, 2020. Abstract CT302.
  2. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol. 2020;38(suppl_15):9503-9503.

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Tremelimumab plus Durvalumab for Patients with Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase 1/2 Study

Tremelimumab plus durvalumab demonstrated an encouraging benefit-risk profile for treatment of unresectable hepatocellular carcinoma.

Although there have been advances in therapies for unresectable hepatocellular carcinoma (HCC), the long-term survival and durable responses are still not favorable in this setting.1 HCC has an immune-suppressed microenvironment, partially mediated by activated immune checkpoint signaling pathways; this contributes to resistance to therapeutics, which is why immunotherapy may be beneficial in the treatment of unresectable HCC.1 A regimen including inhibition of both PD-1/PD-L1 and cytotoxic T-lymphocyte–associated antigen (CTLA)-4 pathways may improve outcomes for patients with unresectable HCC.1 However, combination therapies with anti–CTLA-4 and anti–PD-L1 drugs have higher anti–CTLA-4 dose-dependent toxicity.1 In studies with other cancers, a single priming dose of the anti–CTLA-4 antibody tremelimumab (TREM) has been shown to be enough to produce long-lasting response when combined with a PD-L1 inhibitor. Using just a single priming dose could also limit toxicity while still maintaining or increasing the efficacy of monotherapies.1

The initial phase 1 study of the combination of TREM 75 mg intravenously (IV) every 4 weeks for 4 cycles plus durvalumab (DURV) 1500 mg IV every 4 weeks demonstrated safety and efficacy in treating patients with unresectable HCC.1 Confirmed objective response rate (ORR) was 15%, complete plus partial response was 20%, and complete response plus partial response plus stable disease (16-week disease control rate) was 57.5%.2

There were 4 phase 2 expansion cohorts: (1) TREM monotherapy (750 mg once every 4 weeks for 7 doses, then once every 12 weeks), (2) DURV monotherapy (1500 mg every 4 weeks), (3) TREM plus DURV combination therapy (TREM 75 mg every 4 weeks plus DURV 1500 mg every 4 weeks for 4 doses, followed by DURV 1500 mg every 4 weeks), and (4) TREM 300 mg IV plus DURV 1500 mg for 1 dose, followed by DURV 1500 mg IV every 4 weeks.1 Moreover, all 4 regimens were evaluated to establish if either of the combination regimens could increase efficacy over monotherapy and if a single TREM dose could help reduce the toxicity often accompanying use of anti–CTLA-4 agents.1

Most of the patients in the study had advanced HCC and had progressed on or were intolerant to past therapy with sorafenib.1

The primary end point of the phase 2 study was safety. Secondary end points were ORR, duration of response (DOR), time to response, progression-free survival (PFS), and overall survival (OS).1

TREM had the highest rate of all-grade and grade ≥3 treatment-related adverse events (TRAEs).1 Transaminitis, increased lipase and amylase, and diarrhea were the most common grade ≥3 TRAEs. Serious TRAEs occurred in 24.6% of patients treated with TREM monotherapy, 17.6% with TREM 300 mg plus DURV, 14.6% with TREM 75 mg plus DURV, and 10.9% for DURV alone. The TRAEs that required systemic steroids were most frequent in the TREM-containing regimens (TREM monotherapy, 26.1%; TREM 300 mg plus DURV, 24.3%; TREM 75 mg plus DURV, 24.4%; and DURV alone, 9.9%).1 This was also true for the immune-mediated adverse events (TREM 300 mg plus DURV, 31.1%; TREM 75 mg plus DURV, 26.8%; TREM alone, 24.6%; and DURV alone, 15.8%).1 TRAEs caused patients to discontinue treatment (TREM monotherapy, 13.0%; TREM 300 mg plus DURV, 10.8%; TREM 75 mg plus DURV, 6.1%; and DURV alone, 7.9%). Disease progression was the most common reason for discontinuation in 64.4% of patients.1

ORR was highest for the group administered TREM 300 mg plus DURV (24%; 95% CI, 14.9-35.3).1 Complete responses were seen in 1 patient administered TREM 300 mg plus DURV and in 2 receiving TREM 75 mg plus DURV.1 TREM 300 mg plus DURV and TREM alone had the shortest median time to response of 1.86 months and 1.81 months, respectively. The median DOR was not reached with TREM 300 mg plus DURV; 23.9 months for TREM alone; 13.21 months for TREM 75 mg plus DURV; and 11.17 for DURV.1 For TREM 300 mg plus DURV, the median PFS was 2.17 months (95% CI, 1.91-5.42); 2.07 for DURV (95% CI, 1.84-2.83); 2.69 for TREM (95% CI, 1.87-5.29); and 1.87 for TREM 75 mg plus DURV (95% CI, 1.77-2.53).1

Patients treated with TREM 300 mg plus DURV had an OS rate of 18.73 (95% CI, 10.78-27.27) months, followed by those treated with TREM with 15.1 (95% CI, 11.33-20.50) months, 13.57 (95% CI, 8.74-17.64) months with DURV, and 11.30 (95% CI, 8.38-14.95) months with TREM 75 mg plus DURV.1

In conclusion, TREM as a single priming dose, combined with DURV every 4 weeks improved durable response and safety for patients with unresectable HCC compared with either of these drugs alone or in combination.1

References

  1. Kelley RK, Sangro B, Harris W, et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study. J Clin Oncol. 2021;39:2991-3001.
  2. Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. J Clin Oncol. 2017;35(suppl_15):4073-4073.

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Phase 2 Trial of Nivolumab plus Ipilimumab for Treatment-Naïve Metastatic Uveal Melanoma: Spanish Multidisciplinary Melanoma Group (GEM-1402)

Nivolumab plus ipilimumab demonstrated improvement in overall survival for patients with metastatic uveal melanoma.

Previous studies have shown that single checkpoint inhibitors were not successful in the treatment of patients with metastatic uveal melanoma (MUM). However, the combination of nivolumab (NIVO) plus ipilimumab (IPI) has demonstrated efficacy in metastatic cutaneous melanoma, particularly in tumors with low PD-L1 expression.1 Based on that success, the Spanish Multidisciplinary Melanoma Group performed the GEM-1402 study to investigate the efficacy of NIVO plus IPI in first-line treatment for MUM, specifically looking at 12-month overall survival (OS) in patients with MUM who were not eligible for liver resection.1

This was a phase 2 multicenter study conducted from 2016 to 2017 at 10 centers in Spain with a database lock of July 2019. The patients had Eastern Cooperative Oncology Group performance status ≤1 with treatment-naïve, histologically confirmed, progressive systemic MUM.1 The treatment in the study was NIVO intravenously (IV) 1 mg/kg plus IPI IV 3 mg/kg every 3 weeks for 4 doses. Patients then received NIVO IV 3 mg/kg every 2 weeks. This dosing was continued until there was clinical or objective disease progression (PD), unacceptable toxicity, or patient withdrawal from the study.1 Response to therapy was measured with computed tomography or magnetic resonance imaging every 6 weeks for 12 months, and then once every 12 weeks until discontinuation of treatment or PD, whichever was later.1

The primary end point of the study was 12-month OS, and secondary end points were investigator-assessed response rate and safety.1 Liver toxicity was especially followed, in addition to treatment-related adverse events (TRAEs) and other adverse events.1

Objective response was seen in 6 of the 52 patients (11.5%; 95% confidence interval [CI], 2.9-20.2) with 1 complete response and 5 partial responses, all occurring in the first 9 months of treatment and continued for 15.6 months (95% CI, 1.6-33.8). The most common outcome was stable disease in 51.9% of patients (95% CI, 38.3-65.5) that was maintained for a median of 3.8 months (95% CI, 0.1-21.5). The disease control rate was 63.5% (95% CI, 50.4-76.5).1

Median OS was 12.7 months (95% CI, 7.1-18.3); the 12- and 24-month OS rates were 51.9% (95% CI, 38.3-65.5) and 26.4% (95% CI, 14.2-38.6), respectively.1 Median progression-free survival (PFS) was 3.0 months (95% CI, 2.0-4.1), and 28.8% of all patients were progression-free at 6 months (95% CI, 16.5-41.1) and 19.2% were progression-free at 12 months (95% CI, 8.5-29.9).1

Radiologically significant growth of the patients’ target lesions was seen in 80.8% (95% CI, 70.1-91.5) of patients with PD.1

Of the 38 patients who had died by the time of the database lock, 32 were due to PD, 2 due to TRAEs, and 4 due to other causes.

Cytokine analysis was performed, with a possible association found for OS with expression of interleukin (IL)-1b (P = .022), IL-2 (P = .083), IL-6 (P = .027), IL-8 (P = .05), and vascular endothelial growth factor-A (P = .023), but the finding was not conclusive when the factors were all assessed together.1 DNA analysis was also performed on 41 of the baseline tumor samples. No significant differences were detected for association of mutations in GNAQ, GNA11, SF3B1, or chromosomal alterations with ORR, OS, or PFS.1

TRAEs were observed in 49 of 52 patients (94%), including skin-related events (61.5%), fatigue (57.7%), liver-related events (36.5%), and diarrhea (28.8%). Grade 3 TRAEs occurred in 30 (57.7%) patients. There were 56 serious adverse events; the most frequent serious TRAEs were fever (4), liver-related events (3), and diarrhea (3). There was 1 death with thyroiditis and 1 with Guillain-Barré syndrome that were thought to be treatment-related. Other thyroid-associated serious TRAEs included 1 patient with thyroiditis who recovered, 1 with hypothyroidism, and 1 with hyperthyroidism.1

The investigators concluded that NIVO plus IPI holds promise as a treatment for uveal melanoma, with good OS and a reasonable toxicity profile. The adverse events were similar to those observed in patients with cutaneous melanoma treated with NIVO plus IPI. This study also found that patients with extrahepatic disease, regardless of liver involvement, benefited from this treatment.1

Reference

  1. Piulats JM, Espinosa E, de la Cruz Merino L, et al. Nivolumab plus ipilimumab for treatment-naïve metastatic uveal melanoma: an open-label, multicenter, phase II trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402). J Clin Oncol. 2021;39:586-598.

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First-Line Nivolumab plus Low-Dose Ipilimumab for Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: CheckMate-142

After more than 4 years of follow-up, patients with advanced NSCLC treated with nivolumab plus ipilimumab maintained overall survival rates.

Historically, standard chemotherapy results in poor outcomes when used for treatment of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Previous studies have demonstrated some success with monotherapy using anti– PD-1 drugs.1 This has led to the investigation of combination immunotherapy in this setting.

CheckMate-142, a phase 2, nonrandomized study investigating nivolumab (NIVO)-based treatments for patients with previously treated and untreated MSI-H and non–MSI-H mCRC, demonstrated that NIVO alone and NIVO plus low-dose ipilimumab (IPI) followed by NIVO alone is associated with favorable results as second-line or more therapy.1 NIVO alone or NIVO plus IPI has been FDA-approved for treatment of patients with MSI-H/dMMR mCRC who have failed chemotherapy.1

The current study reported on the results of NIVO plus low-dose IPI as first-line therapy for MSI-H/dMMR mCRC.1

Patients were administered NIVO 3 mg/kg every 2 weeks and low-dose IPI 1 mg/kg every 6 weeks until disease progression, toxicity leading to discontinuation, withdrawal of consent, or death.1 The primary end point was objective response rate (ORR) by investigator assessment (INV). Complete response (CR) and partial response (PR) were measured and used in calculating the primary end point of ORR. Secondary end points were ORR by blinded independent central review (BICR), disease control rate (DCR), calculated as CR, PR, plus stable disease. Progression-free survival (PFS), overall survival (OS), safety and tolerability, and patient-reported outcomes (PROs) were other key end points. Tumors were measured by computed tomography or magnetic resonance imaging.1

For patients treated with the combination of NIVO plus IPI, ORR was 69% (95% confidence interval [CI], 53-82) by INV and 62% (95% CI, 53-82) by BICR.1 DCR was 84% and 78% by INV and BICR, respectively. Progressive disease was observed in 13% of patients by INV and 16% by BICR.1 The median time to response was 2.7 months. The median duration of response was not achieved. However, responders did show ongoing response (71% for ≥12 months), and of responders, 84% had decreasing tumor burden.1

Median PFS overall and in the BRAF and KRAS mutation groups was not reached. The PFS rates in the overall population were 76.4% (95% CI, 60.5-86.6) at 12 months, 76.4% (95% CI, 60.5-86.6) at 18 months, and 73.6% (95% CI, 57.2-84.5) at 24 months. The 24-month PFS was 87.5% (95% CI, 38.7-98.1) in patients with a KRAS mutation, 76.5% (95% CI, 48.8-90.4) for those with BRAF mutation, and 68.4% (95% CI, 35.9-86.8) for the BRAF and KRAS wild-type subgroups.

Median OS was also not reached in the overall population. The OS rate for 12, 18, and 24 months was 84.1% (95% CI, 69.5-92.1), 81.7% (95% CI, 66.8-90.4), and 79.4% (95% CI, 64.1-88.7), respectively.1

PRO questionnaires showed either improvement (measured by the 5-dimensional EuroQol [EQ-5D] Visual Analogue Scale and EQ-5D Utility Index), or stability for quality of life (measured by the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire and the EQ-5D).1

Treatment-related adverse events (TRAEs) were reported by 80% of patients, with the most common TRAEs being pruritus (36%), arthralgia (20%), and hypothyroidism (18%). Grade 3 TRAEs were colitis (4%), adrenal insufficiency, asthenia, congestive cardiomyopathy, gastroenteritis, hypophosphatemia, hypothyroidism, increased blood creatinine, increased transaminases, and pneumonitis (each 2%).1 There was 1 patient with grade 4 respiratory failure and hyponatremia.1 Any-grade serious TRAEs were dermatologic (47%), endocrine (29%), gastrointestinal (20%), hepatic (11%), pulmonary (4%), and renal (2%). Most of these resolved by data cutoff.1

The researchers concluded that NIVO plus low-dose IPI as first-line treatment for MSI-H/dMMR mCRC had robust and durable benefits and an acceptable safety profile.1

Reference

  1. Lenz HJ, Van Cutsem E, Limon ML, et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol. Published online October 12, 2021.

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