Clinical Professor Emeritus, University of California, San Francisco; Professor of Pharmacy,
College of Pharmacy, Touro University–California, Mare Island, Vallejo, CA
Concurrent Nivolumab plus Ipilimumab Superior to Monotherapy in Advanced Melanoma
Background: Immune blockade is one approach that has been found to induce tumor regression in several types of cancer. Ipilimumab, a fully human, immunoglobulin (Ig) G1 monoclonal antibody that blocks cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), has demonstrated overall survival in patients with advanced melanoma. Nivolumab, a fully human, IgG4 antibody that blocks the programmed death 1 (PD-1) receptor, produced durable objective responses in patients with melanoma, renal-cell cancer, and non–small-cell lung cancer. In preclinical models, the combination of CTLA-4 plus PD-1 blockade was shown to be complementary in regulating immune activity, and was hypothesized to increase antitumor activity compared with blockade with either pathway alone.
Method: This phase 1 clinical trial was designed to evaluate the safety and efficacy of combined nivolumab and ipilimumab in patients with advanced melanoma. All patients were aged >18 years; had a diagnosis of measurable, unresectable, stage III or IV melanoma; and had a life expectancy of at least 4 months. A total of 86 patients were treated from December 2009 through February 2013; 53 patients received concurrent therapy with intravenous nivolumab and ipilimumab every 3 weeks for 4 weeks, followed by nivolumab alone every 3 weeks for 4 doses. This combined treatment was subsequently administered every 12 weeks for up to 8 doses. In the sequenced therapy arm, 33 patients who were previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.
Results: The objective response rate (according to the modified World Health Organization criteria) for all patients in the concurrent regimen group was 40% (95% confidence interval [CI], 27-55). Clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was seen in 65% of patients (95% CI, 51-78). At the maximum allowed dose, 53% of patients (95% CI, 28-77) demonstrated objective response with concurrent nivolumab plus ipilimumab compared with only 20% of patients in the sequenced monotherapy group (95% CI, 8-39). Overall, 16 patients in the combined regimen had tumor reductions of ≥80% at 12 weeks. Adverse events of any grade, regardless of whether they were attributed to the therapy, were seen in 98% of patients in the concurrent regimen group. The most common treatment-related adverse events in this patient poulation were rash (55%), pruritus (47%), fatigue (38%), and diarrhea (34%). Grade 3 or 4 adverse events related to therapy were reported in 53% of the patients in the concurrent regimen group, but these were similar to events seen with monotherapy and were reversible. The most common events were related to elevated levels of lipase (13%), aspartate aminotransferase (13%), and alanine aminotransferase (11%). In the sequenced therapy group, the rate of grade 3 or 4 adverse events was 18% with elevated lipase level as the most common event (6%).
Takeaway: Over the past few years, the treatment of malignant melanoma has advanced substantially with the approval of 4 new drugs. Ipilimumab was approved in March 2011 for the treatment of unresectable or metastatic melanoma on the basis of improved overall survival. It appears that the immune response to some tumors, including melanoma, is inversely proportional to the level of expression of PD-1 and PD-1 ligand, which promotes immunosuppression (Topalian SL, et al. N Engl J Med. 2012;366:2443-2454). Inhibitors of PD-1 ligand improve the immune response to melanoma. Nivolumab is one of several PD-1 inhibitors being developed for the treatment of cancers that have a high expression of PD-1 or its ligand. This was a phase 1 study evaluating 2 dose strategies in patients with stage III or IV melanoma.
Previous treatment had been given to 38% of patients assigned to the concurrent strategy and to 100% of those assigned to sequential therapy. Eighty-six patients (53 in the concurrent arm and 33 in the sequential arm) were entered into the study, with 82 patients eligible for efficacy assessment. Treatment-related toxicities were frequent (93% in the concurrent arm and 73% in the sequential arm), which were managed with immunosuppressive therapy (primarily corticosteroids). However, serious side effects occurred in 11 (49%) of those patients treated with the concurrent therapy, resulting in a 21% discontinuation rate, compared with 7 patients (21%) in the sequential arm, and with 3 patients discontinuing therapy. Efficacy was demonstrated in both arms, with 40% of patients responding in the concurrent group and 20% of patients responding in the sequential group. Of the 21 patients who responded, 16 had a >80% tumor shrinkage at 12 weeks, with 5 patients experiencing a complete response.
These are impressive results in a phase 1 study and will obviously lead to phase 2 and probably to phase 3 randomized trials. It appears that nivolumab has complementary effects when combined with ipilimumab, which should be compared with other standard therapies for advanced melanoma. Although toxicity is frequent, it is manageable. The results of this study should lead to a fast-track research strategy for nivolumab.
Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133.
Long-Term Effect of Chemotherapy-Induced Neuropathy Seen in Colorectal Cancer Survivors
Background: Colorectal cancer is the third most common cause of cancer among men and women in the Western world. In 2007, 12,000 patients were diagnosed with colorectal cancer in the Netherlands, and this number is expected to increase to 17,000 in 2020. Because of the increasing prevalence, more patients are living with the long-term adverse effects of this cancer and its treatment. Neuropathy, a common adverse effect of treatment with oxaliplatin, is a major concern. Chemotherapy-induced peripheral neuropathy can be severe, may result in serious limitations of daily functioning, and might therefore have a negative impact on patients’ health-related quality of life (HRQOL). Studies on the association between neuropathy and HRQOL are limited, and most studies have focused on acute instead of chronic neuropathy.
Methods: In a population-based sample, researchers assessed the prevalence and severity of chemo-
therapy-induced neuropathy and its effect on HRQOL in 1643 colorectal cancer survivors at 2 to 11 years after diagnosis. All patients diagnosed with colorectal cancer between 2000 and 2009 who were registered in the Dutch population–based Eindhoven Cancer Registry and included in the PROFILES (Patient Reported Outcomes Following Initial Treatment and Long Term Evaluation of Survivorship) registry were enrolled. Of all of the eligible participants, 83% completed the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and the EORTC QLQ Chemotherapy-Induced Peripheral Neuropathy (CIPN) 20. Of the total groups of respondents, 500 patients (31%) had been treated with chemotherapy. These patients were significantly younger, diagnosed more recently, and were more often diagnosed with colon instead of rectal cancer compared with patients not treated with chemotherapy. They also had a higher disease stage and a higher disease grade at diagnosis, reported a higher body mass index, and were more often employed at the time of the survey.
Results: Among all respondents, the 5 neuropathy subscale–related symptoms that patients reported bothering them the most during the past week were erectile problems (42% of men), trouble hearing (11%), trouble opening jars or bottles (11%), tingling in toes or feet (10%), and trouble walking stairs or standing up (9%). Logistic regression analyses among patients diagnosed from 2007 and onward (eg, after the induction of oxaliplatin) showed that those treated with oxaliplatin more frequently reported tingling (29% vs 8%; P = .001), numbness (17% vs 5%; P = .0047), and aching or burning pain (13% vs 6%; P = .0293) in toes or feet compared with patients who did not receive chemotherapy. Furthermore, those treated with oxaliplatin more frequently reported tingling in toes or feet (29% vs 14%; P = .0127) compared with those treated with chemotherapy other than oxaliplatin. Analyses among patients with colon cancer diagnosed since 2007 showed that both patients treated with oxaliplatin and those receiving chemotherapy without oxaliplatin reported significantly higher scores on EORTC QLQ-CIPN20 sensory scale problems compared with patients not receiving chemotherapy, with these differences being clinically relevant. As for HRQOL, no significant differences were found on EORTC QLQ-C30 subscale scores between colorectal cancer survivors diagnosed since 2007 who were treated with chemotherapy and those treated with chemotherapy with or without oxaliplatin. However, among the total group of patients with colorectal cancer, those with many neuropathy symptoms (eg, upper 10%) reported statistically significant and clinically relevant HRQOL scores on all EORTC QLQ-C30 subscales (P <.01) compared with patients with fewer symptoms.
Takeaway: Oxaliplatin-based chemotherapy is the standard of care for the treatment of stages III and IV colorectal cancer. With an ever-growing aging population and the increase in the overall survival of patients with colorectal cancer, the prevalence of oxaliplatin-induced neuropathy is likely to increase, along with having a major impact on quality of life. This population-based retrospective study evaluated the prevalence of oxaliplatin-induced neuropathy, with emphasis on the duration. The study method included a self-reporting system with 1643 patients responding to the survey (83% response rate). Approximately 30% of patients treated with chemotherapy experienced peripheral neuropathy, which was primarily manifested as sensory neuropathy (tingling, numbness, or burning of the hands and feet). The complication could last 2 to 11 years after completion of therapy. HRQOL scores were worse for patients who developed chronic oxaliplatin-induced neuropathy.
Chemotherapy-induced neuropathy is difficult to prevent and treat. In patients who are at risk for oxaliplatin-induced neuropathy (approximately 30% incidence), a prevention therapy is very welcome. Hopefully, this study will lead to further research for an effective therapy for this condition.
Mols F, Beijers T, Lemmens V, et al. Chemotherapy-induced neuropathy and its association with quality of life among 2- to 11-year colorectal cancer survivors: results from the population-based PROFILES registry. J Clin Oncol. 2013;31:2699-2707.
BTK Targeting with Ibrutinib Shows Good Results in Patients with Relapsed Chronic Lymphocytic Leukemia
Background: Treatment for chronic lymphocytic leukemia (CLL), the most common leukemia in adults, has resulted in few durable remissions. Unlike chronic myeloid leukemia, CLL lacks a common genetic target. However, B-cell receptor signaling has emerged as a driving factor for CLL tumor-cell survival. Bruton’s tyrosine kinase (BTK) is a critical signaling molecule for the activation of several constitutively active pathways of CLL-cell survival. In addition, BTK is essential to chemokine-mediated homing and adhesion of B-cells. Given the importance of B-cell receptor signaling in CLL and the central role of BTK in this pathway, one strategy is to target inhibition of this kinase. Ibrutinib is an orally, bioavailable, potent inhibitor that covalently binds to the cysteine-481 amino acid of the BTK enzyme. Previous clinical studies with ibrutinib have shown that treatment inhibits numerous processes, including extracellular signal-regulated kinase. The drug also has little effect on healthy T-cells, distinguishing it from most regimens that are used for the treatment of CLL.
Methods: In this phase 1b-2, open-label, multicenter study, 85 patients with relapsed or refractory CLL or small lymphocytic lymphoma were randomized to receive 420 mg of ibrutinib (N = 51) or 840 mg of ibrutinib (N = 34). Both doses were administered orally on a continuous schedule until the onset of disease progression or unacceptable toxicity. A majority of these patients had high-risk disease and had received a median of 4 previous therapies. A total of 65% of the patients had advanced-stage disease, 33% had 17p13.1 deletions, and 36% had 11q22.3 deletions. At a median follow-up of 20.9 months, 54 patients (64%) were still receiving treatment and 31 (36%) had discontinued treatment. The primary end point was the safety of the 2 regimens. The secondary end points were the overall response rate (ORR), progression-free survival (PFS), pharmacodynamics, and pharmacokinetics.
Results: The ORRs were 71% in each of the treatment arms with ibrutinib, and an additional 20% of patients in the 420-mg cohort and 15% of patients in the 840-mg cohort experienced a partial response with lymphocytosis. Blood lymphocytosis was generally noted by day 7 in 79% of the patients; it peaked at a median of 4 weeks and then slowly declined. After a follow-up of 26 months, the estimated rate of PFS was 75%, and the rate of overall survival was 83% for all patients, irrespective of the dose. At both doses of ibrutinib, pharmacokinetic data showed rapid absorption and elimination. Furthermore, pharmacodynamic data showed that once-daily ibrutinib provided effective and complete occupancy of BTK. Long-term therapy with ibrutinib was associated with modest toxicity. Most of the adverse events were grade 1 or 2 and included transient diarrhea (47%), upper respiratory tract infection (33%), and fatigue (28%). A majority of the adverse events resolved without the need for suspension of treatment.
Takeaway: Ibrutinib appears to be both relatively safe and efficacious in the treatment of refractory or relapsed CLL or small lymphocytic lymphoma. It is noteworthy that this study, which was initially designed with 2 arms, was expanded to include a third arm of patients with high-risk disease. Most patients had received a previous nucleoside analog, rituximab, or an alkylator. Despite patients receiving an average of 4 previous therapies, the incidence of infectious complications was not observed during the extended period of therapy (unlike with other salvage therapies). Improvement in cytopenias was seen in 71% of patients who were treated at both dose levels. Complete or partial responses increased over time and peaked at 18 months of therapy. The drug was rapidly absorbed and blocked the BTK enzyme almost completely (a reflection of surrogate kinase inhibition). Ibrutinib was well tolerated, with most adverse events rated as grade 1 or 2 regardless of cause. In the 85 patients who were treated, 7 serious adverse events were observed. In the accompanying editorial in the same issue, Foà and Guarini posed several questions about the role of this drug in patients with relapsed or high-risk CLL (Foà R, Guarini A. N Engl J Med. 2013;369:85-87). They suggest that ibrutinib may play a role when used earlier in the treatment plan. It may also provide an option for patients with CLL who often have multiple comorbidities that would preclude the use of more toxic salvage drugs. Ibrutinib is currently not available commercially, but this study may provide enough data to allow for its approval as an orphan drug.
Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42.