In This Article
- Alectinib Shows Superior Outcomes versus Crizotinib in NSCLC with ALK Mutation
- Durvalumab Use After Chemoradiotherapy Prolongs Progression-Free Survival in Stage III NSCLC
- Olaparib Improves Progression-Free Survival in Metastatic Breast Cancer with BRCA Mutation
Alectinib Shows Superior Outcomes versus Crizotinib in NSCLC with ALK Mutation
BACKGROUND: Advanced-stage non–small-cell lung cancer (NSCLC) with ALK mutation is associated with a high risk for central nervous system (CNS) and brain metastases at diagnosis. Crizotinib is the current standard first-line therapy for patients with advanced-stage NSCLC and ALK mutation. In previous studies, alectinib, a highly selective ALK tyrosine kinase inhibitor (TKI) and a CNS penetrant, showed systemic and CNS activity in untreated, advanced NSCLC with ALK mutation. This study compared the safety and efficacy of alectinib and crizotinib in this patient population.
METHODS: The phase 3 ALEX clinical trial randomized 303 patients with untreated, advanced NSCLC and ALK mutation to alectinib 600 mg twice daily or to crizotinib 250 mg twice daily. Patients were randomized based on Eastern Cooperative Oncology Group performance status, race, and CNS metastases at baseline. The primary end point was investigator-assessed progression-free survival (PFS); secondary end points included independent review committee (IRC)-assessed PFS, time to CNS progression, objective response rate, and overall survival. Patients continued treatment until disease progression, unacceptable toxicity, withdrawal, or death.
RESULTS: The median follow-up was 17.6 months with crizotinib and 18.6 months with alectinib. Disease progression or death was 41% in the alectinib group versus 68% in the crizotinib group. The investigator-assessed 12-month event-free survival was 68.4% with alectinib and 48.7% with crizotinib; the hazard ratio (HR) for disease progression or death was 0.47 (P <.001); the median PFS was not reached with alectinib versus 11.1 months with crizotinib. IRC-assessed PFS was 25.7 months with alectinib and 10.4 months with crizotinib; the HR for disease progression or death was 0.50 (P <.001). Time to CNS progression was significantly longer with alectinib than with crizotinib (P <.001). Overall, 12% of patients receiving alectinib had a CNS progression event versus 45% of patients receiving crizotinib; 12-month cumulative CNS progression incidence was 9.4% versus 41.4%, respectively. The investigator-assessed response rate was 82.9% and 75.5%, respectively (P = .09). The duration of response was longer with alectinib than with crizotinib, and the event-free survival rate was 72.5% versus 44.1%, respectively.
In patients with measurable CNS lesions at baseline, CNS response was 81% with alectinib versus 50% with crizotinib; 38% of patients in the alectinib group had a complete CNS response versus 5% in the crizotinib group.
Grade 3 to 5 adverse events occurred in 41% of patients in the alectinib group versus 50% of patients in the crizotinib group. Nausea, diarrhea, and vomiting were more common with crizotinib than with alectinib.
Source: Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377:829-838.
Commentary by Robert J. Ignoffo
During the past 3 to 5 years, the advances that have been made in NSCLC are astonishing. Great strides have been made in the diagnosis of the disease, particularly the discovery of genetic mutations in tyrosine kinase ALK, which have paved the way for using ALK-specific TKIs as a personalized treatment approach. Approximately 60,000 people are diagnosed with ALK-positive NSCLC annually1; most have metastatic disease, and 60% have CNS involvement.2 Alectinib penetrates the CNS more effectively than crizotinib. Thus, alectinib is an attractive drug in this setting, and clearly produces better results than the current standard agent, crizotinib.
In this study, alectinib produced better outcomes than crizotinib in newly diagnosed patients. Of note, approximately 20% of patients with this type of NSCLC have subsequent CNS metastases, indicating resistance to crizotinib.3-5 The J-ALEX study has shown that alectinib is more effective and less toxic than crizotinib in this setting.6 Another study has shown that alectinib is effective in crizotinib-resistant, ALK-positive NSCLC with leptomeningeal metastases.2 Other TKIs are being developed that are effective against ALK-specific resistance genotypes—most noteworthy are brigatinib and lorlatinib, which have shown potent activity in patients with acquired resistance to ALK inhibitors.5
Alectinib is an important new drug for the treatment of ALK-positive NSCLC and appears to be even more effective than crizotinib in this setting. Its role will be determined by results of future trials with the third-generation ALK TKIs in the pipeline, but some cancer centers are now recommending the use of alectinib over crizotinib as first-line therapy.7 Alectinib is currently approved for use in the metastatic setting.
- Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med. 2013;368:2385-2394.
- Gainor JF, Sherman CA, Willoughby K, et al. Alectinib salvages CNS relapses in ALK-positive lung cancer patients previously treated with crizotinib and ceritinib. J Thorac Oncol. 2015;10:232-236.
- Costa DB, Shaw AT, Ou SH, et al. Clinical experience with crizotinib in patients with advanced ALK-rearranged non-small-cell lung cancer and brain metastases. J Clin Oncol. 2015;33:1881-1888.
- Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012;18:1472-1482.
- Muller IB, de Langen AJ, Giovannetti E, Peters GJ. Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: clinical impact of alectinib. Onco Targets Ther. 2017;10:4535-4541.
- Hida T, Nokihara H, Kondo M, et al. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial. Lancet. 2017;390:29-39.
- Eichler AF, Ross ME, Savarese DMF, Vora SR. What’s new in oncology. November 7, 2017. www.uptodate.com/contents/topic.do?topicKey=ONC/8361. Accessed November 13, 2017.
Durvalumab Use After Chemoradiotherapy Prolongs Progression-Free Survival in Stage III NSCLC
BACKGROUND: Platinum-based doublet chemotherapy plus radiation (chemoradiotherapy) remains the standard of care for patients with stage IIIB or IIIC, locally advanced non–small-cell lung cancer (NSCLC), but most patients receiving chemoradiotherapy have progressing disease. Preclinical studies suggest that chemoradiotherapy may increase programmed-cell death ligand 1 (PD-L1) expression, which can predict response to durvalumab, a selective, high-affinity, anti–PD-L1 antibody. This study was an interim analysis of the phase 3 PACIFIC clinical trial in patients with stage III NSCLC without disease progression after ≥2 chemoradiotherapy cycles.
METHODS: A total of 709 patients were randomized 1 to 42 days after chemoradiotherapy to durvalumab or to placebo every 2 weeks for up to 12 months. The co-primary end points included progression-free survival (PFS), as assessed by a blinded independent central review, and overall survival (OS). The secondary end points were 12- and 18-month PFS, the objective response rate (ORR), duration of response, time to death or distant metastasis, OS at 24 months, side-effect profile, health-related quality of life, pharmacokinetic profile, and immunogenicity. Study enrollment was not limited to PD-L1 expression.
RESULTS: The median PFS was 16.8 months with durvalumab and 5.6 months with placebo. The 12-month PFS was 55.9% with durvalumab and 35.3% with placebo; the 18-month PFS was 44.2% and 27.0%, respectively. PFS benefit with durvalumab was reported across all prespecified subgroups, regardless of PD-L1 expression. The median time to death or to distant metastasis was 23.2 months with durvalumab and 14.6 months with placebo. The rate of new lesions was 20.4% and 32.1%, and the rate of new brain metastases was 5.5% and 11.0%, respectively. The ORR was 28.4% with durvalumab versus 16.0% with placebo (P <.001); 72.8% of patients who received durvalumab had ongoing response at 18 months versus 46.8% with placebo.
Grade 3 or 4 adverse events were 29.9% with durvalumab and 26.1% with placebo; pneumonia was the most common event in both groups—4.4% versus 3.8%, respectively. Overall, 15.4% of patients receiving durvalumab and 9.8% of patients receiving placebo discontinued treatment because of an adverse event; pneumonitis or radiation pneumonitis and pneumonia were the most common reason in both groups.
Source: Antonia SJ, Villegas A, Daniel D, et al; for the PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. N Engl J Med. 2017;377:1919-1929.
Commentary by Robert J. Ignoffo
Approximately 33% of patients are diagnosed with stage III NSCLC. Despite multimodality treatment, the 5-year OS is a poor 15%. Although platinum-based doublet chemoradiotherapy is the preferred treatment for patients with good performance status, relapse with metastatic disease is common. Thus, a strategy that prolongs relapse-free survival or prevents relapse is desirable. Targeted drugs, including cetuximab, erlotinib, and crizotinib, have not improved survival in this setting.1
The goal of this study was improved outcomes after definitive adjuvant chemoradiotherapy with durvalumab, a selective, high-affinity, anti–PD-L1 antibody. The PD-L1 antigen is present in a high percentage of patients with NSCLC. The study results were impressive, with an approximate tripling of PFS and almost a doubling of ORR. The PFS was not affected by PD-L1 expression status or by smoking history. The OS results are still pending. Durvalumab is well-tolerated, although 15.4% of patients discontinued treatment because of adverse events, including pneumonitis.
Durvalumab received accelerated approval by the US Food and Drug Administration in May 2017 for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or after platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Durvalumab is currently the only immunotherapy shown to be effective in prolonging PFS after platinum-based chemotherapy.
- Schild SE, Ramalingam SS, Vallières E. Management of stage III non-small cell lung cancer. September 14, 2017. www.uptodate.com/contents/management-of-stage-iii-non-small-cell-lung-cancer. Accessed November 13, 2017.
Olaparib Improves Progression-Free Survival in Metastatic Breast Cancer with BRCA Mutation
BACKGROUND: Olaparib is an oral poly(ADP-ribose) polymerase (PARP) inhibitor indicated for patients with ovarian cancer and BRCA mutation. Olaparib has also demonstrated efficacy in patients with BRCA mutation–positive metastatic breast cancer. The OlympiAD study compared the safety and efficacy of olaparib with single-agent chemotherapy in this setting.
METHODS: This open-label, multicenter, international, phase 3 study included 302 patients with HER2-negative breast cancer and BRCA mutation who had received ≤2 chemotherapy regimens and neoadjuvant or adjuvant treatment or treatment for metastatic disease with an anthracycline and a taxane. Patients were randomized to olaparib 300 mg twice daily or to the physician’s choice single-agent chemotherapy with capecitabine, eribulin, or vinorelbine in 21-day cycles (standard therapy). The primary end point was progression-free survival (PFS), as assessed by an independent central review. The secondary end points included safety outcomes; overall survival (OS); objective response rate (ORR); health-related quality of life, as assessed by the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30); and time to second progression or death after a first progression.
RESULTS: The median PFS was 7.0 months with olaparib and 4.2 months with standard therapy; the hazard ratio for disease progression or death was 0.58 (P <.001). At 12 months, 25.9% of patients who received olaparib were free of disease progression or death versus 15.0% with standard therapy. The median time from a second progression event was 13.2 months and 9.3 months, respectively. The OS was not significantly different between the groups. The ORR was 59.9% and 28.8%, respectively, with 9.0% of patients achieving complete response with olaparib versus 1.5% of patients with standard therapy. The median duration of response was 6.4 months versus 7.1 months, respectively.
Patient-reported outcomes using QLQ-C30 showed that the adjusted mean change in the QLQ-C30 score from baseline was 3.9 with olaparib versus –3.6 with standard therapy. The median time to a clinically meaningful decrease in the QLQ-C30 score was not reached with olaparib versus 15.3 months with standard therapy.
Grade ≥3 adverse events rate was 36.6% with olaparib versus 50.5% with standard therapy. The majority of adverse events with olaparib were grade 1 or 2. Overall, 4.9% of patients who received olaparib discontinued treatment because of adverse events versus 7.7% of patients who received standard therapy.
Source: Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523-533.
This article and the commentary were published in December 2017. On January 12, 2018, the FDA approved olaparib for use in this patient population based on the results of this study.
Commentary by Robert J. Ignoffo
Approximately 5% of patients with breast cancer have a BRCA mutation, which is associated with an aggressive form of the disease, particularly in triple-negative breast cancer. BRCA1 and BRCA2 are tumor-suppressor genes involved in the repair of DNA double-strand breaks, by way of the homologous recombination repair pathway.1 PARP enzymes are important for repairing DNA single-strand breaks. Phase 2 clinical trials of olaparib have shown positive results in metastatic breast cancer with BRCA mutation. This open-label phase 3 study compared olaparib with standard chemotherapy, demonstrating a significant benefit for the PARP inhibitor in terms of PFS but not in OS. Patients receiving olaparib were able to continue therapy for 8.2 months versus only 3.4 months among those receiving chemotherapy. Side effects, occurring in ≥15% of patients, that were more common with olaparib than with standard therapy were anemia, nausea, vomiting, fatigue, headache, and cough; by contrast, neutropenia, palmar-plantar erythrodysesthesia, and increased liver function enzymes were more common with chemotherapy. Grade 3 toxicities were also less common with olaparib than with chemotherapy.
Olaparib is not yet approved by the FDA for breast cancer with BRCA mutation. It appears to be as equally effective as chemotherapy in improving PFS and has a different toxicity profile. Olaparib’s use in this setting will likely be predicated on patient performance status and eventual approval by the FDA.
- Walsh CS. Two decades beyond BRCA1 /2: homologous recombination, hereditary cancer risk and a target for ovarian cancer therapy. Gynecol Oncol. 2015;137:343-350.