August 2014, Vol 3, No 5
Anti–PD-1 Antibodies in NSCLC and Renal Cell Carcinoma
Attendees at ASCO got a look at maturing data for the anti–PD-1 monoclonal antibody nivolumab in non–small cell lung cancer (NSCLC) and at early results for this drug in other tumor types. They also heard early results for pembrolizumab. In phase 1 and 2 trials, these immunotherapies made a strong showing.
The phase 1 multicohort CA209-012 trial evaluated nivolumab as a single agent and in combination with ipilimumab, chemotherapy, and erlotinib. Nivolumab monotherapy in the first-line setting produced responses in 30% of patients, with median duration of response not reached. “Responses are ongoing in 4 of 6 (67%) responders,” reported Scott Gettinger, MD, of Yale Cancer Center, New Haven, CT.
Progression-free survival (PFS) at 24 weeks was 60%, median PFS was 47.2 weeks in patients with nonsquamous histology and 15.1 in those with squamous tumors; 1-year overall survival (OS) was 75%, and median OS was not reached at the time of analysis.
All the responders expressed the PD-L1 ligand, ie, were “PD-L1–positive,” which some believe might serve as a biomarker of activity. In this subgroup, the results were most impressive, with 1-year OS of 80%.
Nivolumab Plus Ipilimumab
Could 2 immune checkpoint inhibitors be better than 1? That question was asked in 1 cohort of the CA209-012 trial involving 49 chemotherapy-naive patients treated with nivolumab plus ipilimumab, followed by nivolumab monotherapy until progression. Depending on dose and histology, objective responses were observed in 11% to 33% of patients. Responses were ongoing in 75% of responders at the time of analysis.
At 24 weeks, median PFS ranged from 20% to 51%, and median PFS was 14.4 to 16.1 weeks. Median OS was 44 weeks in one subset and was not reached in the other arms. Response rates and median PFS were similar whether patients were PD-L1–positive or PD-L1–negative.
“The findings suggest this combination may be suitable for PD-L1–positive and –negative patients,” according to Scott Antonia, MD, of H. Lee Moffitt Cancer Center, Tampa, FL.
Nivolumab Plus Chemotherapy or Erlotinib
Antonia also presented results on the 56 patients who received nivolumab plus a platinum-based chemotherapy doublet, followed by nivolumab until progression. Responses were observed in 33% to 47% of patients in both squamous and nonsquamous histology subsets. Outcomes were most impressive in the subgroup receiving pemetrexed/cisplatin plus nivolumab 10 mg/kg, with a 24-week PFS rate of 71% and 1-year OS of 87%.
Another cohort of 21 patients was treated with nivolumab combined with erlotinib. Responses were observed in 19%, 3 ongoing at the time of analysis, with an estimated duration of response of more than 1 year. PFS at 24 weeks was 51%, median PFS was 29.4 weeks, 1-year survival was 73%, and median OS was not yet reached.
“Responses were seen in patients who had previously received multiple lines of EGFR inhibitor therapy, as well as patients with T790M mutations [which are difficult to treat],” said Naiyer A. Rizvi, MD, of Memorial Sloan Kettering Cancer Center, New York City.
Combining PD-1 blockade with therapies that target mutant EGFR signaling may enhance responses and provide durable benefit, the authors concluded.
Pembrolizumab (MK-3475) in Previously Treated Patients
Another phase 1 study of 217 previously treated patients with NSCLC found strong antitumor activity for pembrolizumab. The objective response rate was 20% and was higher among patients expressing PD-L1 (23%) versus those who did not (9%). Of the PD-L1–positive patients who responded, 82% remain on treatment, according to Edward B. Garon, MD, of the University of California, Los Angeles.
Nivolumab in Renal Cell Carcinoma
Results from the phase 2 CheckMate-010 trial in advanced kidney cancer showed that single-agent nivolumab produced responses in 20% to 22% of patients and yielded 1-year survival rates of 63% to 72% in patients with prior antiangiogenic treatment. In previously treated patients, median OS was 25 months with 2 mg/kg dosing.
In a phase 1b trial of previously treated as well as treatment-naive patients, nivolumab combined with ipilimumab produced responses in 43% to 48% and was associated with 24-week PFS rate of 65%.
“These data are encouraging as we seek to identify new treatments for patients, particularly those who progress following treatment with antiangiogenic therapy, as they have limited options,” said Robert Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York City.
Tolerability of Anti–PD-1 Agents
The toxicities associated with anti–PD-1 agents are primarily immune-related and transient, though some can be concerning, the investigators acknowledged.
As a single agent, nivolumab was associated with adverse events in 85% of patients, but only 20% were grade 3/4. For the combination of nivolumab and ipilimumab, grade 3/4 adverse events were reported by 49% across the arms, primarily during induction, not maintenance. Pneumonitis grade 3/4 occurred in 6% and was reversible. Serious diarrhea and colitis occurred in 8%, and liver enzymes were elevated in 6%. One-third of patients discontinued due to adverse events, and 3 patients died of drug-related toxicities (1 each from colitis, pulmonary hemorrhage, and toxic epidermal necrolysis).
When given with chemotherapy, treatment-related grade 3/4 adverse events occurred in 45%, most commonly pneumonitis, fatigue, and acute renal failure. Many were laboratory abnormalities reported in 1 patient each. In combination with erlotinib, the toxicities were predictable.
With pembrolizumab, almost two-thirds of patients had at least 1 drug-related adverse event of any grade, and 10% had grade 3/4 toxicity. Grade 3/4 pneumonitis was observed in 4 patients.
Investigators of the studies have suggested that clinicians can learn to manage the immune-related toxicities associated with anti–PD-1 agents.
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