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Immunotherapy Combinations Gain Traction in Lung Cancer


Combining immunotherapies with each other or with other agents such as chemotherapy and growth factor inhibitors holds promise for better tapping their benefit in patients with lung cancer, data from several studies suggest. Results show that strategic combinations can achieve higher response rates, more durable responses, and may make immunotherapy an option for a broader population of patients. Here we review some of the data from three trials presented at the International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer.

Pembrolizumab/Chemotherapy in Nonsquamous NSCLC

The multicohort randomized phase II KEYNOTE-021 trial evaluated combinations of pembrolizumab (Keytruda), an immune checkpoint inhibitor of programmed cell death protein 1 (PD-1), with chemotherapy and various other agents among patients with non–small cell lung cancer (NSCLC).

“We know that concomitant chemotherapy with [immune] checkpoint blockade can lead to release of tumor antigen and potential stimulation of the immune system,” explained first author Corey J. Langer, MD, Director of Thoracic Oncology and Professor of Medicine at the Hospital of the University of Pennsylvania in Philadelphia.


This combination of pembrolizumab and chemotherapy could conceivably be an effective treatment option for chemotherapy-naive advanced nonsquamous NSCLC.
— Corey J. Langer, MD

He reported results for 123 patients with advanced nonsquamous NSCLC without epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) aberrations who were treated in the first-line setting with carboplatin and pemetrexed (Alimta) chemotherapy, with or without pembrolizumab. All were permitted to receive pemetrexed as maintenance therapy.

After a median follow-up of 10.6 months, in the intent-to-treat population, the overall response rate was 55% with chemotherapy plus pembrolizumab, compared with 29% with chemotherapy alone (P = .0016).1,2

The rate with the combination was similar for patients whose tumors were negative and positive for the programmed cell death ligand 1 (PD-L1) biomarker using the ≥ 1% cutoff for positivity (57% and 54%). However, it was 80% in the subset whose tumors were strongly positive at the ≥ 50% cutoff, vs 35% with chemotherapy alone.

Progression-free survival was superior with the combination as compared with chemotherapy alone (median, 13.0 vs 8.9 months; hazard ratio, 0.53). Overall survival did not differ (75% and 72% at 1 year), but the trial was not powered for this outcome, Dr. Langer cautioned.

Toxicities were somewhat more common when pembrolizumab was added to chemotherapy, although patients were also on treatment for a longer time. The rate of grade 3 or worse treatment-related adverse events was 39% with the combination vs 26% with chemotherapy alone. Possibly immune-related adverse events of any grade included hypothyroidism (15% with the combination and 5% with chemotherapy alone), hyperthyroidism (8% and 2%), and pneumonitis (5% and 0%).

“This combination could conceivably be an effective treatment option for chemotherapy-naive advanced nonsquamous NSCLC. And there is in fact an ongoing phase III trial that is about two-thirds accrued looking at chemotherapy alone or chemotherapy plus pembrolizumab,” Dr. Langer pointed out, referring to KEYNOTE-189.

Nivolumab/Ipilimumab in Small Cell Lung Cancer

The phase I/II CheckMate 032 trial is evaluating dual immunotherapy in patients with recurrent small cell lung cancer, testing nivolumab (Opdivo), another PD-1 inhibitor, combined with ipilimumab (Yervoy), an immune checkpoint inhibitor of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4).

Matthew D. Hellmann, MD, a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York, reported updated results for 159 patients treated with nivolumab monotherapy or in combination with ipilimumab (nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg for four doses, followed by nivolumab at 3 mg/kg every 2 weeks as monotherapy). With this update, the respective median follow-up durations were 15.7 and 21.0 months, respectively.3


Survival with nivolumab, with or without ipilimumab, represents a promising step forward for patients with small cell lung cancer.
— Matthew D. Hellmann, MD

The overall response rate was 25% with the combination (up slightly from the 23% at last presentation4) and 11% with monotherapy. “Response rates were similar in those with platinum-sensitive and -resistant disease and by line of therapy,” he noted. The respective median duration of response was 11.7 months and not reached.

The estimated 2-year overall survival rate was 30% with the nivolumab/ipilimumab combination and 17% with nivolumab alone. This survival rate has seldom exceeded 10% in previous trials of other therapies in this patient population, Dr. Hellmann commented.

“In many, but not all, diseases, PD-L1 expression is associated with an increased likelihood of benefit from anti–PD-1 therapies. However, that does not appear to be the case in small cell lung cancer,” he noted. Overall survival was similar whether patients had tumor PD-L1 expression below or above the ≥ 1% cutoff for positivity; moreover, only a minority of patients (17%) with small cell lung cancer had tumor PD-L1 expression exceeding 1%.

Rates of treatment-related toxicity of any grade and of grade 3 or 4 were higher with the combination, but the rate of events leading to treatment discontinuation was low overall, 11% with the combination and 5% with monotherapy. There were two treatment-related deaths in the combination arm (including one from myasthenia gravis).

Immunotherapy Combinations for Lung Cancer

  • Among 123 patients with untreated advanced nonsquamous NSCLC in the KEYNOTE-021 trial, the overall response rate was 55% with chemotherapy and pembrolizumab, compared with 29% with chemotherapy alone.
  • Among 159 patients with recurrent small cell lung cancer in the CheckMate 032 trial, the overall response rate was 25% with the combination of nivolumab and ipilimumab, compared with 11% with nivolumab alone.
  • Among 34 patients with previously treated nonsquamous NSCLC in the KEYNOTE-099 trial, the overall response rate was 29.4% with the combination of pembrolizumab and necitumumab.

“Survival with nivolumab, with or without ipilimumab, represents a promising step forward for patients with small cell lung cancer, with an estimated 2-year overall survival of 30% in patients treated with combination immunotherapy. This result is simply not possible with other types of anticancer therapy in late-stage disease,” Dr. Hellmann maintained. “But still, work is desperately needed to identify predictors of response, especially as PD-L1 does not appear to associate with benefit in this disease.”

“On the basis of this efficacy and safety, nivolumab with or without ipilimumab was recently added to the National Comprehensive Cancer Network® Guidelines for the treatment of recurrent small cell lung cancer,”5 he pointed out. “Additionally, expansion in this study with 250 additional patients with second- and third-line small cell lung cancer randomized to receive nivolumab alone or nivolumab/ipilimumab has recently completed accrual, and initial results are expected in 2017.”

Pembrolizumab/Necitumumab in Nonsquamous NSCLC

The phase Ib I4X-MC-JFCQ trial is testing the combination of pembrolizumab with necitumumab (Portrazza), an antibody against EGFR in patients with metastatic NSCLC who have received at least one prior line of therapy. Benjamin Besse, MD, PhD, Head of the Thoracic Pathology Committee and medical oncologist at the Gustave Roussy Cancer Campus in Villejuif, France, reported interim results for the 34 patients with nonsquamous NSCLC.6


This combination of pembrolizumab and necitumumab seems to be active whatever the expression of PD-L1 by the tumor, and there were no particular additive toxicities.
— Benjamin Besse, MD, PhD

The overall response rate was 29.4% in this cohort. It was above average among patients who were current or former smokers (37%), whose tumors were mostly negative for PD-L1 (50% PD-L1–negative, 15% weakly positive, 15% strongly positive, and 20% unknown), and who received more than two lines of chemotherapy in 56% of the cases. With a median follow-up of 6.0 months, the median progression-free survival was 6.9 months, and the 6-month rate was 55.1%, Prof. Besse reported.

“The side effects recapitulate the side effects of both pembrolizumab and necitumumab,” he noted. The most common grade 3 or 4 treatment-emergent adverse events included hypomagnesemia (9%), rash (9%), and venous thromboembolism (9%), which were likely related to necitumumab, he said.

“This combination seems to be active whatever the expression of PD-L1 by the tumor, and there were no particular additive toxicities to be noted. Data in squamous NSCLC, another population treated in this phase Ib trial, will be presented later,” Prof. Besse concluded. ■

Disclosure: Dr. Langer’s institution receives research support from Advantagene, Clovis, Genentech/Roche, GlaxoSmithKline, Inovio, and Merck; is an advisor to Ariad, AstraZeneca, Bristol-Myers Squibb, Celgene, Clovis, and Genentech/Roche; and is on data safety monitoring committees for AbbVie, Amgen, Lilly, Peregrine, SWOG, and Synta. Dr. Hellmann is a consultant to AstraZeneca, Bristol-Myers Squibb, Genentech, Janssen, Merck, and Novartis and has received research funding from Bristol-Myers Squibb and Genentech. Prof. Besse has received research funding from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis Oncology, Eli Lilly, GlaxoSmithKline, Onxeo, Pfizer, Puma Biotechnology, Roche/Genentech, and Servier; and has received expenses from Bristol-Myers Squibb/Medarex, Novartis, Pfizer, Pierre Fabre, and Roche. 

References

1. Langer C, Gadgeel SM, Borghaei H, et al: Pembrolizumab + carboplatin and pemetrexed as 1st-line therapy for advanced non–small cell lung cancer: KEYNOTE-021 cohort G. 2016 World Conference on Lung Cancer. Abstract MA09.02. Presented December 6, 2016.

2. Langer CJ, Gadgeel SM, Borghaei H, et al: Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: A randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 17:1497-1508, 2016. 

3. Hellmann MD, Antonia SJ, Ponce S, et al: Nivolumab alone or with ipilimumab in recurrent small cell lung cancer: 2-year survival and updated analyses from the CheckMate 032 trial. 2016 World Conference on Lung Cancer. Abstract MA09.05. Presented December 6, 2016.

4. Antonia SJ, Lopez-Martin JA, Bendell JC, et al: Checkmate 032: Nivolumab alone or in combination with ipilimumab for the treatment of recurrent small cell lung cancer. 2016 ASCO Annual Meeting. Abstract 100.

5. National Comprehensive Cancer Network® (NCCN®): NCCN Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer. v2.2017. Available at https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Accessed February 22, 2017.

6. Besse B, Garrido P, Puente J, et al: Efficacy and safety of necitumumab and pembrolizumab combination therapy in stage IV nonsquamous non-small cell lung cancer. 2016 World Conference on Lung Cancer. Abstract MA09.11. Presented December 6, 2016.


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