Clinical Trials Study the Role of Immunotherapy in the First-Line Setting of Non–Small Cell Lung Cancer


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In 2016, the KEYNOTE-024 trial set the bar for first-line immunotherapy in non–small cell lung cancer (NSCLC). Trial results showed that pembrolizumab (Keytruda), an antibody to programmed cell death protein 1 (PD-1), reduced the risk of disease progression or death by 50% and the risk of death by 40% relative to chemotherapy in patients with untreated advanced disease having at least 50% of tumor cells positive for programmed cell death ligand 1 (PD-L1) and lacking any sensitizing epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) aberrations.1

As a result of these impressive data, pembrolizumab became the first immune checkpoint inhibitor to be approved by the U.S. Food and Drug Administration (FDA) for first-line therapy in NSCLC. Will it be possible to improve on its performance? A trio of trials evaluating new antibodies and antibody combinations have set their sights on this goal.

CheckMate 012: Two Inhibitors Better Than One?

Combining two checkpoint inhibitors that unleash the immune system’s antitumor response by different mechanisms may be more efficacious than using just one of them as first-line therapy for NSCLC, suggests an update of the CheckMate 012 trial.2


The addition of ipilimumab to nivolumab appeared to result in a higher overall response rate, longer progression-free survival, and at least numerically higher 1-year overall survival rates.
— Scott N. Gettinger, MD

The phase I trial tested the combination of nivolumab (Opdivo), an antibody to PD-1, and ipilimumab (Yervoy), an antibody to cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) that primes the immune system by inducing tumor infiltration of effector T cells and depleting suppressor cells in the tumor microenvironment.

“The combination of nivolumab and ipilimumab has demonstrated increased clinical activity compared to either agent alone across tumor types, most notably for melanoma, where it is approved for use,” noted lead author Scott N. Gettinger, MD, Associate Professor of Medicine (Medical Oncology) at the Yale Cancer Center in New Haven, Connecticut.

Dr. Gettinger reported updated data for 129 patients from three of CheckMate 012’s many cohorts: nivolumab at 3 mg/kg monotherapy every 2 weeks; nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 12 weeks; and nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks. Initial results were reported after a median follow-up of about 12 months.3

With a median follow-up now of 22 months in the monotherapy cohort and 16 months in the two combination therapy cohorts pooled, the overall response rates were 23% and 43%, respectively. For each, the rate increased with tumor PD-L1 expression, from 13% and 21%, respectively, in patients with < 1% expression, to 28% and 57% in patients with ≥ 1% expression, and finally to 50% and 92% in patients with ≥ 50% expression.

Median progression-free survival was 3.6 months in the monotherapy cohort and more than twice that, 8.0 months, in the pooled combination cohort. Values were similar or higher in analyses restricted to patients with ≥ 1% PD-L1 positivity (3.5 and 12.7 months) and with ≥ 50% PD-L1 positivity (8.3 months and not reached).

Novel First-Line Immunotherapies for NSCLC

  • In the CheckMate 012 trial, median progression-free survival was 3.6 months with nivolumab monotherapy and 8.0 months with nivolumab/ipilimumab combination therapy among 129 patients unselected with respect to PD-L1 expression.
  • In the BIRCH trial, the overall response rate with atezolizumab was 25% in 138 patients with PD-L1 positivity of 2 or 3 in tumor cells or tumor-infiltrating immune cells.
  • In the JAVELIN Solid Tumor trial, the overall response rate with avelumab was 22.4% in 156 patients unselected with respect to PD-L1 expression.

The 1-year overall survival rate was 73% with monotherapy and 76% with combination therapy. Corresponding values were 69% and 87% among patients with ≥ 1% PD-L1 positivity and 83% and 100% among patients with ≥ 50% PD-L1 positivity.

“Not surprisingly, we saw slightly higher grade 3 or 4 toxicity rates with the combination, but these toxicities were manageable,” Dr. Gettinger reported. Adverse events of these grades occurred in 19% of patients with monotherapy, 42% with the less-frequent combination therapy, and 31% with the more-frequent combination therapy.

“The addition of ipilimumab to nivolumab appeared to result in a higher overall response rate, longer progression-free survival, and at least numerically higher 1-year overall survival rates,” he summarized. “Efficacy with nivolumab plus ipilimumab was enhanced with increasing tumor PD-L1 expression, although we did see activity in patients whose tumors did not exhibit PD-L1 expression.”

“We are going to go forward with nivolumab every 2 weeks and ipilimumab at 1 mg/kg every 6 weeks in further trials evaluating this combination,” including the CheckMate 227 trial, noted Dr. Gettinger.

BIRCH: Durable Efficacy of Atezolizumab

Atezolizumab (Tecentriq), an antibody to PD-L1 approved by the FDA for second-line use in NSCLC regardless of tumor PD-L1 status, produced long-lasting responses when used as first-line therapy for PD-L1–positive NSCLC, according to updated data from the phase II BIRCH trial.4

Patients in the trial had tumors showing higher PD-L1 expression by immunohistochemistry using a scale of 0 to 3, with a score of either 2 or 3 in tumor cells (TCs) or tumor-infiltrating immune cells (ICs). All were treated with atezolizumab every 3 weeks.


These results indicate that single-agent atezolizumab has durable efficacy in the first-line setting.
— Marina C. Garassino, MD

With a median follow-up of 22.5 months among the 138 patients being treated in the first-line setting, the overall response rate was 25% (18% with TC2/IC2 and 34% with TC3/IC3), reported first author Marina C. Garassino, MD, Medical Director of the IRCCS Istituto Nazionale dei Tumori Foundation, Milan, Italy. The median duration of response was 16.5 months.

Median progression-free survival was 7.3 months, and the 12-month rate was 32.5%. Median overall survival was 23.5 months (26.9 months with TC3/IC3), and the 12-month rate was 66.4% (61.5% with TC3/IC3).

Although 60% of patients had a treatment-related adverse event, few of these events were grade 3 or 4. The most common immune-mediated adverse events of any grade were rash (7%) and hypothyroidism (5%).

“These results indicate that single-agent atezolizumab has durable efficacy in the first-line setting,” Dr. Garassino maintained. “Atezolizumab was well tolerated, and the safety profile was similar to the other anti–PD-1 and anti–PD-L1 compounds and all the other atezolizumab NSCLC studies.”

“We are awaiting the final results for the phase III trial evaluating atezolizumab as a single agent over chemotherapy in the first-line setting,” said Dr. Garassino, referring to the IMpower 110 trial.

JAVELIN Solid Tumor: Avelumab Active

Avelumab (MSB0010718C), an investigational anti–PD-L1 antibody, has good activity when used to treat NSCLC in the first-line setting, according to early findings of the JAVELIN Solid Tumor trial.5

The phase I multicohort dose-escalation and dose-expansion trial enrolled patients with various tumor types. “This is probably the biggest phase I study in the world, with over 1,700 patients,” noted senior author Claire F. Verschraegen, MD, Medical Director of Hematology and Oncology at the University of Vermont Cancer Center in Burlington.

She reported findings for 156 patients with advanced NSCLC treated in the first-line setting. They were unselected with respect to PD-L1 expression (56.4% had positive tumors using the cutoff of ≥ 1% of cells staining), but they could not have any activating EGFR or ALK aberrations.

Patients were treated with avelumab every 2 weeks. “This monoclonal antibody preserves the antibody-dependent cellular cytotoxicity, which may give an additional advantage for immune stimulation by this agent,” Dr. Verschraegen noted.


[Avelumab] preserves antibodydependent cellular cytotoxicity, which may give an additional advantage for immune stimulation by this agent.
— Claire F. Verschraegen, MD

With a median treatment duration of 20 weeks and a minimum follow-up of 13 weeks, the overall response rate was 22.4%. Eighty percent of patients who had a response experienced their response by the time of their second assessment. Median progression-free survival was 17.6 weeks, and the 24-week rate was 37.2%.

“Treatment-related adverse events were very mild, similar to atezolizumab,” Dr. Verschraegen reported. The rate of any-grade events was 66%, and the rate of grade 3 or 4 events was 10.9%. Overall, 10.3% of patients had potentially immune-related events.

“These are very preliminary results. We need more time to define the results better,” she acknowledged.

“Currently, a phase III trial is ongoing, comparing single-agent avelumab with first-line chemotherapy in NSCLC,” she added, referring to the JAVELIN Lung 100 trial. ■

Disclosures: Claire F. Verschraegen reported no potential conflicts of interest. Scott N. Gettinger, MD, has received institutional research funding and consulting fees from Bristol-Myers Squibb. Marina C. Garassino, MD, has received research support from Pfizer and is a consultant for AstraZeneca, Bristol-Myers Squibb, Celgene, Roche, Merck Sharp & Dohme, and Eli Lilly.

References

1. Reck M, Rodríguez-Abreu D, Robinson AG, et al: Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med 375:1823-1833, 2016.

2. Gettinger SN, Rizvi N, Chow LQ, et al: First-line nivolumab monotherapy and nivolumab plus ipilimumab in patients with advanced NSCLC: Long-term outcomes from CheckMate 012. 2016 World Conference on Lung Cancer. Abstract OA03.01. Presented December 5, 2016.

3. Hellmann MD, Rizvi NA, Goldman JW, et al: Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): Results of an open-label, phase 1, multicohort study. Lancet Oncol 18:31-41, 2017.

4. Garassino MC, Rizvi N, Besse B, et al: Atezolizumab as 1L therapy for advanced NSCLC in PD-L1–selected patients: Updated ORR, PFS and OS data from the BIRCH study. 2016 World Conference on Lung Cancer. Abstract OA03.02. Presented December 5, 2016.

5. Jerusalem G, Chen FL, Spigel D, et al: JAVELIN Solid Tumor: Safety and clinical activity of avelumab (anti-PD-L1) as first-line treatment in patients with advanced NSCLC. 2016 World Conference on Lung Cancer. Abstract OA03.03. Presented December 5, 2016.


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