Expert Point of View: David Planchard, MD, PhD, Luboš Petruželka, MD, PhD, and Clarissa ­Baldotto, MD, MSc


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Three invited discussants explored the results of these recent immunotherapy studies in lung cancer as well as their potential clinical implications at the International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer.

KEYNOTE-021 trial

“Pembrolizumab (Keytruda) is currently approved in the first-line setting for patients with a high expression of programmed cell death ligand 1 (PD-L1). Nevertheless, many patients do not have a good response to immunotherapy approaches or can’t receive it,” for example, because their tumor PD-L1 expression does not meet the ≥ 50% threshold, noted invited discussant David Planchard, MD, PhD, of the Department of Medical Oncology (Thoracic Unit), Institut-Gustave Roussy, in Villejuif, France. “Alternative strategies are required to achieve optimal therapeutic benefit.”


KEYNOTE-021 is a nice phase II trial, but a very positive phase II trial may not be positive in a phase III trial.
— David Planchard, MD, PhD

The 55% response rate seen in KEYNOTE-021 with the combination of pembrolizumab and chemotherapy regardless of tumor PD-L1 status exceeded the 45% seen with pembrolizumab alone in the similar KEYNOTE-024 among patients having PD-L1 expression of ≥ 50%, he noted.1 Although the 80% response rate in patients with ≥ 50% expression was “quite impressive,” that group was small, so more data are needed.

“There is a clear benefit in terms of progression-free survival,” but the impact on overall survival is uncertain, according to Dr. Planchard. “We should be cautious that there was a lot of censoring of data due to benefit in terms of overall survival,” as patients in the chemotherapy alone group could go on to receive pembrolizumab.

The observed rates of grade 3 and 4 toxicity—39% with chemotherapy plus pembrolizumab and 26% with chemotherapy alone—are similar or higher than the 26% seen with pembrolizumab alone in the KEYNOTE-024 trial.1

“This is only a phase II trial. It’s a nice phase II trial…, but a very positive phase II trial may not be positive in a phase III trial, so it’s important to await the results of the phase III trial, which is ongoing,” he summarized. “And there are numerous other trials ongoing with the combination of programmed cell death protein 1 (PD-1) or PD-L1 inhibitors and chemotherapy.”

CheckMate 032

The updated CheckMate 032 data show “encouraging survival” in small cell lung cancer with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), according to invited discussant Luboš Petruželka, MD, PhD, of the First Faculty of Medicine, Charles University Prague in the Czech Republic.

Luboš Petruželka, MD, PhD

Luboš Petruželka, MD, PhD

“Immune checkpoint blockade in small cell lung cancer seems to be a light at the end of the tunnel because in contrast to non–small cell lung cancer (NSCLC), few advances have been made in the systemic treatment of small cell lung cancer,” he commented. “Scientific interest and research funding have been mainly directed toward NSCLC, and small cell lung cancer seems to have been forgotten.”

“Adding anti–CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] to anti–PD-1 therapy is among the most promising approaches for improving survival in recurrent small cell lung cancer,” Dr. Petruželka maintained. However, “the role of PD-L1 as a potential biomarker for patient selection still remains unclear, and further research is needed.”

“There are other ongoing studies based on these encouraging results. And we are especially waiting for studies that have just finished and will be presented next year,” he concluded, pointing to CheckMate 451 (a phase III trial of nivolumab or nivolumab/ipilimumab as maintenance therapy in extensive-stage small cell lung cancer after first-line chemotherapy) and CheckMate 331 (a phase III trial of nivolumab vs chemotherapy in relapsed small cell lung cancer after first-line chemotherapy).

KEYNOTE-099

In KEYNOTE-099, “PD-L1 status was determined and apparently did not correlate with the results of the trial, but epidermal growth factor receptor [EGFR] status was not determined in this trial,” commented invited discussant Clarissa ­Baldotto, MD, MSc, Medical Director of Grupo COI, Integrated Oncology Clinics, in Rio de Janeiro, Brazil. This might be important, as previous data from a squamous NSCLC population suggest that benefit of necitumumab (Portrazza) is restricted to patients with EGFR-positive tumors.2

Clarissa Baldotto, MD, MSc

Clarissa Baldotto, MD, MSc

Reassuringly, the safety profile seen with the combination of pembrolizumab and necitumumab was similar to what would be expected with the individual agents, so combining them does not seem to have produced new toxicity, she said.

The median progression-free survival of 6.9 months with the combination compares with 3.7 months in patients overall and 6.3 months with pembrolizumab alone in those with high PD-L1 expression in the KEYNOTE-001 trial,3 Dr. Baldotto noted. Similarly, the response rates seen (29.4% overall and 40% with strongly positive PD-L1 expression) compare with 19.4% overall and 45.2% with high PD-L1 expression in that earlier trial.

Therefore, “when looking at efficacy, we need to wait for further data to decide whether what we are looking at is really the combination or just the isolated activity of pembrolizumab,” she concluded. ■

Disclosure: Dr. Planchard has served as a consultant for AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, GSK, Lilly, MSD, Pfizer, Roche, Sanofi, Pierre Fabre, Merck, and Novartis. Dr. Petruželka reported no potential conflicts of interest. Dr. Baldotto has served as an advisor to MSK, Roche, Bristol-Myers Squibb, Boehringer Ingelheim, and AstraZeneca; and received travel expenses from MSD.

References

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

2. Paz-Ares L, et al: Subgroup analyses of patients with epidermal growth factor receptor (EGFR)-expressing tumors in SQUIRE. 2016 European Lung Cancer Conference. Abstract 132O_PR.

3. Garon EB, et al: Pembrolizu­mab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018-2028, 2015.


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