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Frontline Pembrolizumab for PD-L1–Positive Gastric Cancer: Kohei Shitara, MD

Kohei Shitara, MD.

Gastric or gastroesophageal junction (G/GEJ) cancer constitutes the third leading cause of cancer death worldwide, and more therapeutic options are needed. In results from the phase 3 KEYNOTE-062 study, published last week in JAMA Oncology, Kohei Shitara, MD, and colleagues reported that in patients with previously untreated G/GEJ cancer with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater, pembrolizumab, alone or in combination with chemotherapy, was noninferior but not superior to chemotherapy alone. In patients with a PD-L1 CPS of 10 or greater, pembrolizumab monotherapy showed a potential benefit, but one that could not be statically tested owing to the study design. In this interview with i3 Health, Dr. Shitara, Chief of the Department of Experimental Therapeutics and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, discusses the KEYNOTE-062 results and other notable research advances in the treatment of PD-L1–positive G/GEJ cancer.

What prompted you to investigate first-line pembrolizumab alone or in combination with chemotherapy for PD-L1–positive advanced G/GEJ cancer?

Kohei Shitara, MD: The phase 2 KEYNOTE-059 study previously showed activity of pembrolizumab for PD-L1–positive G/GEJ cancer with a CPS ≥1, leading to the accelerated FDA approval of pembrolizumab as third-line or later treatment for PD-L1–positive patients. Two phase 2 trials were conducted to confirm the survival benefit of pembrolizumab: KEYNOTE-061 in the second line and KEYNOTE-062 in the first line.

Can you comment on the significance of your results in KEYNOTE-062?

Dr. Shitara: Pembrolizumab monotherapy was noninferior to chemotherapy in terms of overall survival in the CPS ≥1 population, based on a predefined statistical test. However, the overall survival curve clearly crossed the median, the same as in KEYNOTE-061, suggesting that the CPS ≥1 population was a mixed population with various levels of pembrolizumab efficacy. Patients with CPS ≥10 and those with microsatellite instability­–high (MSI-H) tumors suggested a greater treatment effect of pembrolizumab. These results did not lead to official approval of pembrolizumab in the first line.

Were any of the results surprising to you?

Dr. Shitara: Unexpectedly and contradictory to previous KEYNOTE 061 results, Asian versus non-Asian population showed different outcomes to pembrolizumab monotherapy, with longer survival with Asians in the pembrolizumab monotherapy arm. I suspect that better Eastern Cooperative Oncology Group (ECOG) performance status and lower tumor burden are possible reasons behind this difference, but further multifactorial analysis with clinical factors and biomarkers are necessary to correctly interpret the results.

The results for pembrolizumab/chemotherapy combination treatment showed some trend of improvement in overall survival, but this was not statistically significant. This is very disappointing, considering the many successes of chemotherapy combinations in other tumor types, such as non-small cell lung cancer (NSCLC). One pitfall of the study is the complicated statistical plan to spend alpha error for several end points, in addition to a relatively small sample size.

Are there any plans to further investigate first-line pembrolizumab monotherapy in patients with PD-L1 CPS ≥10?

Dr. Shitara: To my knowledge, there are currently no ongoing phase 3 trials with first-line pembrolizumab monotherapy.

What other options are being investigated for PD-L1–positive G/GEJ cancer?

Dr. Shitara: The KEYNOTE-859 study is ongoing to investigate pembrolizumab in combination with oxaliplatin-based first-line chemotherapy. Recently, CheckMate 649 showed that chemotherapy plus nivolumab improved overall survival in CPS ≥5 and in all enrolled patients, suggesting utility of this combination. This is great news for us and for our patients. It may be necessary to discuss differences between the CheckMate 649 and KEYNOTE-062 studies based on statistical plan, patient characteristics, and backbone chemotherapy. We previously reported promising activity of combination therapy with lenvatinib and pembrolizumab for gastric cancer, which will be evaluated in a randomized study in the future.

Can you offer any words of advice to oncologists as they seek to optimize outcomes for their patients with advanced G/GEJ cancer?

Dr. Shitara: Both KEYNOTE-061 and KEYNOTE-062 suggest that optimal patient selection is important to the use of anti–PD-1 monotherapy in earlier treatment lines. Combined positive score is one of the predictive factors, but it is still insufficient, and we need further biomarker research, including tumor mutational burden or immunophenotype. Chemotherapy in combination with anti–PD-1 therapy holds promise based on the press release of CheckMate 649, and optimal population for such treatment should be discussed after disclosure of detailed results.

About Dr. Shitara

Kohei Shitara, MD, is Chief of the Department of Experimental Therapeutics and Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan. Dr. Shitara's primary research interests include the development of new cancer treatments, the optimization of chemotherapy regimens for gastrointestinal cancer, and translational research through the development of molecular targeted agents. Dr. Shitara has published nearly 200 peer-reviewed articles in these fields.

For More Information

Shitara K, Van Cutsem E, Bang YJ, et al (2020). Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. [Epub ahead of print] DOI:10.1001/jamaoncol.2020.3370

Bang YJ , Kang YK , Catenacci DV , et al (2019). Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study. Gastric Cancer, 22(4):828-837. DOI:10.1007/s10120-018-00909-5

Fuchs CS, Özgüroğlu M, Bang YJ, et al (2020). Pembrolizumab versus paclitaxel for previously treated patients with PD-L1–positive advanced gastric or gastroesophageal junction cancer (GC): update from the phase III KEYNOTE-061 trial. J Clin Oncol (ASCO Virtual Scientific Program Abstracts), 38(suppl_15). Abstract 4503. DOI:10.1200/JCO.2020.38.15_suppl.4503

Clinicaltrials.gov (2020). Pembrolizumab (MK-3475) plus chemotherapy versus placebo plus chemotherapy in participants gastric or gastroesophageal junction (GEJ) adenocarcinoma (MK-3475-859/KEYNOTE-859). NLM identifier: NCT03675737.

Bristol Myers Squibb (2020). CheckMate-649, a phase 3 trial evaluating Opdivo (nivolumab) plus chemotherapy vs. chemotherapy, meets primary endpoints demonstrating superior overall survival and progression-free survival in first-line treatment of gastric and esophageal cancer. Available at: https://news.bms.com/news/details/2020/CheckMate--649-a-Phase-3-Trial-Evaluating-Opdivo-nivolumab-Plus-Chemotherapy-vs.-Chemotherapy-Meets-Primary-Endpoints-Demonstrating-Superior-Overall-Survival-and-Progression-Free-Survival-in-First-Line-Treatment-of-Gastric-and-Esophageal-Cancers/default.aspx

Kawazoe A, Fukuoka S, Nakamura Y, et al (2020). Lenvatinib plus pembrolizumab in patients with advanced gastric cancer in the first-line or second-line setting (EPOC1706): an open-label, single-arm, phase 2 trial. Lancet Oncol, 21(8):1057-1065. DOI:10.1016/S1470-2045(20)30271-0.

Kumagai S, Togashi Y, Kamada T, et al (2020). The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies. Nat Immunol. [Epub ahead of print] DOI:10.1038/s41590-020-0769-3

Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily represent those of i3 Health.

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