In advanced gastric cancer and gastroesophageal junction cancer, treatment options remain limited. Results of the phase 3 CheckMate 649 and phase 2/3 ATTRACTION-4 studies, both of which investigated chemotherapy with or without nivolumab in patients with previously untreated unresectable, advanced, or recurrent gastric/gastroesophageal junction (G/GEJ) cancer, were recently presented at the European Society of Medical Oncology (ESMO) Virtual Congress 2020. CheckMate 649 reported significant improvements in overall survival and progression-free survival for nivolumab/chemotherapy in 955 patients with human epidermal growth factor receptor 2 (HER2)-negative disease and a programmed death–ligand 1 (PD-L1) combined positive score (CPS) ≥5. ATTRACTION-4 reported significant improvements in median progression-free survival but not in median overall survival for nivolumab/chemotherapy in 724 Asian patients with HER2-negative disease, regardless of PD-L1 status. In this interview with i3 Health, Kohei Shitara, MD, an investigator on both studies, discusses the trials' results, adverse events of concern with nivolumab/chemotherapy, and ongoing research in advanced G/GEJ cancer.
What are the greatest challenges of treating patients with unresectable, advanced, or recurrent G/GEJ cancer?
Kohei Shitara, MD: Chemotherapy is the standard treatment for patients with unresectable, advanced, or recurrent gastric/GEJ cancer. However, treatment options are still limited. Doublet chemotherapy with fluoropyrimidines and platinum agents has been the most widely used first-line treatment for multiple decades. However, reported median survival was usually less than one year in past global trials. Trastuzumab is approved for HER2-positive disease, but only 15% of patients have HER2-positive disease. Therefore, new front-line treatments which could improve survival are eagerly awaited.
Can you comment on the significance of your results in CheckMate 649 and ATTRACTION-4?
Dr. Shitara: CheckMate 649 is a large, global phase 3 trial to compare doublet chemotherapy––CAPOX (capecitabine/oxaliplatin) or FOLFOX (leucovorin/fluorouracil/oxaliplatin)––with nivolumab versus chemotherapy alone as first-line treatment for HER2-negative G/GEJ/esophageal adenocarcinoma. Progression-free survival and overall survival of patients with PD-L1 CPS ≥5, the study's coprimary end points, were significantly improved with the combination therapy. Of note, the median overall survival of the combination treatment was 14.4 months; thus, this is the first global study for the HER2-negative population that has produced a median survival exceeding one year. Secondary end points of overall survival in patients with CPS ≥1 and in all patients were also improved. Objective responses were also higher by 15% with the combination therapy.
ATTRACTION-4 is an Asian phase 2/3 trial to investigate chemotherapy (CAPOX or S-1 plus oxaliplatin) with or without nivolumab. The trial was conducted in Japan, Korea, and Taiwan. Progression-free survival, a primary end point, was significantly improved with the combination therapy, but the difference in overall survival, another primary end point, was not significant. Of note, median overall survival exceeded 17 months in both treatments, with higher usage of post-study chemotherapy including immune checkpoint inhibitor than CheckMate 649, which might dilute the survival difference. Further exploratory sensitive analysis taking into account the usage of post-study anti–programmed cell death protein 1 (PD-1) therapy may be helpful to interpret the overall survival result of ATTRACTION-4. Also, it would be good to analyze CPS status. But progression-free survival benefit is apparent, which supports the use of this combination in the Asian population. I believe that these results showed clinically meaningful efficacy of chemotherapy plus nivolumab as first-line treatment for G/GEJ cancer.
What adverse events are of particular concern for patients with unresectable, advanced, or recurrent G/GEJ cancer being treated with nivolumab plus chemotherapy, and how are these best managed?
Dr. Shitara: Grade 3/4 or higher adverse events were increased with combination therapy in both CheckMate 649 and ATTRACTION-4 by around 10%, but they were reported to be manageable, without new safety signals. Looking at the details, adverse events in the endocrine, hepatic, gastrointestinal, and skin systems are increased by around 10% in both trials, suggesting immune-related toxicities due to the addition of nivolumab. When we encounter these events, it is important to consider causality of each drug because immune-related toxicities sometimes require administration of corticosteroids.
What questions do you encounter from patients with advanced G/GEJ cancer, and how do you counsel them?
Dr. Shitara: If I am asked by patients for the best treatment for unresectable G/GEJ cancer, I would recommend chemotherapy plus nivolumab based on the Checkmate 649 trial.
What further research needs to be done regarding chemotherapy plus nivolumab for this patient population?
Dr. Shitara: One clinical question is whether chemotherapy plus nivolumab should be recommended for patients with CPS ≥5 or for all patients. We may need further discussion looking at outcomes in the CPS <5 or PD-L1–negative population. Another question is the exact long-term outcome after this combination therapy. The CheckMate 649 trial met the primary end points at the interim analysis; thus, follow-up was relatively short. Longer follow-up might be helpful to discuss two-year survival rates or tails of survival curves. Also, the trial is still ongoing to evaluate combination therapy with nivolumab and ipilimumab, so let's wait to see how the results play out.
An additional issue is that the reasons underlying the difference in results between Checkmate 649/ATTRACTION-4 and the negative KEYNOTE-062 trial with first-line pembrolizumab remain unclear, although statistical plan, number of patients, backbone platinum agents, or difference in post-study treatments may be possible reasons for the contrasting outcomes. Overall, I think that results from Checkmate 649 and ATTRACTION-4 are sufficient to recommend first-line chemotherapy plus nivolumab for G/GEJ cancer patients.
What other research looks promising in advanced G/GEJ cancer?
Dr. Shitara: After the introduction of front-line chemotherapy plus nivolumab, further research is important to clarify the resistance mechanisms to this combination and develop additional treatments to overcome them. Since CheckMate 649 excluded patients with HER2-positive status, combinations of HER2-targeting therapy and chemotherapy warrant further investigation. Based on promising results from a phase 2 study, the phase 3 KEYNOTE-811 trial is ongoing. 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. Finally, several trials are now ongoing to investigate PD-1 inhibitors in the perioperative setting, and I am looking forward to seeing the results in the near future.
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
Moehler M, Shitara K, Garrido M, et al (2020). Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Ann Oncol (ESMO Virtual Congress Abstracts), 31(suppl_4):S1142-S1215. Abstract LBA6_PR. DOI:10.1016/annonc/annonc325
Boku N, Ryu MH, Oh D, et al (2020). Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. Ann Oncol (ESMO Virtual Congress Abstracts), 31(suppl_4):S1142-S1215. Abstract LBA7_PR. DOI:10.1016/annonc/annonc325
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
Janjigian YY, Maron SB, Chatila WK, et al (2020). First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. Lancet Oncol, 21(6):821-831. DOI:10.1016/S1470-2045(20)30169-8
Clinicaltrials.gov (2020). Pembrolizumab/placebo plus trastuzumab plus chemotherapy in human epidermal growth factor receptor 2 positive (HER2+) advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (MK-3475-811/KEYNOTE-811). NLM identifier: NCT03615326.
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
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily represent those of i3 Health.