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More Data for Upfront PD-1 Inhibition in Gastric, Esophageal Cancer

— Updates from two landmark trials show consistent benefits across subgroups, PD-L1 expression

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SAN FRANCISCO -- Immunotherapy solidified its role in gastric and esophageal cancer with updated results from two landmark clinical trials reported here.

With 12 more months of follow-up, the addition of nivolumab (Opdivo) or pembrolizumab (Keytruda) to chemotherapy maintained significant advantages in overall survival (OS) and progression-free survival (PFS) versus chemotherapy alone as first-line therapy for advanced/metastatic disease.

In both trials, the results of which were reported at the Gastrointestinal Cancers Symposium, the OS hazard was reduced by about 25%. The PFS benefit was slightly greater with pembrolizumab than with nivolumab (36% vs 21%), but both differences achieved statistical significance versus chemotherapy.

In the KEYNOTE-590 trial of pembrolizumab, the OS benefits were consistent across all levels of PD-L1 expression but somewhat greater with a combined positive score (CPS) ≥10. Similarly, the addition of nivolumab had a beneficial effect on OS at all PD-L1 CPS cutoffs but the trial was enriched for higher cutoffs.

Together the two trials "cleared the way to immunotherapy in the first-line treatment and will probably change the paradigm of treatment" for advanced gastroesophageal cancer, said invited discussant Stefano Cascinu, MD, of the San Raffaele Research Hospital in Milan. However, the trials left several unanswered questions in their wake.

"To optimize the treatment we need to address some issues, beginning with how to single out the patients who will or will not respond," said Cascinu. "PD-L1 may be a negative marker in that most patients with a low level of PD-L1 may respond, but if you use this as a continuous variable, it may be informative about the magnitude of benefit, for instance. This may be useful to discuss with the patient regarding the expected benefit."

Data from other studies have raised questions about the reproducibility of the findings in certain commonly encountered clinical situations, such as second PFS (PFS2), malnourished patients, and peritoneal involvement, he continued. Finally, can a PD1-L1 inhibitor be used as first-line treatment for advanced esophageal cancer in patients who previously received adjuvant nivolumab?

CheckMate 649

Positive results from CheckMate 649 supported the approval of nivolumab in combination with chemotherapy as initial treatment for patients with advanced/metastatic gastroesophageal cancer. Follow-up continued to allow for expanded safety and efficacy analyses, said Kohei Shitara, MD, of the National Cancer Center Hospital East in Kashiwa, Japan.

The primary analysis included 1,600 patients who were randomized to conventional combination chemotherapy with or without nivolumab. The trial had dual primary endpoints of OS and PFS.

Performed after 12 months of follow-up, the analysis showed a median OS of 13.8 months with the addition of nivolumab versus 11.6 months without it, representing a 21% reduction in the hazard ratio. Median PFS was 7.7 months with nivolumab and 6.9 months without it, also a 21% reduction in the hazard. Both differences achieved statistical significance.

The updated analysis showed persistence in the advantages for the nivolumab arm in the form of a 24-month OS rate of 28% versus 19% and a 24-month PFS rate of 16% versus 10%. PFS2 on first subsequent therapy also favored the nivolumab arm, with median values of 12.2 versus 10.4 months, respectively. The difference represented a 25% reduction in the hazard for disease progression or death (95% CI 0.67-0.84), Shitara reported.

Analyses by PD-L1 expression showed that the addition of nivolumab improved OS across the range of values from <1 to ≥10 CPS. Similarly, the overall response rate in all patients was 58% with nivolumab and 46% with chemotherapy alone. Similar differences were observed for all levels of PD-L1 expression.

In the subgroup of patients with CPS ≥5, nivolumab led to a significantly longer duration of response (DOR; 9.7 vs 7.0 months). DOR favored the nivolumab arm for patients with lower levels of PD-L1 expression, but the difference did not achieve statistical significance (7.7 vs 6.9 months).

The addition of nivolumab to chemotherapy was associated with more grade 3/4 treatment-related adverse events (TRAEs; 60% vs 45%), grade 3/4 serious TRAEs (17% vs 10%) TRAEs (any grade) leading to discontinuation (38% vs 25%), and treatment-related deaths (2% vs <1%). However, Shitara said no new or unexpected adverse events were observed.

"Nivolumab plus chemotherapy continued to demonstrate clinically meaningful improvement in efficacy versus chemotherapy, with an acceptable safety profile," he concluded. "These data further support the use of nivolumab plus chemotherapy as standard first-line treatment in patients with advanced gastric, gastroesophageal junction (GEJ), and esophageal adenocarcinoma."

KEYNOTE-590

A similar message came from the updated analysis of KEYNOTE-590. The trial involved 749 patients with untreated advanced/metastatic esophageal or GEJ cancer. They all received standard chemotherapy and were randomized to pembrolizumab or placebo. OS and PFS in all patients and in prespecified subgroups by PD-L1 expression were the primary endpoints.

The primary analysis showed a median OS of 12.4 months with pembrolizumab versus 9.8 months with placebo and a median PFS of 6.3 versus 5.8 months. The 12-month OS and PFS rates were 51% versus 39% and 25% versus 12%, respectively. After 24 months of follow-up, pembrolizumab maintained advantages for OS (26% vs 16%) and PFS (12% vs 3%), reported Jean-Philippe Metges, MD, of the University Hospital Center and the National Institute of Cancer and Hematology in Brest, France.

Analysis of OS by PD-L1 expression in esophageal squamous cell carcinoma (ESCC) showed advantages for the pembrolizumab arm in patients with CPS ≥10 and those with lower levels of expression, consistent with the overall results. Median OS ranged from 12.6 to 13.9 months with pembrolizumab and from 8.8 to 9.8 months with placebo. Median PFS improved slightly in the CPS ≥10 subgroup (7.5 vs 5.5 months) as compared with all patients with ESCC (6.3 vs 5.8 months).

The subgroup of patients with adenocarcinoma also benefited from PD-1 inhibition. Median OS was 11.6 months with pembrolizumab and 9.9 months with placebo. Median PFS was 6.3 versus 5.7 months, respectively.

The overall response rate was 45% with pembrolizumab and 29.3% with chemotherapy. More than three times as many patients in the pembrolizumab arm had responses that persisted for 24 months or longer (20.4% vs 6.2%).

Quality of life, pain, and dysphagia scores were similar over time between the two treatment groups. TRAEs occurred in a similar proportion of patients in each group, although more patients in the pembrolizumab arm discontinued treatment because of TRAEs (21.1% vs 12.4%).

"These longer-term data further support first-line pembrolizumab plus chemotherapy as a new standard-of-care in patients with locally advanced and metastatic esophageal cancer, including GEJ adenocarcinoma," Metges said in conclusion.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined 鶹ý in 2007.

Disclosures

The CheckMate 649 trial was supported by Bristol Myers Squibb.

Shitara disclosed relationships with Bristol Myers Squibb, Takeda, AbbVie, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Astellas Pharma, Chugai Pharma, Eisai, and Mediscience Planning.

The KEYNOTE-590 trial was supported by Merck.

Metges disclosed relationships with Bristol Myers Squibb, Eli Lilly, Novartis, Sanofi, SynCore, Amgen, LEO Pharma, and MSD Oncology.

Primary Source

Gastrointestinal Cancers Symposium

Shitara K, et al "Nivolumab plus chemotherapy versus chemo as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma: Expanded efficacy, safety, and subgroup analyses from CheckMate 649" GiCS 2022; Abstract 240.

Secondary Source

Gastrointestinal Cancers Symposium

Metges JP, et al "First-line pembrolizumab plus chemotherapy versus chemotherapy in advanced esophageal cancer: Longer-term efficacy, safety, and quality of life results from the phase III KEYNOTE-590 study" GiCS 2022; Abstract 241.