FDA’s ODAC Votes Against Continuation of Pembrolizumab Third-Line Indication in Gastric/GEJ Cancer

The FDA’s Oncologic Drugs Advisory Committee has voted 6 to 2 against the continued approval of pembrolizumab as indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1 who experienced disease progression on or after 2 or more prior lines of therapy, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2-targeted therapy.

The FDA’s Oncologic Drugs Advisory Committee (ODAC) has voted 6 to 2 against the continued approval of pembrolizumab (Keytruda) as indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (combined positive score [CPS] ≥1) who experienced disease progression on or after 2 or more prior lines of therapy, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2-targeted therapy.

This represents the first negative vote in the ongoing ODAC meetings on accelerated immunotherapy approvals without confirmatory benefit.

“I believe the accelerated approval for pembrolizumab in the third-line setting was appropriate based on the modest response rates in KEYNOTE-059 and the clear unmet need, but the landscape…has clearly changed. And it’s highly unlikely that by third-line therapy patients will [not] have received some form of immune checkpoint therapy previously. Of note, KEYNOTE-061 and -062 are troubling in their lack of positive data. Although the data from KEYNOTE-059 are obviously extremely encouraging, it also further supports the fact that patients are GEJ cancer will likely have received immune checkpoint therapy, as well as gastric cancer in the frontline setting. So at this time, I don’t believe the indication should continue as written,” said panelist Christopher H. Lieu, MD, when explaining his vote.

Initial approval was granted in September 2017 based on findings from the phase 2 KEYNOTE-059 trial (NCT02335411), which showed responses in patients with gastric/GEJ adenocarcinoma treated with pembrolizumab in the third-line setting or beyond.

The objective response rate was 13.3% (95% CI, 8.2%-20.0%) among patients with microsatellite stable disease or undetermined status. The median duration of response ranged from 2.8+ to 19.4+ months.

Diane Reidy-Lagunes, MD, who voted in favor of continued approval for the pembrolizumab indication in gastric cancer, pointed to the tail of the curve seen in the KEYNOTE-059 trial where patients could receive benefit from the treatment. “Often there is a tail of the curve, and it would be terribly devastating for a patient to not receive the therapy, recognizing there are access programs with disparities of healthcare and differences in the way that patients are treated throughout our country, I was nervous that they may not be able to get that. I think that the potential [KEYNOTE]-859 could have shown an overall survival benefit. But, being able to test us and start line setting was just going to be too difficult to do. Having said that, I think that, as my colleague said, [KEYNOTE]-061 and [KEYNOTE]-062 really did prove that single-agent therapy really did not seem to pan out as compared to [the combination with chemotherapy].”

The randomized phase 3 KEYNOTE-061 (NCT02370498) and KEYNOTE-062 (NCT02494583) trials, which explored the use of pembrolizumab in the second-line and first-line settings, respectively, were intended to show confirmatory benefit for the PD-1 inhibitor. However, neither study showed significant benefit for pembrolizumab over chemotherapy.

In KEYNOTE-061, pembrolizumab was compared with paclitaxel in patients with PD-L1–positive (CPS ≥1) advanced gastric/GEJ cancer that had progressed on first-line chemotherapy with a platinum and fluoropyrimidine. In this population the median overall survival was 9.1 months (95% CI, 6.2-10.7) with pembrolizumab versus 8.3 months (95% CI, 7.6-9.0) with paclitaxel (HR, 0.82; 95% CI, 0.66-1.03; 1-sided P = .0421). Progression-free survival (PFS) favored paclitaxel with a median PFS of 1.5 months (95% CI, 1.4-2.0) with pembrolizumab and 4.1 months (95% CI, 3.1-4.2) with paclitaxel (HR, 1.27; 95% CI, 1.03-1.57).

In KEYNOTE-062, pembrolizumab demonstrated noninferiority for pembrolizumab monotherapy in comparison with chemotherapy alone in patients with untreated, locally advanced, unresectable, or metastatic gastric/GEJ cancer with PD-L1–positive (CPS≥ 1) expression. The median OS was 10.6 months with pembrolizumab and 11.1 months with chemotherapy (HR, 0.91; 99.2% CI, 0.69-1.18), but PFS also favored chemotherapy (HR, 1.64; 95% CI, 1.36-1.98).

However, in the frontline trial, the combination of pembrolizumab and chemotherapy did show a benefit over chemotherapy alone with a median OS of 12.5 months (95% CI, 10.8-13.9) with the combination versus 11.1 months (95% CI, 9.2-12.8) with chemotherapy alone (HR, 0.85; 95% CI, 0.70-1.03; P = .046).

The panelists who voted against maintaining the indication pointed to the changing landscape in gastric/GEJ cancers and how significantly it has changed from when the original accelerated approval was first granted.

Since the accelerated approval for this indication was granted in 2017, the treatment landscape in gastric/GEJ cancer has evolved to include trifluridine/tipiracil (TAS-102; Lonsurf) in the third-line setting, granted in February 2019; fam-trastuzumab deruxtecan-nxki (Enhertu) for patients with HER2-positive locally advanced or metastatic gastric/GEJ adenocarcinoma, granted in January 2021; and most recently, nivolumab (Opdivo) in combination with chemotherapy for the frontline treatment of patients with advanced or metastatic gastric/GEJ cancer and esophageal adenocarcinoma, which was granted earlier in the month.

As a result of these newer options, a majority of the panel felt that benefit for immunotherapy was not supported or best in this third-line setting, or that the patient would now be more likely to receive an immune checkpoint inhibitor in an earlier line of therapy, which could change the benefit for pembrolizumab in the third-line setting.

Mark Lewis, MD, also suggested that none of the ongoing studies of pembrolizumab in gastric/GEJ cancer could answer the true benefit of the agent in this setting: “My main concern is that none of the pending studies as best I could tell, would definitively answer the question of either monotherapy or the position in terms of lines of therapeutic sequencing for this agent. And given that, I couldn't see any other outcome. Beyond that, this accelerated approval would remain essentially approved ad infinitum.”

Reference

April 27-29, 2021: Meeting of the Oncologic Drugs Advisory Committee Meeting Announcement. FDA website. Accessed April 29, 2021.