by Mike Bassett, Staff Writer, MedPage Today August 11, 2022

VIENNA -- Long-term results from the phase III KEYNOTE-604 trial appeared to strengthen the case of pembrolizumab (Keytruda) combined with platinum etoposide as a first-line treatment for patients with extensive-stage small cell lung cancer.

The updated analysis demonstrated that after 3.5 years of follow-up, the combination "continues to show what I would consider to be clinically meaningful improvement -- certainly in progression-free survival, and perhaps in overall survival" compared with patients who received chemotherapy alone, reported Charles Rudin, MD, Memorial Sloan Kettering Cancer Center, New York, here at the World Conference on Lung Cancer (WCLC).

The updated results showed median progression-free survival (PFS) of 4.8 versus 4.3 months in favor of pembrolizumab versus the study's control arm (HR 0.70, 95% CI 0.57-0.85), with 2-year PFS rates of 11.1% and 0.5%, respectively, and 3-year rates of 6.9% and 0.5%.

Median overall survival (OS) was 10.8 months in the pembrolizumab arm versus 9.7 months in the control arm arm (HR 0.76, 95% CI 0.63-0.89), with 3-year OS rates in the pembrolizumab arm almost triple those of chemotherapy alone (15.5% versus 5.9%).

WCLC discussant Virginie Westeel, MD, PhD, of Hôpital Jean Minjoz in Besançon, France, noted that the updated results from KEYNOTE-604 are similar to those from the CASPIAN trial, which evaluated durvalumab (Imfinzi) plus platinum-etoposide versus platinum-etoposide alone as a first-line treatment of extensive-stage small cell lung cancer, and served as the basis for an FDA approval in that setting.

Thus, KEYNOTE-604 "confirms the current standard treatment of platinum-based chemotherapy with an immune checkpoint inhibitor," Westeel said, adding that the results also outline the need for biomarkers to better select patients who will benefit from immunotherapy.

Initial results from KEYNOTE-604 demonstrated improved PFS with a hazard ratio of 0.75 (95% CI 0.61-0.91, P=0.0023), with 12-month PFS estimates of 13.6% with pembrolizumab and 3.1% with placebo.

However, while pembrolizumab prolonged OS -- the trial's second primary endpoint -- it failed to meet the prespecified statistical significance threshold (HR 0.80, 95% CI 0.64-0.98, P=.0164). Twenty-four month estimated OS estimates were 22.5% and 11.2%, for pembrolizumab and placebo, respectively.

Referring to the updated analysis Rudin said the "progression-free survival shows a story here."

"These patients stopped therapy after two years and in the control arm there is essentially no long-term progression-free survival on chemotherapy, but for the patients who got pembrolizumab there is a significant tail of the curve," Rudin said. "And, of course, it's much lower than we want it to be, but these are patients who are surviving long-term with extensive-stage small cell lung cancer off therapy now for multiple years. And that is a real paradigm shift for us as oncologists."

During a press briefing, Rudin noted that OS curves will include patients who are receiving second-, third-, and even fourth-line therapies, and could even be in hospice programs. "These patients who are remaining progression free are really in a different class," he said. "They are not suffering relapses, and that's important."

As for the OS results, "small cell lung cancer is a tough disease, and unfortunately remains quite lethal," Rudin observed. "But, there is a real tail on this survival curve, and there are real survivors past three years, and this is true in the various subsets we looked at."

The overall response rate, as reported in the initial analysis, was 70.6% in the pembrolizumab group, and 61.% with placebo. In the updated analysis, "the tail of the curve comes out," Rudin noted, with 10% of patients who responded to pembrolizumab having a duration of response equal to or greater than 42 months, compared with 0.8% in the control group.

KEYNOTE-604 was conducted at 140 sites in 18 countries, and included 453 patients ≥ 18 years with histologically or cytologically confirmed SCLC not previously treated with systemic therapy, an ECOG performance status of 0 or 1, and a life expectancy >3 years. Patients with brain metastases were eligible.

Patients were assigned to receive pembrolizumab 200 mg every 3 weeks or placebo up to 35 cycles plus four cycles standard-dose etoposide and platinum.

Rudin reported that 18 patients completed all 35 cycles of pembrolizumab, 14 of whom remained alive as of the last assessment and are living off treatment.

This small number of patients who have benefitted long term from immunotherapy can't be distinguished by clinical factors, Rudin said during the press briefing. "Their age is the same as everybody else; three of them had liver metastases and three had brain metastases at baseline. They really look clinically like everyone else."

If these patients can't be differentiated by clinical factors, "how close are we to biomarkers for small cell lung cancer, and when we will be able to find those patients who are long-term responders?" Brendon M. Stiles, MD, Weill Cornell Medicine, New York, who moderated the pressed briefing, asked Rudin.

"That's the key question," Rudin answered. "Who are these 18 patients, how can you find them, and how can you apply the lessons learned there to the rest of the 95% of patients who, unfortunately, did not benefit in that way?"

Rudin said he and his team have these patients' tissue, which provides a valuable data set that will help them "cull out" the special features of those tumors that respond.

"Our sequencing analysis is ongoing right now, and we're eager to see the results of that," he added. "We'll know more about who is in the tail of the curve soon."

Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

The study was sponsored by Merck Sharp & Dohme.

Rudin reported relationships with AbbVie, Amgen, AstraZeneca, Daiichi Sankyo, Epizyme, Genentech Roche, Ipsen, Jazz, Kowa, Lilly, Merck, Syros, Bridge Medicines, Earli, and Harpoon Therapeutics.

International Association for the Study of Lung Cancer

Source Reference: Rudin CM, et al "First-line pembrolizumab or placebo combined with etoposide and platinum for ES-SCLC: KEYNOTE-604 long-term follow-up results" WCLC 2022; Abstract 1849

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