Four Cycles of Chemotherapy Plus Tremelimumab and Durvalumab Demonstrate Optimized Outcomes in Metastatic NSCLC

Niels Reinmuth, MD, PhD

The use of 4 cycles of chemotherapy plus durvalumab (Imfinzi) with or without tremelimumab-actl (Imjudo) was associated with improved or sustained response and similar toxicity compared with chemotherapy alone as frontline therapy in patients with metastatic non–small cell lung cancer (NSCLC), according to post hoc exploratory findings from the phase 3 POSEIDON trial (NCT03164616) presented at the 2023 European Lung Cancer Congress.¹

Among all patients who achieved stable disease (SD) after the second chemotherapy cycle (n = 560), 22.9% (n = 128; 95% CI, 19.4%-26.6%) improved to partial response (PR) after cycle 4 of treatment. Divided by treatment arm, 26.1% (95% CI, 19.9%-33.2%), 23.5% (95% CI, 17.5%-30.4%), and 19.4% (95% CI, 14.2%-25.6%) of patients in the tremelimumab, durvalumab, and chemotherapy (n = 47/180); durvalumab and chemotherapy (n = 42/179); and chemotherapy alone (n = 39/201) arms experienced improved response from SD in cycle 2 to PR after cycle 4 of treatment.

Additionally, patients in all 3 respective arms experienced a larger median reduction from baseline in their target lesion size by cycle 4 (-18.00; -16.10; -14.95) compared with cycle 2 (-11.15; -12.20; -10.60).

Furthermore, among all patients who achieved complete response or PR after the second chemotherapy cycle (n = 252), 89.7% (n = 226; 95% CI, 85.2%-93.1%) maintained their response after cycle 4. Divided by treatment arm, 90.6% (95% CI, 82.9%-95.6%), 92.6% (95% CI, 85.3%-97.0%), and 83.9% (95% CI, 72.3%-92.0%) of patients in the tremelimumab, durvalumab, and chemotherapy (n = 87/96); durvalumab and chemotherapy (n = 87/94); and chemotherapy alone (n = 52/62) arms maintained their response from cycle 2 to after cycle 4 of treatment.

Similarly, patients in all 3 respective arms experienced a larger median reduction from baseline in their target lesion size by cycle 4 (-48.95; -47.10; -45.45) compared with cycle 2 (-37.80; -38.35; -36.50).

“These exploratory data support the use of 4 chemotherapy cycles, in combination with limited course tremelimumab and durvalumab until progression, to optimize response and tumor shrinkage in patients with metastatic NSCLC, including some harder-to-treat subgroups,” lead study author Niels Reinmuth, MD, PhD, leader of the Thoracic Oncology Department at Asklepios Lung Clinic in Munich-Gauting, Germany, said in a presentation of the data.

POSEIDON is a global, randomized, open-label, multicenter study. Eligible patients had EGFR and ALK wild-type stage IV NSCLC; an ECOG performance status of 0 or 1; previously untreated disease in the metastatic setting; and a tumor biopsy and baseline plasma sample for circulating tumor DNA analysis.

Per the study design, 1013 patients were randomly assigned 1:1:1 to 4 cycles of tremelimumab plus durvalumab and chemotherapy; 4 cycles of durvalumab and chemotherapy; or up to 6 cycles of chemotherapy alone. In each arm, treatment was administered every 3 weeks. Following treatment completion, patients received maintenance therapy with tremelimumab during week 16 plus pemetrexed (Alimta) every 4 weeks; pemetrexed alone; or pemetrexed monotherapy. Maintenance therapy was continued until progressive disease.

PFS and OS comparing durvalumab plus chemotherapy with or without tremelimumab with chemotherapy alone served as alpha-controlled end points.

Previously presented primary findings from the POSEIDON trial demonstrated a statistically significant improvement in PFS (HR, 0.72; 95% CI, 0.60-0.86; P = .0003) and OS (HR, 0.77; 95% CI, 0.65-0.92; P = .0030) with tremelimumab, durvalumab, and chemotherapy vs chemotherapy alone in patients with EGFR and ALK wild-type metastatic NSCLC. Objective response rate (ORR) and duration of response (DOR) were also improved with both regimens vs chemotherapy alone. These data served as the basis for the regimen’s approval in the US, Japan, and European Union.^1,2

In the present analysis, the addition of durvalumab with or without tremelimumab “did not seem to compromise the number of cycles of chemotherapy [patients received],” Reinmuth said. In the triplet arm, 78.5% (n = 259) of patients received at least 4 cycles of chemotherapy compared with 81.7% (n = 273) and 74.2% (n = 247) in the combination and chemotherapy alone arms, respectively. In the maintenance setting, 75.3% (n = 149/198), 80.3% (n = 159/198), and 64.2% (n = 131/204) of patients received pemetrexed.

Durvalumab plus chemotherapy with or without tremelimumab also demonstrated improved ORR in the overall population and regardless of histology compared with chemotherapy alone, although the benefit was “much more pronounced in nonsquamous vs squamous histology,” Reinmuth said.

Overall, the ORR was 38.8% with tremelimumab, durvalumab, and chemotherapy; 41.5% with durvalumab plus chemotherapy; and 24.4% with chemotherapy alone. In the nonsquamous population, the ORRs were 45.5%, 44.3%, and 23.7%, respectively. In the squamous population, the ORRs were 27.4%, 37.3%, and 25.6%, respectively.

Median DOR in the overall triplet, doublet, and chemotherapy alone arms was 9.5 months (95% CI, 7.2-not evaluable [NE]), 7.0 months (95% CI, 5.7-9.9), and 5.1 months (95% CI, 4.4-6.0), demonstrating superiority with the immunotherapy-based regimens, Reinmuth noted. In the nonsquamous population, median DOR was 16.4 months (95% CI, 9.3-NE), 10.6 months (95% CI, 6.6-NE), and 6.0 months (95% CI, 4.4-8.7), respectively. In the squamous population, median DOR was 5.6 months (95% CI, 4.3-7.2), 5.5 months (95% CI, 4.9-6.7), and 4.8 months (95% CI, 3.7-5.2), respectively.

In the overall population, the percentage of patients remaining in response at 1 year in the triplet, doublet, and chemotherapy alone arms was 49.7% (95% CI, 40.4%-58.4%), 38.9% (95% CI, 30.1%-47.6%), and 21.4% (95% CI, 12.7%-31.6%). In the nonsquamous population, 58.6% (95% CI, 47.5%-68.2%), 48.7% (95% CI, 37.1%-59.3%), and 34.4% (95% CI, 20.8%-48.4%) of patients remained in response at 12 months, respectively. In the squamous population, these rates were 23.3% (95% CI, 9.9%-40.0%), 20.3% (95% CI, 9.7%-33.6%), and 0%, respectively.

Notably, patients with mutations in STK11, KEAP1, and KRAS appeared to have the largest improvement from SD in cycle 2 to PR after cycle 4 with the triplet (n = 5/17, 29.4%; n = 4/11, 36.4%; and n = 13/31, 41.9%, respectively). However, the small sample size and overlapping confidence intervals prevented investigators from drawing definitive conclusions. In the durvalumab and chemotherapy arm, the conversion rates were 15.4% (n = 2/13), 28.6% (n = 4/14), and 27.3% (n = 9/33) in the STK11-, KEAP1-, and KRAS-mutant populations, respectively. With chemotherapy alone, these rates were 12.5% (n = 2/16), 0% (n = 0/5), and 7.7% (n = 2/26), respectively.

Regarding safety, the occurrence of grade 3/4 adverse effects (AEs) and serious AEs originating in each cycle was similar across all 3 arms. Such events were “vastly related to chemotherapy,” Reinmuth said, and included anemia, leukopenia, nausea, thrombocytopenia, and vomiting.

“Two additional cycles of chemotherapy did not meaningfully contribute to toxicity, and the addition of durvalumab with or without tremelimumab did not compromise the ability to administer the planned 4 cycles of chemotherapy,” Reinmuth concluded.

Disclosures: Dr Reinmuth reported honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Hoffman-La Roche, Janssen, Lilly, Merck, MSD, Pfizer, Symphogen, and Takeda; payment for consulting from AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Hoffman-La Roche, Merck, MSD, and Pfizer; and study sponsorship from AstraZeneca.

References

1. Reinmuth N, Cho BC, Luft A, et al. Patterns of response in metastatic NSCLC after 2 and 4 cycles of chemotherapy, alone or with durvalumab +- tremelimumab, in the phase 3 POSEIDON study. Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 177.
2. FDA approves tremelimumab in combination with durvalumab and platinum-based chemotherapy for metastatic non-small cell lung cancer. News release. FDA. November 10, 2022. Accessed March 31, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs