The combination of dual checkpoint inhibition plus chemotherapy could be the new standard of care in first-line metastatic non–small cell lung cancer (NSCLC), according to data presented during the International Association for the Study of Lung Cancer (IASLC) 2021 World Conference on Lung Cancer.¹ Findings from the phase III POSEIDON trial showed significantly improved progression-free and overall survival in patients with metastatic NSCLC who received first-line durvalumab and tremelimumab plus chemotherapy versus chemotherapy alone.

When combined with chemotherapy, durvalumab plus tremelimumab lowered the risk of death by 23%, with a median overall survival of 14.0 months vs 11.7 months for chemotherapy alone. Median progression-free survival also improved to 6.2 months with dual checkpoint inhibition plus chemotherapy, compared with 4.8 months with chemotherapy alone. Durvalumab inhibits the PD-L1 pathway, and tremelimumab is a CTLA-4 antibody.

“Durvalumab plus tremelimumab plus chemotherapy represents a potential new front-line treatment option for metastatic NSCLC.”

— Melissa L. Johnson, MD

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“The POSEIDON trial showed that patients who received durvalumab and tremelimumab and chemotherapy experienced statistically significant and clinically meaningful improvements in both progression-free and overall survival compared with patients on chemotherapy alone,” said lead study author Melissa L. Johnson, MD, Director of the Lung Cancer Research Program at Sarah Cannon Research Institute, Nashville. “Durvalumab plus tremelimumab plus chemotherapy represents a potential new front-line treatment option for metastatic NSCLC.”

Immunotherapies targeting the PD-1/PD-L1 pathway have transformed the treatment of metastatic NSCLC as monotherapy and in combination with chemotherapy, noted Dr. Johnson. She added that emerging evidence suggests that adding anti–CTLA-4 therapy to anti–PD-1/PD-L1 may further prolong survival outcomes.

Study Methods

For the randomized, open-label POSEIDON trial, Dr. Johnson and colleagues enrolled 1,013 patients from 153 cancer centers around the world. The study evaluated durvalumab with and without tremelimumab in combination with chemotherapy regimens as first-line treatment of squamous or nonsquamous metastatic NSCLC.

POSEIDON randomly assigned patients with treatment-naive, EGFR/ALK wild-type metastatic NSCLC (1:1:1) to receive one of the following three regimens:

Durvalumab (1,500 mg) and chemotherapy every 3 weeks for four cycles followed by durvalumab (1,500 mg) every 4 weeks until disease progression

Durvalumab (1,500 mg) with tremelimumab (75 mg) concurrently with chemotherapy every 3 weeks for up to four cycles, followed by durvalumab (1,500 mg) every 4 weeks until disease progression, with one additional dose of tremelimumab after the fourth dose of chemotherapy

Chemotherapy every 3 weeks for up to six cycles.

Investigators had their choice of five different chemotherapy regimens: platinum and gemcitabine for patients with squamous histology; platinum and pemetrexed for patients with nonsquamous histology; or nab-paclitaxel and carboplatin for patients with either histology.

The final progression-free survival analysis occurred in July 2019, at 76% maturity, whereas the final overall survival analysis occurred in March 2021, at 81% maturity.

Treatment Combination Reduces Risk of Death by 23%

As Dr. Johnson reported, patients treated with a short course of tremelimumab in addition to durvalumab and chemotherapy experienced a 23% reduction in the risk of death vs chemotherapy alone. The treatment combination also reduced the risk of disease progression or death by 28% compared with chemotherapy alone, with a median progression-free survival of 6.2 months vs 4.8 months.

An estimated 33% of patients who received the triplet regimen were alive at 2 years, compared with 22% given chemotherapy alone. The median overall survival improved to 14 months with dual immune checkpoint blockade plus chemotherapy vs 11.7 months for chemotherapy alone, said Dr. Johnson. She also noted that the survival benefit was more prominent among patients with nonsquamous histology.

“The clinical significance of POSEIDON is that adding tremelimumab to durvalumab and chemotherapy provides added benefit for patients with tumors with low expression of PD-L1.”

— Melissa L. Johnson, MD

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Although progression-free survival was significantly improved for patients receiving durvalumab plus chemotherapy compared with chemotherapy alone (5.5 months vs 4.8 months), overall survival did not reach statistical significance, Dr. Johnson reported.

The overall safety profile of the combination regimen was also comparable to previous reports of immunotherapy plus chemotherapy, with no new safety signals identified. Moreover, adding tremelimumab to durvalumab plus chemotherapy did not lead to a meaningful increase in treatment discontinuation, according to Dr. Johnson.

Stratifying Patients by PD-L1 Expression

Finally, Dr. Johnson highlighted a subgroup analysis based on PD-L1 levels; it showed a benefit for all patients who received chemoimmunotherapy, regardless of PD-L1 status. Although patients who had tumors with high expression of PD-L1 (PD-L1–high) were particularly responsive to dual checkpoint blockade, said Dr. Johnson, the addition of tremelimumab to chemotherapy plus the anti–PD-L1 backbone reduced the hazard ratio in favor of overall survival among patients who had tumors with low expression of PD-L1 (< 1%).

“One of the take home points from this study is that PD-L1 was evaluated in the overall survival subgroup analysis, and there was an improvement for patients who received chemoimmunotherapy across all PD-L1 levels shown, especially PD-L1–high. However, I do think that if you look specifically at patients who had tumors with low expression of PD-L1 (< 1%), that’s where the addition of the tremelimumab to the chemotherapy/PD-L1 backbone did move the hazard ratio in favor of overall survival.

“The clinical significance of POSEIDON is that adding tremelimumab to durvalumab and chemotherapy provides added benefit for patients with tumors with low expression of PD-L1,” concluded Dr. Johnson. 

DISCLOSURE: The POSEIDON trial was sponsored by AstraZeneca. Dr. Johnson has an immediate family member who has served as a consultant or advisor to Astellas Pharma and Otsuka; has served as an institutional consultant or advisor to AbbVie, Achilles Therapeutics, Association of Community Cancer Centers, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Genentech/Roche, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen Oncology, Lilly, Loxo, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, and Sanofi; has received institutional research funding from AbbVie, Acerta Pharma, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, AstraZeneca, Atreca, BeiGene, Birdie, Boehringer Ingelheim, Checkpoint Therapeutics, Corvus Pharmaceuticals, CytomX Therapeutics, Daiichi Sankyo, Dynavax, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Hengrui Pharmaceutical, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon, Lilly, Loxo, Lycera, Merck, Mirati Therapeutics, Neovia Oncology, Novartis, OncoMed, Pfizer, Regeneron, Ribon Therapeutics, Sanofi, Shattuck Labs, Stem CentRx, Syndax, Takeda, Tarveda Therapeutics, TCR2 Therapeutics, University of Michigan, and WindMIL; and has been reimbursed for travel, accommodations, or other expenses by AbbVie, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo, EMD Serono, Exelixis, Genentech, Incyte, Janssen Oncology, Lilly, Merck, Novartis, Pfizer, Sanofi, Sysmex, and Vapotherm.

REFERENCE

1. Johnson ML, Cho BC, Luft A, et al: Durvalumab ± tremelimumab + chemotherapy as first-line treatment for mNSCLC: Results from the phase 3 POSEIDON study. IASLC 2021 World Conference on Lung Cancer. Abstract PL02.01. Presented September 9, 2021.