Melissa L. Johnson, MD

As reported in the Journal of Clinical Oncology by Melissa L. Johnson, MD, and colleagues, the pivotal phase III POSEIDON trial has shown significantly improved progression-free and overall survival with the addition of tremelimumab and durvalumab to platinum-based chemotherapy in the first-line treatment of metastatic non–small cell lung cancer (NSCLC) without EGFR/ALK alterations.

The trial supported the November 10, 2022, approval of tremelimumab in combination with durvalumab plus chemotherapy in this setting.

Study Details

In the open-label trial, 1,013 patients from sites in 18 countries were randomly assigned 1:1;1 between June 2017 and September 2018 to receive either:

• Tremelimumab at 75 mg, durvalumab at 1,500 mg, and chemotherapy for up to four 21-day cycles followed by durvalumab at 1,500 mg every 4 weeks until disease progression, with one additional tremelimumab dose after chemotherapy at week 16 (fifth dose; n = 338)
• Durvalumab at 1,500 mg plus chemotherapy for up to four 21-day cycles followed by durvalumab at 1,500 mg every 4 weeks until disease progression (n = 338)
• Chemotherapy for up to six 21-day cycles (n = 337).

Chemotherapy options included carboplatin plus nab-paclitaxel regardless of histology; cisplatin or carboplatin plus gemcitabine for squamous histology; and cisplatin or carboplatin plus pemetrexed (with pemetrexed maintenance if eligible) for nonsquamous histology.

The primary endpoints were progression-free and overall survival for durvalumab plus chemotherapy vs chemotherapy; key secondary endpoints were progression-free and overall survival for tremelimumab/durvalumab plus chemotherapy.

Progression-Free and Overall Survival

At data cutoffs in July 2019 for progression-free survival and in March 2021 for overall survival, median follow-up durations for censored patients were 10.3 months (range = 0.0–23.1 months) and 34.9 months (range = 0.0–44.5 months), respectively.

For the durvalumab plus chemotherapy group vs chemotherapy group, median progression-free survival was 5.5 vs 4.8 months (hazard ratio [HR] = 0.74, 95% confidence interval [CI] = 0.62–0.89, P = .0009) and median overall survival was 13.3 vs 11.7 months (HR = 0.86, 95% CI = 0.72–1.02, P = .0758); overall survival at 24 months was 29.6% vs 22.1%.

For the tremelimumab/durvalumab plus chemotherapy group vs chemotherapy group, median progression-free survival was 6.2 vs 4.8 months (HR = 0.72, 95% CI = 0.60–0.86, P = .0003) and median overall survival was 14.0 vs 11.7 months (HR = 0.77, 95% CI = 0.65–0.92, P = .0030); overall survival at 24 months was 32.9% vs 22.1%.

Totals of 36.4% of patients in the tremelimumab/durvalumab plus chemotherapy group, 41.1% of the durvalumab plus chemotherapy group, and 57.6% of the chemotherapy group received subsequent systemic anticancer therapy. Second-line immunotherapy was received by 33.2% of patients in the chemotherapy group and by 6.5% of the other two groups, whereas rates of second-line chemotherapy were similar across groups.

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 51.8% of patients in the tremelimumab/durvalumab plus chemotherapy group, 44.6% of the durvalumab plus chemotherapy group, and 44.4% of the chemotherapy group; the most common in all groups were anemia (17.3%, 15.3%, 20.4%, respectively) and neutropenia (16.1%, 12.6%, 12.0%, respectively). Serious treatment-related adverse events occurred in 27.6%, 19.5%, and 17.7% of patients, respectively. Treatment-related adverse events led to discontinuation of therapy in 15.5%, 14.1%, and 9.9%, respectively. Death related to treatment occurred in 11 patients (3.3%), 7 patients (2.1%), and 8 patients (2.4%), respectively.

The investigators concluded, “Durvalumab plus chemotherapy significantly improved progression-free survival vs chemotherapy. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved overall survival and progression-free survival vs chemotherapy, without meaningful additional tolerability burden, representing a potential new option in first-line metastatic NSCLC.”

Dr. Johnson, of Sarah Cannon Research Institute—Tennessee Oncology, Nashville, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by AstraZeneca. For full disclosures of the study authors, visit ascopubs.org.