POSEIDON Update Confirms OS Benefit of Tremelimumab/Durvalumab Plus Chemo in mNSCLC

Solange Peters, MD, PhD

A limited course of tremelimumab (Imjudo) added to frontline durvalumab (Imfinzi) and chemotherapy provided a sustained overall survival (OS) benefit vs chemotherapy alone in patients with previously untreated metastatic non­–small cell lung cancer (mNSCLC), according to findings from the prespecified 5-year OS update from the phase 3 POSEIDON trial (NCT03164616), which were presented at the 2023 ESMO Immuno-Oncology Congress.¹

At a median follow-up of 63.4 months (range, 0.0-73.9), patients who received durvalumab/tremelimumab/chemotherapy (n = 338) achieved a median OS of 14.0 months (95% CI, 11.7-16.1) vs 11.6 months (95% CI, 10.5-13.1) with chemotherapy alone (n = 337; HR, 0.76; 95% CI, 0.64-0.89), with 5-year OS rates of 15.7% and 6.8%, respectively. Furthermore, in the cohort of patients who received durvalumab/chemotherapy (n = 338), the median OS was 13.3 months (95% CI, 11.4-14.7) with a 5-year OS rate of 13.0%. When compared with chemotherapy alone, the hazard ratio (HR) was 0.84 (95% CI, 0.72-1.00).

“Across patient subgroups, long-term OS benefit was generally consistent with the intention-to-treat population,” lead study author Solange Peters, MD, PhD, of the Department of Oncology at the University Hospital of Lausanne in Switzerland, stated in a presentation of the data. “Consistent with earlier analyses, the addition of tremelimumab to durvalumab and chemotherapy provided an OS benefit regardless of PD-L1 expression, and specifically and importantly, also in PD-L1–negative patients.”

POSIEDON enrolled 1013 patients with EGFR or ALK wild-type stage IV NSCLC and an ECOG performance status of 0 or 1 who had received no prior treatment for metastatic disease and had available tumor biopsy and baseline plasma samples for circulating tumor DNA (ctDNA) analysis.

Patients were stratified by PD-L1 expression (tumor cells ≥50% vs <50%), histology (nonsquamous vs squamous), and disease stage (IVA vs IVB). Patients were randomly assigned 1:1:1 to receive durvalumab/limited-course tremelimumab/chemotherapy once every 3 weeks for 4 cycles followed by 1 additional dose of post-chemotherapy tremelimumab at week 16 only plus durvalumab maintenance once every 4 weeks until progressive disease (PD), with the option to receive pemetrexed once every 4 weeks; durvalumab/chemotherapy once every 3 weeks for 4 cycles followed by durvalumab monotherapy once every 4 weeks until PD; or platinum-based chemotherapy once every 3 weeks for a maximum of 6 cycles. Durvalumab was administered at 1500 mg and tremelimumab was administered at 75 mg.

The alpha-controlled end points in POSEIDON were PFS and OS for durvalumab/chemotherapy vs chemotherapy and tremelimumab plus durvalumab/chemotherapy vs chemotherapy.

Previous data from POSEIDON demonstrated that first-line treatment with tremelimumab plus durvalumab/chemotherapy led to statistically significant progression-free survival (PFS) and OS improvements compared with chemotherapy alone in patients with metastatic NSCLC, with respective HRs of 0.72 (95% CI, 0.60-0.86; P = .0003) and 0.77 (95% CI, 0.65-0.92; P = .0030).² These findings supported the November 2022 FDA approval of first-line tremelimumab plus durvalumab/chemotherapy for patients in this population.³ Moreover, durvalumab plus chemotherapy provided a significant PFS benefit vs chemotherapy alone (HR, 0.74; 95% CI, 0.62-0.89; P = .0009). Although the data did not reach statistical significance, the combination was associated with a positive trend for OS improvement (HR, 0.86; 95% CI, 0.72-1.02; P = .0758).²

The end points in the prespecified long-term follow-up analysis were OS, serious adverse effects (AEs), and exposure.

The long-term OS benefit with tremelimumab/durvalumab/chemotherapy (n = 214) vs chemotherapy alone (n = 214) was greater in the population of patients with nonsquamous disease, with a median OS of 17.2 months (95% CI, 14.9-21.8) and 13.0 months (95% CI, 10.6-15.1), respectively (HR, 0.81; 95% CI, 0.66-1.00), and respective 5-year OS rates of 20.5% and 9.1%, respectively. In the cohort of patients with nonsquamous disease who received durvalumab/chemotherapy (n = 209), the median OS was 14.8 months (95% CI, 11.8-18.3); when compared with those who received chemotherapy alone, the HR was 0.81 (95% CI, 0.66-1.00). The 5-year OS rate with durvalumab plus chemotherapy was 16.4%.

In the cohort of patients with squamous disease, the median OS was 10.4 months (95% CI, 8.4-12.7) with tremelimumab/durvalumab/chemotherapy (n = 124) vs 10.5 months (95% CI, 8.0-11.7) with chemotherapy alone (n = 122; HR, 0.85; 95% CI, 0.65-1.10), with respective 5-year OS rates of 7.3% and 2.9%. In the cohort of patients with squamous disease who received durvalumab plus chemotherapy (n = 128), the median OS was 11.5 months (95% CI, 9.4-14.0) and when compared with those who received chemotherapy alone, the HR was 0.82 (95% CI, 0.64-1.07). In the durvalumab/chemotherapy group with squamous disease, the 5-year OS rate was 7.6%.

Of the patients with nonsquamous histology, 6% had only evaluable tissue, 52% had evaluable tissue and ctDNA, and 38% had only evaluable ctDNA. The mutation-evaluable population comprised 96% of the patients with nonsquamous disease. Among these patients, 30% had KRAS mutations, 6% had KEAP1 mutations, and 14% had STK11 mutations. Moreover, 6% of patients had cooccurring KRAS and STK11 mutations, and 1% of patients each had cooccurring KRAS and KEAP1 mutations, cooccurring KEAP1 and STK11 mutations, and cooccurring KRAS, KEAP1, and STK11 mutations.

Patients with nonsquamous disease and STK11 mutations maintained an OS benefit with tremelimumab/durvalumab/chemotherapy (n = 31) vs chemotherapy alone (n = 22), with respective median OS of 15.0 months (95% CI, 8.2-23.8) and 10.7 months (95% CI, 6.0-14.9; HR, 0.57; 95% CI, 0.32-1.04), and respective 5-year OS rates of 12.9% and 0.0%. In the cohort of patients with STK11-mutated disease who received durvalumab/chemotherapy (n = 34), the median OS was 6.9 months (95% CI, 3.6-12.9) and the 5-year OS rate was 5.9%. When compared with those given chemotherapy alone, the HR was 1.02 (95% CI, 0.59-1.80).

In the population of patients with nonsquamous STK11 wild-type disease, the median OS was 17.2 months (95% CI, 14.9-22.1) with tremelimumab/durvalumab/chemotherapy (n = 177) vs 13.4 months (95% CI, 11.5-16.8) with chemotherapy alone (n = 179; HR, 0.71; 95% CI, 0.56-0.90), and the 5-year OS rates were 22.0% and 10.4%, respectively. In the cohort of patients with STK11 wild-type disease who received durvalumab/chemotherapy (n = 169), the median OS was 17.1 months (95% CI, 13.3-22.3) and the 5-year OS rate was 17.7%. When compared with the chemotherapy-alone arm, the HR was 0.79 (95% CI, 0.63-1.00).

Patients with KEAP1 mutations also maintained an OS benefit with tremelimumab plus durvalumab/chemotherapy (n = 22) vs chemotherapy alone (n = 6) across histologies, with respective median OS of 13.7 months (95% CI, 7.2-26.5) and 8.7 months (95% CI, 5.1-not evaluable; HR, 0.43; 95% CI, 0.16-1.25) and respective 5-year OS rates of 10.0% and 0.0%. In the cohort of patients with KEAP1-mutated disease who received durvalumab/chemotherapy (n = 23), the median OS was 8.1 months (95% CI, 4.0-12.9) and the 5-year OS rate was 7.2%. When compared with those given chemotherapy alone, the HR was 0.77 (95% CI, 0.31-2.15).

In the population of patients with KEAP1 wild-type disease, across histologies, the median OS was 14.0 months (95% CI, 11.8-16.1) with tremelimumab/durvalumab/chemotherapy (n = 303) vs 12.1 months (95% CI, 10.6-13.9) with chemotherapy alone (n = 312; HR, 0.76; 95% CI, 0.64-0.90), with 5-year OS rates of 16.2% and 7.0%, respectively. In the cohort of patients with KEAP1 wild-type disease who received durvalumab/chemotherapy (n = 307), the median OS was 13.5 months (95% CI, 11.7-14.9) and the 5-year OS rate was 13.0%. When compared with the chemotherapy-alone arm, the HR was 0.83 (95% CI, 0.70-0.98).

In the population of patients with nonsquamous, KEAP1-mutated disease, the HR vs chemotherapy was 0.33 (95% CI, 0.10-1.15) with tremelimumab/durvalumab/chemotherapy and 0.67 (95% CI, 0.23-2.17) with durvalumab/chemotherapy.

Patients with nonsquamous disease and KRAS mutations also maintained an OS benefit with tremelimumab/durvalumab/chemotherapy (n = 60) vs chemotherapy alone (n = 53), with respective median OS of 25.7 months (95% CI, 9.9-36.7) and 10.4 months (95% CI, 7.3-12.6; HR, 0.55; 95% CI, 0.36-0.83) and respective 5-year OS rates of 21.7% and 8.1%. In the cohort of patients with KRAS-mutated disease who received durvalumab/chemotherapy (n = 69), the median OS was 12.6 months (95% CI, 7.5-16.9) and the 5-year OS rate was 20.3%. When compared with the chemotherapy-alone arm, the HR was 0.74 (95% CI, 0.50-1.09).

In the population of patients with nonsquamous, KRAS wild-type disease, the median OS was 17.1 months (95% CI, 13.4-20.1) with tremelimumab/durvalumab/chemotherapy (n = 148) vs 14.4 months (95% CI, 12.6-18.3) with chemotherapy alone (n = 148; HR, 0.78; 95% CI, 0.61-1.00), and 5-year OS rates of 20.3% and 9.5%, respectively. In the cohort of patients with KRAS wild-type disease who received durvalumab/chemotherapy (n = 134), the median OS was 17.1 months (95% CI, 12.3-22.6) and the 5-year OS rate was 13.1%. The HR for OS with durvalumab chemotherapy vs chemotherapy alone was 0.87 (95% CI, 0.68-1.12).

A total of 331, 335, and 331 patients in the tremelimumab/durvalumab/chemotherapy, durvalumab/chemotherapy, and chemotherapy alone arms, respectively, received treatment. At data cutoff, 19 and 13 patients in the tremelimumab/durvalumab/chemotherapy and durvalumab/chemotherapy arms, respectively, were still receiving durvalumab, and 10 and 8 patients, respectively, were still receiving maintenance pemetrexed.

Moreover, in the tremelimumab plus durvalumab/chemotherapy, durvalumab/chemotherapy, and chemotherapy alone arms, respectively, 35.8%, 42.9%, and 57.6% of patients received subsequent systemic anticancer therapy. In the tremelimumab/durvalumab/chemotherapy arm, 6.5%, 3.8%, 32.5%, and 1.2% of patients received subsequent immunotherapy, subsequent targeted therapy, subsequent chemotherapy, or another subsequent therapy, respectively. These respective rates were 7.1%, 5.0%, 38.8%, and 0.3% in the durvalumab/chemotherapy arm and 32.6%, 6.5%, 35.9%, and 1.5% in the chemotherapy-alone arm.

Patients in the tremelimumab/durvalumab/chemotherapy and durvalumab/chemotherapy arms each received a median of 8.0 durvalumab doses (range, 1-80). In these arms, the respective median durations of durvalumab treatment were 29.8 weeks (range, 1.1-317.4) and 28.7 weeks (range, 0.1-315.6). In the tremelimumab plus durvalumab/chemotherapy arm, 10.9%, 8.2%, and 6.1% of patients received durvalumab for at least 3 years, at least 4 years, and at least 5 years, respectively. In the durvalumab/chemotherapy arm, these rates were 8.4%, 5.7%, and 4.5%, respectively. Furthermore, 66.1% of patients in the tremelimumab plus durvalumab/chemotherapy arm received at least 5 tremelimumab doses.

In the tremelimumab plus durvalumab/chemotherapy, durvalumab/chemotherapy, and chemotherapy alone arms, serious all-cause AEs occurred in 45.8%, 40.7, and 35.1% of evaluable patients, respectively. In these populations, all-cause AEs led to death in 13.0%, 10.8%, and 9.0% of patients, respectively. Treatment-related serious AEs occurred in 27.6%, 19.8%, and 17.7% of patients, respectively. Treatment-related AEs leading to death were observed in 3.3%, 2.1%, and 2.4% of patients, respectively. Since the final analysis, 7 additional patients had serious AEs, including 1 serious AE that was considered treatment related. Furthermore, 4 additional patients experienced AEs leading to death, none of which were determined to be treatment related.

“These results support the use of tremelimumab plus durvalumab plus chemotherapy as a frontline treatment option for patients with mNSCLC, including what we call the harder-to-treat subgroups,” Peters concluded.

Based on these findings, the ongoing phase 3 TRITON trial (NCT06008093) is evaluating the efficacy of durvalumab/tremelimumab/chemotherapy vs pembrolizumab (Keytruda) plus chemotherapy in patients with mNSCLC.⁴

Editor’s Note: Dr Peters has disclosed having consultation/advisory roles with AbbVie, Amgen, Arcus, AstraZeneca, Bayer, Beigene, BerGenBio, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead, GSK, Hutchmed, Illumina, Incyte, Ipsen, iTeos, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Nykode Therapeutics, Novartis, Novocure, PharmaMar, Promontory Therapeutics, Pfizer, Regeneron, Roche/Genentech, Sanofi, Seattle Genetics, and Takeda; being on the Board of Directors for Galencia; having spoken at organized public events for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Foundation Medicine, GSK, Illumina, Ipsen, Merck Sharp and Dohme, Mirati, Novartis, Pfizer, Roche/Genentech, Sanofi, and Takeda; and having received grants/research support as the principal investigator in trials sponsored by Amgen, Arcus, AstraZeneca, Beigene, Bristol Myers Squibb, GSK, iTeos, Merck Sharp and Dohme, Mirati, PharmaMar, Promontory Therapeutics, Roche/Genentech, and Seattle Genetics.

The POSEIDON trial was funded by AstraZeneca.

References

1. Peters S, Cho BC, Luft A, et al. LBA3 - Durvalumab (D) ± tremelimumab (T) + chemotherapy (CT) in first-line metastatic (m) NSCLC: 5-year overall survival (OS) update from the POSEIDON study. Ann Oncol. 2023;20(suppl 1):100535. doi:10.1016/iotech/iotech100535
2. Johnson ML, Cho BC, Luft A, et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non–small-cell lung cancer: the phase III POSEIDON study. J Clin Oncol. 2023;41(suppl 6):1213-1227. doi:10.1200/JCO.22.00975
3. FDA approves tremelimumab in combination with durvalumab and platinum-based chemotherapy for metastatic non-small cell lung cancer. FDA. November 10, 2022. Accessed January 2, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-and-platinum-based-chemotherapy-metastatic-non
4. A study to investigate the efficacy of durvalumab plus tremelimumab in combination with chemotherapy compared with pembrolizumab in combination with chemotherapy in metastatic non-small cell lung cancer (NSCLC) patients (TRITON). ClinicalTrials.gov. Updated December 20, 2023. Accessed January 2, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT06008093