Baseline Characteristics Not Tied to Benefit With Durvalumab/Tremelimumab and Chemo in Metastatic NSCLC

Byoung Chul Cho, MD, PhD

Treatment with durvalumab (Imfinzi) plus tremelimumab-actl (Imjudo) and chemotherapy led to higher rates of long-term clinical benefit compared with chemotherapy alone in the treatment of patients with first-line metastatic non–small cell lung cancer (NSCLC), according to data from an exploratory analysis of the phase 3 POSEIDON trial (NCT03164616) presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.¹

However, baseline patient demographics and disease characteristics were not associated with predicting long-term benefit for patients treated with the triplet or chemotherapy alone.

Findings showed that the 12-month progression-free survival (PFS) rate was 16.6% for patients treated with the triplet regimen (n = 338), compared with 15.7% for patients treated with durvalumab plus chemotherapy (n = 338) and 6.8% for patients treated with chemotherapy alone (n = 337). Notably, it was found that patients who experienced a PFS of 12 months or more had an improved overall response rate (ORR), duration of response (DOR), and overall survival (OS) vs patients in the PFS less than 12 months, irrespective of treatment group.

In the triplet arm, the median OS was not reached (NR; 95% CI, not estimable [NE]–NE) for patients with a PFS of at least 12 months and 10.4 months (95% CI, 9.5-12.6) for those with a PFS of less than 12 months. In the doublet arm, the median OS was NR (95% CI, NE-NE) and 10.4 months (95% CI, 9.1-12.2) for the PFS of at least 12 months and the PFS of less than 12 months subgroups, respectively. In the chemotherapy arm, the median OS was NR (95% CI, 33.1-NE) and 10.7 months (95% CI, 9.7-12.2), respectively.

The 24-month OS rates were 89.1% (95% CI, 77.4%-95.0%), 88.7% (95% CI, 76.5%-94.7%), and 87.0% (95% CI, 64.8%-95.6%) for patients who achieved a PFS of at least 12 months in the triplet, doublet, and chemotherapy arms, respectively. In patients who had a PFS of less than 12 months, those rates were 21.6% (95% CI, 17.0%-26.6%), 18.4% (95% CI, 14.1%-23.1%), and 17.2% (95% CI, 13.2%-21.7%), respectively.

“Although there were higher percentages of patients with some unfavorable prognostic factors at baseline in the PFS [of less than 12 months] subgroup across treatment arms, baseline demographics and disease characteristics did not appear to identify patients who derive long-term benefit with durvalumab plus tremelimumab and chemotherapy vs chemotherapy,” lead study author, Byoung Chul Cho, MD, PhD, and colleagues, wrote in a poster presentation of the data. Cho is a medical oncologist and professor in the Division of Medical Oncology and chief of the Yonsei Cancer Center in Seoul, South Korea.

In November 2022, the FDA approved treatment of durvalumab plus tremelimumab and chemotherapy for the treatment of adult patients with metastatic NSCLC without sensitizing EGFR mutation or ALKaberrations.² The European Union approved the same treatment regimen of patients with metastatic NSCLC in February 2023.³ Both regulatory approvals were supported by results from POSEIDON.

Prior findings from the global, randomized, open-label, multicenter showed that durvalumab plus tremelimumab and platinum-based chemotherapy led to a statistically significant and clinically meaningful improvement in OS compared with chemotherapy alone (HR, 0.77; 95% CI, 0.65-0.92; P = .0030). The median OS was 14 months (95% CI, 11.7-16.1) with the triplet vs 11.7 months (95% CI, 10.5-13.1) with chemotherapy alone.²

In the exploratory analysis, investigators aimed characterize patients who derived long-term clinical benefit from treatment, using a preliminary threshold of a PFS of 12 months or more, in patients treated during POSEIDON.¹

Patients with EGFR and ALK wild-type, stage IV metastatic NSCLC were eligible for the POSEIDON trial. Notably, patients needed to have an ECOG performance status of 0 or 1 and previously untreated disease in the metastatic setting.

Upon enrollment, patients were randomly assigned 1:1:1 to 75 mg of tremelimumab plus 1500 mg of durvalumab and chemotherapy every 3 weeks for 4 cycles, followed by 1 additional dose of tremelimumab, plus continuous durvalumab given every 4 weeks until disease progression; 1500 mg of durvalumab plus chemotherapy every 3 weeks for 4 cycles, followed by durvalumab maintenance every 4 weeks until disease progression; or platinum-based chemotherapy alone every 3 weeks for up to 6 cycles.

For the subgroup analyses, a PFS of 12 months or greater was used as the preliminary threshold to define long-term clinical benefit.

In patients treated with the triplet therapy who achieved a PFS of 12 months or more (n = 56), the median age was 62 years (range, 47-87) and 76.8% of patients were male; 64.3% were White and 21.4% were Asian; 33.9% of patients had an ECOG performance status of 0 and 66.1% had a performance status of 1; 85.7% had nonsquamous histology and 14.3% had squamous histology; and 58.9% of patients had a stage IVA disease and 39.3% had a stage IVB disease. Moreover, 25%, 53.6%, and 21.4% of patients were current, former, and never smokers, respectfully; 20.7% and 14.3% of patients had central nervous system (CNS) metastases and liver metastases, respectively, and 33.9% of patients had a PD-L1 expression of less than 1%.

In patients treated with the triplet therapy who did not achieve a PFS of 12 months or more (n = 282), the median age was 63 years (range, 27-85), and 69.8% of patients were male; 54.4% were White and 35.4% were Asian; 32.3% of patients had an ECOG performance status of 0 and 67.7% had a performance status of 1; 58.9% had nonsquamous histology and 41.1% had squamous histology; and 48.9% of patients had a stage IVA disease and 50.7% had stage IVB disease. Moreover, 24.8%, 58.5%, and 16.7% of patients were current, former, and never smokers, respectfully; 9.6% of patients had CNS metastases, 21.6% had liver metastases, and 37.6% of patients had a PD-L1 expression of less than 1%.

In patients treated with durvalumab and chemotherapy, 53 patients achieved a PFS of 12 months or more, and 285 did not. Of these patient groups, the median ages were 65 years (range, 42-81) and 64 years (range, 32-87), respectively. The majority of patients were male (69.8% and 75.8%, respectively), White (50.9% and 54.4%), had an ECOG performance status of 1 (60.4% and 69.1%), and had nonsquamous histology (84.9% and 57.5%). The rates of stage IVA disease were 66% and 47.4%, respectively. The majority were former smokers (54.7% and 56.5%, respectively) Notably, 13.2% and 7.4% had CNS metastases, 5.7% and 20.7% had liver metastases, and 26.4% and 34.7% of patients had a PD-L1 expression of less than 1%.

Finally, in patients treated with chemotherapy alone, 23 patients achieved a PFS of 12 months or more and 314 did not. Of these patient groups, the median ages were 60 years (range, 38-78) and 64 (range, 32-84), respectively. The majority were male (52.2% and 75.2%, respectively) had an ECOG performance score of 1 (60.9% and 64.6%), had nonsquamous histology (95.7% and 61.1%). The rates of stage IVA disease were 56.5% and 48.7%, respectively. Most patients in both subgroups (52.2% and 57%, respectively) were former smokers. Additionally, 8.7% and 13.7%, respectively, had CNS metastases, 13% and 24.5% had liver metastases, and 47.8% and 37.9% of patients had a PD-L1 expression of less than 1%.

In patients who achieved a PFS of 12 months or greater, the rates of treatment-related adverse effects (TRAEs) were 96.4%, 96.2%, and 100% in the triplet, doublet, and chemotherapy arms, respectively. Those rates were 92%, 87.2%, and 88.7%, respectively, in patients who achieved a PFS of less than 12 months. TRAEs led to treatment discontinuation rates of 25%, 22.6%, and 8.7% of patients who had a PFS of at least 12 months in the triplet, doublet, and chemotherapy arms, respectively. In the PFS less than 12 months group, these discontinuation rates were 13.5%, 12.5%, and 10%, respectively.

in the PFS of 12 months or greater group, the rates of death due to TRAEs in the triplet, doublet, and chemotherapy arms were 1.8%, 1.9%, and 0%, respectively. Those rates were 3.6%, 2.1%, and 2.6%, respectively, in the PFS of less than 12 months group.

“Despite receiving more treatment, there was no evidence that participants who had a PFS of 12 months or more had higher rates of severe or serious AEs. However, these participants had more AEs thought to be related to the mechanism of durvalumab [and tremelimumab] of activating the immune system compared with [patients] who had PFS of less than 12 months,” Cho concluded.

References

1. Cho BC, Perez ID, Lowery C, et al. Durvalumab ± tremelimumab + chemotherapy in first-line metastatic NSCLC: Characterisation of patients with PFS ≥12 months in POSEIDON. Presented at: 2023 World Conference on Lung Cancer; September 10-12, 2023; Singapore. Poster P1.06-05.
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 September 11, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-disco-burst-edition-fda-approval-imjudo-tremelimumab-combination-imfinzi-durvalumab-and-platinum
3. Imfinzi plus Imjudo approved in the EU for patients with advanced liver and non-small cell lung cancers. AstraZeneca. News release. February 22, 2023. Accessed September 11, 2023. https://www.astrazeneca.com/media-centre