Durvalumab + tremelimumab + chemo: A new first-line SoC for mNSCLC?

The combination of durvalumab, tremelimumab, and chemotherapy in the first-line setting improved progression-free survival (PFS) and overall survival (OS) in patients with metastatic non-small-cell lung cancer (mNSCLC), according to results of the phase III POSEIDON trial.

“The POSEIDON trial showed that patients who received durvalumab and tremelimumab and chemotherapy experienced statistically significant and clinically meaningful improvements in both PFS and OS compared to patients on chemotherapy alone,” remarked study author Dr Melissa Johnson from the Sarah Cannon Research Institute, Tennessee Oncology, PLLCC, Nashville, Tennessee, US, at WCLC 2021.

Participants in this multinational study (153 centres worldwide) were 1,013 patients (median age 63–65 years) with stage 4 NSCLC without EGFR or ALK alterations, were treatment-naïve for metastatic disease, and had an ECOG performance status of 0–1. They were randomized 1:1:1 to receive four cycles of durvalumab (1,500 mg) + chemotherapy* Q3W followed by durvalumab (1,500 mg Q4W) + pemetrexed** until disease progression; four cycles of durvalumab (1,500 mg) + chemotherapy* + tremelimumab (75 mg) Q3W, followed by durvalumab + pemetrexed** (plus a fifth dose of tremelimumab) until disease progression; or ≤6 cycles of platinum-based chemotherapy* Q3W followed by pemetrexed** until disease progression.

Durvalumab + chemotherapy led to a significant improvement in PFS vs chemotherapy only (median 5.5 vs 4.8 months; hazard ratio [HR], 0.74, 95 percent confidence interval [CI], 0.62–0.89; p=0.00093). There was a non-significant trend toward improved OS with durvalumab + chemotherapy vs chemotherapy only (median 13.3 vs 11.7 months; HR, 0.86, 95 percent CI, 0.72–1.02; p=0.07581). [WCLC 2021, abstract PL02.01]

Both PFS and OS were significantly improved with the durvalumab + tremelimumab + chemotherapy regimen compared with chemotherapy only (PFS: median 6.2 vs 4.8 months; HR, 0.72, 95 percent CI, 0.60–0.86; p=0.00031; OS: median 14.0 vs 11.7 months; HR, 0.77, 95 percent CI, 0.65–0.92; p=0.00304).

Objective response rate was improved with both durvalumab + chemotherapy and durvalumab + tremelimumab + chemotherapy compared with chemotherapy only (41.5, 38.8, and 24.4 percent, respectively; odds ratio [OR], 2.26, 95 percent CI, 1.61–3.19 and OR, 2.00, 95 percent CI, 1.43–2.81, respectively, vs chemotherapy only). Duration of response (DoR) was also longer with durvalumab + chemotherapy and durvalumab + tremelimumab + chemotherapy compared with chemotherapy only (median 7.0, 9.5, and 5.1 months, respectively). At 12 months, 38.9, 49.7, and 21.4 percent of patients in the durvalumab + chemotherapy, durvalumab + tremelimumab + chemotherapy, and chemotherapy-only arms, respectively, remained in response.

Both the PFS and OS benefits appeared more prominent among patients with non-squamous compared with squamous histology, said Johnson.

Among patients with non-squamous histology, compared with chemotherapy only, the PFS HRs for durvalumab + chemotherapy and durvalumab + tremelimumab + chemotherapy were 0.77 and 0.66, respectively, while the OS HRs were 0.82 and 0.70, respectively. Among patients with squamous histology, the PFS HRs for durvalumab + chemotherapy and durvalumab + tremelimumab + chemotherapy were 0.68 and 0.77, respectively, and the OS HRs 0.84 and 0.88, respectively, compared with chemotherapy only. The DoR benefits were also more evident among patients with non-squamous histology (median 10.6, 16.4, and 6.0 months with durvalumab + chemotherapy, durvalumab + tremelimumab + chemotherapy, and chemotherapy only) compared with those with squamous histology (5.5, 5.6, and 4.8 months, respectively). 

Forty-one, 36.4, and 57.6 percent of patients on durvalumab + chemotherapy, durvalumab + tremelimumab + chemotherapy, and chemotherapy only, respectively, received subsequent systemic anticancer therapy. Thirty-three percent of chemotherapy-only recipients received subsequent immunotherapy, compared with 6.5 percent each of the durvalumab + chemotherapy and durvalumab + tremelimumab + chemotherapy groups.

Acceptable safety

All-cause adverse event (AE) rates were comparable across the durvalumab + chemotherapy, durvalumab + tremelimumab + chemotherapy, and chemotherapy-only groups (96.1, 97.3, and 96.1 percent, respectively), as were grade 3–4 AEs (54.8, 53.3, and 51.7 percent, respectively), and serious AEs (40.1, 44.2, and 35.1 percent, respectively).

Similar findings were noted with regard to grade 3–4 treatment-related AEs (TRAEs; 44.6, 51.8, and 44.4 percent, respectively) and serious TRAEs (19.5, 27.6, and 17.7 percent, respectively). TRAEs led to treatment discontinuation in 14.1, 15.5, and 9.9 percent, respectively, and to death in seven, 11, and eight patients in those respective groups. The most frequent grade 3–4 immune-mediated AE in the durvalumab + chemotherapy and durvalumab + tremelimumab + chemotherapy arms was hepatic events (2.4 and 2.1 percent, respectively).

“Overall, the safety profile was similar across all three arms, with no new safety signals identified,” noted Johnson. “Adding tremelimumab to durvalumab + chemotherapy did not lead to a meaningful increase in treatment discontinuation,” she said.

A potential new first-line SoC

“Immunotherapies targeting the PD-1/PD-L1 pathway have transformed the treatment of mNSCLC as monotherapy and in combination with chemotherapy,” said Johnson.

“There is emerging evidence that adding anti-CTLA-4 to anti-PD-L1 ± chemotherapy might confer additional clinical and long-term survival benefit in selected patient populations,” she continued. [N Engl J Med 2019;381:2020-2031; Lancet Oncol 2021;22:198-211]

“Durvalumab + tremelimumab + chemotherapy represents a potential new first-line treatment option for mNSCLC,” she concluded.