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Adding two immunotherapeutic drugs to chemotherapy significantly improved progression-free survival (PFS) and overall survival (OS) in untreated metastatic non-small cell lung cancer, according to a secondary analysis of a randomized trial.

Median PFS improved from 4.8 months with chemotherapy alone to 6.2 months with the addition of the PD-L1 inhibitor durvalumab (Imfinzi) and the CTLA-4 inhibitor tremelimumab. Median OS increased from 11.7 to 14.0 months with the two checkpoint inhibitors. Patients with nonsquamous tumors appeared to derive greater benefit from the addition of tremelimumab.

The overall results with durvalumab plus tremelimumab and chemotherapy were marginally better than with durvalumab plus chemotherapy, but the trial was not designed to compare results with one versus two immunotherapeutic agents, as reported by Melissa Johnson, MD, of the Sarah Cannon Research Institute in Nashville, during the virtual World Conference on Lung Cancer (WCLC).

"First-line durvalumab plus tremelimumab and chemotherapy demonstrated statistically significant and clinically meaningful improvements in both PFS and overall survival versus chemotherapy, especially among the nonsquamous patients," Johnson said of the results.

"The safety profile was similar to previous reports of immunotherapy plus chemotherapy, with no new safety signals identified with the addition of tremelimumab. Therefore, durvalumab plus tremelimumab plus chemotherapy represents a potential new frontline treatment option for metastatic non-small cell lung cancer," she added.

Although the dual-immunotherapy regimen significantly improved PFS and OS versus chemotherapy alone, key questions remain unanswered, said the invited discussant for the study, Julie Brahmer, MD, of the Johns Hopkins Kimmel Cancer Institute in Baltimore.

Examining results across different trials, she said a PD-1/L1 inhibitor plus chemotherapy seems appropriate for PD-L1-positive tumors, although the POSEIDON results were not specifically analyzed by histology.

"I don't see that a CTLA-4 plus PD-L1 plus chemotherapy gives me any advantage in this group, though I would like to see the tail of the [survival] curve and see whether there's any advantage," said Brahmer. "For PD-L1-negative disease, I do think CTLA-4 antibodies seem to provide a benefit. If you look at the squamous-cell histology, you can see this advantage, seemingly, over a single-agent IO [immuno-oncology] plus chemotherapy."

The addition of tremelimumab was generally well tolerated but was not cost-free in terms of toxicity, she noted.

"Is the slightly increased toxicity worth the slightly increased long-term duration of response, improved progression-free survival, and overall survival?" Brahmer asked. "Which patient populations truly need CTLA-4 immune checkpoint blockade? To get to this we need to find the biomarker for CTLA-4 benefit. A practical question: Is there room in the clinic for another CTLA-4 antibody, in addition to the nivolumab [Opdivo]-ipilimumab [Yervoy] combinations?"

The previously reported phase III MYSTIC trial showed that durvalumab alone or combined with tremelimumab did not improve PFS or OS as compared with chemotherapy as initial treatment for metastatic NSCLC. Following the path created by nivolumab and ipilimumab, investigators in the POSEIDON trial sought to determine whether adding one or both of the checkpoint inhibitors to chemotherapy would improve survival as compared with chemotherapy alone.

The trial included 1,013 patients with untreated metastatic NSCLC, randomized to receive chemotherapy alone or in combination with durvalumab or durvalumab plus tremelimumab. The primary endpoints were PFS and OS for the comparison of single-agent durvalumab plus chemotherapy versus chemotherapy alone.

The key secondary endpoints, analyzed only if either primary endpoint was positive, were PFS and OS for the dual-immunotherapy regimen versus chemotherapy alone.

As , the primary analysis showed that durvalumab plus chemotherapy significantly improved median PFS versus chemotherapy alone (5.5 vs 4.8 months, P=0.00093). With continued follow-up for OS, the results did show a numerical advantage for the durvalumab arm, but the difference did not achieve statistical significance (13.3 vs 11.7 months, P=0.07581).

With a median follow-up of 10.3 months for PFS and 34.9 months for OS, the secondary analysis showed significant improvement in PFS and OS with add-on durvalumab-tremelimumab versus chemotherapy (HR 0.72, P=0.00031; HR 0.77, P=0.00304). Twice as many patients in the durvalumab-tremelimumab group were alive without progression at 12 months (26.6% vs 13.1%), and the 12-month OS was 32.9% vs 22.1% in favor of the dual-immunotherapy regimen.

As Brahmer noted in her comments, an OS subgroup analysis showed similar results with durvalumab plus chemotherapy for squamous and nonsquamous tumor (HR 0.84 and HR 0.82, respectively), and the benefits of durvalumab appeared to tail off with decreasing PD-L1 positivity from ≥50% to <1% (HR 0.63 to HR 0.99).

In contrast, durvalumab plus tremelimumab was associated with relatively greater benefit for the PD-L1 <1% subgroup (HR 0.77) and for nonsquamous tumors (HR 0.70 vs HR 0.88 for squamous histology).

Grade 3/4 treatment-related adverse events (AEs) occurred more often with durvalumab plus tremelimumab (51.8% vs 44.6% with durvalumab alone), as did serious AEs (27.6% vs 19.5%). Fatal AEs and AEs leading to treatment discontinuation occurred in a similar portion of patients treated with one or two checkpoint inhibitors.

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