First-line durvalumab-tremelimumab regimen improves outcomes in NSCLC subset
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First-line treatment with durvalumab plus tremelimumab and chemotherapy appeared effective for patients with metastatic non-small cell lung cancer, according to randomized phase 3 study results.
In addition, findings from the POSEIDON trial presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer revealed no new safety signals with the combination.
“Durvalumab [Imfinzi, AstraZeneca] targets PD-L1— which is expressed within tumor cells — while tremelimumab [MedImmune/AstraZeneca] targets CTLA-4, which is more commonly expressed on cells in metastatic lymph nodes in addition to the tumor microenvironment,” Melissa Johnson, MD, director of the lung cancer research program at Sarah Cannon Research Institute, told Healio.
“These antibodies act on different immune checkpoints that tend to be more highly expressed on different cells, and the idea is that their actions are complimentary,” Johnson added. “Tremelimumab acts early in the immune response to lower the threshold for T-cell activation and enables more T-cells to be activated, whereas durvalumab acts later on at the level of the tumor.”
The anti-CTLA-4 antibody ipilimumab (Yervoy, Bristol Myers Squibb) can be combined safety with chemotherapy for patients with lung cancer, and it also can be used with durvalumab.
“Since chemotherapy plus immunotherapy is now the first-line standard treatment for many patients with lung cancer, a natural next step was to ask whether durvalumab plus tremelimumab could also be combined with chemotherapy safely and whether it might be more effective than [anti-PD-1 therapy] plus chemotherapy alone can be for patients with NSCLC — in particular for a subset like [patients with PD-L1 expression less than 1%, for whom] even chemotherapy with immune therapy does not always work well,” Johnson said.
The POSEIDON trial evaluated durvalumab with or without tremelimumab in combination with investigator’s choice of chemotherapy as first-line treatment for 1,013 patients with squamous or nonsquamous metastatic NSCLC.
Researchers randomly assigned patients to one of three regimens.
They assigned 338 patients (median age, 64.5 years; 74.9% men; 53.8% white) to 1,500 mg durvalumab every 4 weeks with four cycles of platinum-based chemotherapy once every 3 weeks.
They assigned 338 patients (median age, 63 years; 79.6% men; 60.7% white) to durvalumab plus 75 mg tremelimumab every 4 weeks plus chemotherapy, followed by maintenance therapy with durvalumab alone or durvalumab plus one dose of tremelimumab.
And they assigned 337 patients (median age, 64 years; 73.6% men; 53.1% white) up to six cycles of chemotherapy alone.
Overall, 28.8% of patients had PD-L1 expression on 50% or more of tumor cells. Nearly half (49.6%) had stage IVB disease and approximately 37% had squamous histology.
Co-primary endpoints included PFS by blinded independent review and OS for durvalumab plus chemotherapy vs. chemotherapy alone. Secondary endpoints included PFS and OS for durvalumab plus tremelimumab plus chemotherapy vs. chemotherapy groups.
Researchers reported significantly longer median PFS among patients assigned durvalumab plus chemotherapy than those assigned chemotherapy alone (5.5 months vs. 4.8 months; HR = 0.74; 95% CI, 0.62-0.89). Researchers also observed a trend for improved median OS with durvalumab plus chemotherapy vs. chemotherapy alone (13.3 months vs. 11.7 months; HR = 0.86; 95% CI, 0.72-1.02).
Researchers reported significantly improved median PFS for patients assigned durvalumab plus tremelimumab and chemotherapy vs. chemotherapy alone (6.2 months vs. 4.8 months; HR = 0.72; 95% CI, 0.6-0.86). They also reported a trend toward improved median OS with durvalumab plus tremelimumab and chemotherapy (14 months vs. 11.7 months; HR = 0.77; 95% CI, 0.65-0.92).
“In particular, we noticed improved separation of the curves with the addition of tremelimumab, with a characteristic flattening of the curve that we have come to look for with the addition of anti-CTLA-4 agents,” Johnson said.
Results also showed higher objective response rates and longer duration of response among patients treated with immunotherapy plus chemotherapy. More than twice as many patients assigned durvalumab, tremelimumab and chemotherapy than the control regimen remained in response at 12 months (49.7% vs. 21.4%).
The addition of tremelimumab did not seem to affect the exposure of patients to chemotherapy or durvalumab, and investigators observed no new safety signals.
“The results of the POSEIDON trial provide another potential first-line treatment option for metastatic NSCLC,” Johnson said. “[Because] all treatment does not ‘fit’ all [patients with lung cancer], durvalumab plus tremelimumab plus chemotherapy offers one more option for patients and physicians to choose from. We found this may be a treatment option for patients with tumors expressing low levels of PDL1-expression.”
Despite the efficacy observed with immunotherapy, few biomarkers exist to help guide selection of first-line treatment, Johnson said.
“In much the same way that a [next-generation sequencing] profile helps us select the correct targeted therapy for appropriate patients, we need a way to discern which option — anti-PD-1/PD-L1, anti-PD-1/PD-L1 plus chemotherapy, anti-PD-1/CTLA-4 or anti-PD-1/CTLA-4 plus chemotherapy — is best for a particular patient,” Johnson added. “We need a way to figure out which patients will develop immune-mediated toxicities and — beyond initial treatment with immunotherapy with or without chemotherapy — who will respond to additional immunotherapy-based therapies, while who would be better served with additional chemotherapy or novel antibody-drug conjugates.”
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Johnson M, et al. Abstract PL02.01. Presented at: IASLC 2021 World Conference on Lung Cancer (virtual meeting); Sept. 8-14, 2021.
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