Adding two immune checkpoint inhibitors (ICIs) to platinum-based chemotherapy significantly improved both progression-free survival (PFS) and overall survival (OS) in comparison with chemotherapy alone for patients with metastatic non–small cell lung cancer (NSCLC) in the POSEIDON trial.
The study involved over 1000 patients with stage IV NSCLC. Participants were randomly assigned to receive either two ICIs (tremelimumab and durvalumab [Imfinzi]) plus chemotherapy, or one immunotherapy (durvalumab) plus chemotherapy, or chemotherapy alone.
Adding durvalumab to chemotherapy significantly improved PFS by 26% but did not significantly improve OS, the researchers report.
However, adding both tremelimumab and durvalumab significantly increased both PFS (by 28%) and OS (by 23%). Median OS was 14.0 months, vs 11.7 months for chemotherapy.
The results were presented on September 9 at a presidential symposium of the World Conference on Lung Cancer (WCLC) 2021.
The two immunotherapies act at different immune checkpoints ― tremelimumab acts at CTLA-4, and durvalumab acts at programmed cell death protein–1/programmed cell death–ligand-1 (PD-1/PD-LI). Both drugs are from AstraZeneca, which sponsored the POSEIDON trial.
With no new safety signals identified, the triple therapy combination “represents a potential new frontline treatment option for metasatic non–small cell lung cancer,” said lead researcher Melissa L. Johnson, MD, from the Sarah Cannon Research Institute, Nashville, Tennessee.
Reacting to the new results in a discussion of the paper, Julie R. Brahmer, MD, from Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medicine, Baltimore, Maryland, said that with so many first-line treatment choices now available for advanced NSCLC, she feels like “a kid in the candy store.”
POSEIDON may give her “another choice,” but she pointed out that there are some aspects of the study to consider.
The study required patients to undergo four cycles of chemotherapy along with immunotherapy, “which certainly is standard in many of our practices.”
However, only two cycles of chemotherapy were given in the CheckMate 9LA trial, in which nivolumab (Opdivo) and ipilimumab (Yervoy) were added to chemotherapy for the treatment of stage IV NSCLC. This combination of immunotherapies, which block CTLA-4 and PD-1, is similar to the combination that was studied in the current trial, and it is already approved for use in some patients with lung cancer.
“Also key to point out,” said Brahmer, is that in POSEIDON trial, “there was a trend toward more poor prognostic factors in the chemotherapy arm, where these patients had more liver or central nervous system metastases.”
Despite these differences, the survival outcomes were similar in the two trials, and in both trials, the tails of the curves indicate that “we need to see long-term data” to determine whether the benefit is ongoing.
Which Patients for Which Combos?
Considering all the data from key trials in advanced NSCLC, Brahmer said that she believes that for patients with high PD-L1 expression, treatment with a single immunotherapy directed against PD-1 or PD-L1 “is appropriate” and that she didn’t see that adding a CTLA-4 inhibitor to the PD-L1 inhibitor and chemotherapy would give any advantage.
“But for PD-L1-negative disease, I do think CTLA-4 antibodies seem to provide a benefit, specifically seen in the CheckMate studies,” particularly for patients with squamous disease, although she noted that in POSEIDON, histology and PD-L1 status have not been analyzed.
Brahmer concluded that although in the current study, the triple therapy improved survival outcomes, several key questions remain.
These include determining what CTLA-4 inhibition adds to PD-L1 blockade and asking whether the “slightly increased toxicity” is “worth the slightly increased long-term duration of response” and improved survival outcomes.
Furthermore, it needs to be determined “which populations truly need” the combined approach; “to get to this, we need to find the biomarker for CTLA-4 benefit,” Brahmer said.
She also noted “a practical question: Is there room in the clinic for another CTLA-4 antibody in addition to the nivolumab/ipilimumab combinations?”
This last point was appreciated on social media. Jill Feldman, a lung cancer patient and advocate, described it on Twitter as a “great question.”
She said that for her, “options equal hope,” but that it is “critical” to give the “best treatment first.”
“So as a patient, I would ask: How do I know/you know which treatment would be best for me?”
With “so many options in the first-line setting,” subsets of patients who may benefit from quadruplet therapy vs monotherapy need to be defined, commented Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia, Pennsylvania. He added, “PD-L1 may be one biomarker, but we need more.”
More Details of the POSEIDON Trial
In the POSEIDON trial, investigators had the choice of different chemotherapy regimens: platinum/gemcitabine for patients with squamous disease, platinum/pemetrexed for patients with nonsquamous disease, and nab-paclitaxel/carboplatin for patients with disease of either histology, Johnson reported.
It is noteworthy that the majority of patients were from Eastern Europe and Asia, “and the proportion of squamous patients enrolled was higher than is typically seen in mixed histology lung cancer studies,” she added.
The patients were stratified by PD-L1 expression at a cutoff of 50%, disease stage, and tumor histology.
Overall, 1013 patients were enrolled. The three treatment arms were relatively well balanced in terms of baseline characteristics.
Johnson noted that there were “a few minor imbalances” in the durvalumab plus tremelimumab arm, with “fewer females, fewer Asians, and fewer never-smokers relative to the other two arms.”
The primary endpoint analysis after a median follow-up of 10.3 months demonstrated that PFS was significantly improved with durvalumab plus chemotherapy over chemotherapy alone, at a median of 5.5 months vs 4.8 months (hazard ratio [HR], 0.74; P = .00093).
Although OS improved numerically with the addition of durvalumab to chemotherapy, it did not reach significance (13.3 months vs 11.7 months with chemotherapy alone; HR, 0.86; P = .07581).
The positive PFS benefit with durvalumab plus chemotherapy triggered a secondary endpoint analysis, which showed that adding tremelimumab to durvalumab plus chemotherapy improved both survival outcomes.
Median PFS with the triple combination therapy was 6.2 months, significantly longer than the 4.8 months seen with chemotherapy alone (HR, 0.72; P = .00031).
At 12 months, 26.6% of patients who underwent treatment with durvalumab plus tremelimumab plus chemotherapy had not experienced disease progression, compared with 13.1% in the chemotherapy-alone arm.
OS was also significantly improved, at 14.0 months among patients in the triple therapy arm vs 11.7 in the chemotherapy-alone arm (HR, 0.77; P = .00304).
The results also showed that at 24 months, 32.9% of triple therapy patients were still alive, vs 22.1% in the chemotherapy-alone arm.
Analysis indicated that “most subgroups favored the addition of immunotherapy to chemotherapy.” There was a “trend towards improved survival for all patients treated with durvalumab plus tremelimumab plus chemotherapy,” Johnson said.
This was seen “in particular for the nonsquamous patients” and for those with tumor PD-L1 expression of <1%, he added.
It is notable that for a large proportion of combination-therapy patients, response had continued at 12 months. This was the case for 38.9% of those who underwent treatment with durvalumab plus chemotherapy and for 49.7% of those given triple therapy, vs 21.4% in the chemotherapy-alone arm.
As was seen across the whole cohort, among patients with nonsquamous disease, PFS and OS improved with the addition of immunotherapy. Of those patients with nonsquamous disease, 95.5% received pemetrexed plus platinum chemotherapy.
However, among patients with squamous tumors, of whom 88.3% received gemcitabine plus platinum chemotherapy, PFS and OS were “poor…across all treatment arms,” Johnson reported, “with little separation of the curves.”
She highlighted the fact that the proportion of patients who experienced grade 3/4 adverse events, whether of any cause or treatment related, was only slightly higher in the two immunotherapy arms, indicating that “most events were driven by the chemotherapy.”
The rates of treatment discontinuation and adverse events leading to death were also similar across the three treatment arms, albeit they were slightly higher with the addition of immunotherapy.
Johnson also noted that although there were more immune-mediated adverse events with durvalumab plus tremelimumab plus chemotherapy compared to durvalumab plus chemotherapy, the “majority were grade 1/2 and were manageable.”
The most common immune-mediated events in the two immunotherapy arms were hypothyroid and hepatic events, pneumonitis, dermatitis, and rash.
The study was sponsored by AstraZeneca. Johnson reports numerous relationships with pharmaceutical companies. Brahmer reports relationships with Amgen, AstratZeneca, BMA, Genentech/Roche, Eli Lilly, Eisai, GlaxoSmithKline, Janssen, Merck, RAPT Therapeutics Inc, Regeneron, Revolution Medicine, and Sanofi.
World Conference on Lung Cancer (WCLC) 2021: Abstract PL02.01. Presented September 10, 2021.
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