The study involved over 1,000 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 reported. However, adding both tremelimumab and durvalumab significantly increased both PFS (by 28%) and OS (by 23%). Median OS was 14.0 months versus 11.7 months for chemotherapy.
The results were presented on Sept. 9 at a presidential symposium of the World Conference on Lung Cancer 2021.
The two immunotherapies act at different immune checkpoints – tremelimumab acts at CTLA-4, and durvalumab acts at programmed death–1/PD–ligand 1 (PD-L1). 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 metastatic non–small cell lung cancer,” said lead researcher Melissa L. Johnson, MD, from the Sarah Cannon Research Institute, Nashville, Tenn.
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, 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 Dr. Brahmer, is that, in the 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, Dr. 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.
Dr. Brahmer concluded that, although the triple therapy improved survival outcomes in the current study, 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,” Dr. 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 versus monotherapy need to be defined, commented Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia. He added that “PD-L1 may be one biomarker, but we need more.”