The addition of the CTLA-4 inhibitor tremelimumab to durvalumab and chemotherapy in the first-line setting has already demonstrated an overall survival and progression-free survival benefit vs chemotherapy alone in patients with metastatic non–small cell lung cancer (NSCLC). According to data presented at the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer (WCLC), however, the triplet combination may also improve survival in difficult-to-treat subgroups of the disease.¹

Results from the exploratory analysis of the phase III ­POSEIDON study also favored the triplet combination with respect to depth of response, incidence of response, and durability when compared with durvalumab plus chemotherapy or chemotherapy alone. Even in the subgroups characterized by poor responses to any treatment, authors of the study reported that the addition of a limited course of tremelimumab to durvalumab and chemotherapy led to more frequent and deeper responses, including complete responses with sustained disease control.

Solange Peters, MD, PhD

“This study is exploratory in nature, but these data suggest the use of tremelimumab plus durvalumab and chemotherapy is a potential first-line treatment of metastatic NSCLC in harder-to-treat patient subgroups, such as those with STK11-, KEAP1-, or KRAS-mutated tumors,” said lead study author Solange Peters, MD, PhD, Chair and Professor of Medical Oncology at the University Hospital of Lausanne, Switzerland.

As Dr. Peters explained, CTLA-4 inhibition activates and expands the T-cell population, leading to increased T-cell infiltration at the tumor site, whereas PD-L1 inhibition overcomes T-cell suppression at the tumor site. These two therapies have been shown to work effectively in combination with chemotherapy, which brings initial disease control and promotes tumor antigen presentation through direct killing of tumor cells, she added.

“With clinical experience, patient populations with poor outcomes on current standard-of-care treatments are beginning to emerge,” Dr. Peters continued. “STK11-mutated and KEAP1-tumors, for example, are associated with a poor prognosis, being immunologically ‘cold’ and lacking T-cell infiltration. KRAS-mutated tumors are generally responsive to PD-L1–based therapy, unless associated with co-mutations such as STK11 and KEAP1,” she said.

Study Methods

The phase III POSEIDON study randomly assigned 1,013 patients with metastatic NSCLC to first-line treatment with one of the following three regimens: tremelimumab plus durvalumab plus chemotherapy; durvalumab plus chemotherapy; or chemotherapy alone. Investigators stratified patients by tumor cell PD-L1 expression (≥ 50% vs < 50%), disease stage (IVA vs IVB), and histology (squamous vs nonsquamous).

The study’s primary outcomes were progression-free and overall survival in patients with or without functional mutations in KRAS, STK11, or KEAP1. For this exploratory analysis of data from POSEIDON, Dr. Peters and colleagues looked at outcomes by STK11, KEAP1 and KRAS mutational status. 

Triplet Combination: More Frequent and Deeper Responses

As Dr. Peters reported, 96% of randomly assigned patients with nonsquamous cell histology had tumors that were molecularly characterized. KRAS, STK11, and KEAP1 mutations were seen in 30%, 14%, and 6% of these patients, respectively.

In this exploratory analysis, researchers observed a trend for overall survival benefit with first-line tremelimumab and durvalumab plus chemotherapy vs chemotherapy alone in STK11-mutated (hazard ratio [HR] = 0.56), KEAP1-mutated (HR = 0.43), and KRAS-mutated (HR = 0.56) nonsquamous cell carcinoma. Similar trends were observed for progression-free survival.

In these patient subgroups, the addition of a limited course of tremelimumab to durvalumab and four cycles of chemotherapy also led to more frequent and deeper responses, including complete responses, with sustained disease control, said Dr. Peters, and the median duration of response has still not been met. The overall response rates were 45.2%, 45.5%, and 55.0% for STK11-, KEAP1-, and KRAS-mutated subgroups, respectively. 

“The small sample size of some subgroups limits interpretation, but these data support tremelimumab plus durvalumab plus chemotherapy as a potential first-line option for patients with these hard-to-treat mutations that have been characterized by poor response to therapy in the past, including immunotherapy,” Dr. Peters concluded. 

DISCLOSURE: Dr. Peters reported financial relationships with AbbVie, Amgen, Arcus, AstraZeneca, Bayer, BeiGene, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, F-Star, Fishawack, Foundation Medicine, Genzyme, Gilead Sciences, GSK, IIlumina, Imedex, IQVIA, Incyte, iTeos, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Novocure, Oncology Education, PharmaMar, Phosplatin Therapeutics, PER, Pfizer, PRIME, Regeneron, RMEI, Roche/Genentech, RTP, Sanofi, Seattle Genetics, Takeda, and Vaccibody.

REFERENCE

1. Peters S, Cho BC, Luft A, et al: Association between KRAS/STK11/KEAP1 mutations and outcomes in POSEIDON: Durvalumab ± tremelimumab + chemotherapy in mNSCLC. 2022 World Conference on Lung Cancer. Abstract OA15.04. Presented August 9, 2022.