After 4 years, a limited course of five cycles of tremelimumab added to durvalumab plus chemotherapy extended overall survival in patients with metastatic non–small cell lung cancer (NSCLC) compared with chemotherapy alone, according to an updated exploratory analysis of the phase III POSEIDON trial, presented at the European Society for Medical Oncology (ESMO) Congress 2022.1
Study Details and Primary Results
Results of the primary analysis of POSEIDON were presented at the International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer.2 In the randomized, open-label, global, multicenter phase III study, 1,013 treatment-naive patients with EGFR/ALK wild-type metastatic NSCLC were randomly assigned in a 1:1:1 ratio to one of three treatment arms:
- Durvalumab at 1,500 mg plus chemotherapy every 3 weeks for four cycles followed by durvalumab at 1,500 mg every 4 weeks until disease progression
- The same dose of durvalumab plus a limited course of tremelimumab at 75 mg concurrently with chemotherapy every 3 weeks for up to four cycles, followed by durvalumab at 1,500 mg every 4 weeks as maintenance until disease progression, with one additional dose of tremelimumab after chemotherapy (week 16)
- Chemotherapy every 3 weeks for up to six cycles.
Eligibility criteria included stage IV NSCLC; EGFR/ALK wild-type mutations; an Eastern Cooperative Oncology Group performance status of 0 or 1; treatment-naive for metastatic disease; and tumor biopsy and baseline plasma samples for circulating tumor DNA (ctDNA). All patient tumors were molecularly characterized via sequencing of tissue and/or ctDNA samples.
Durvalumab plus tremelimumab and chemotherapy reduced the risk of death by 23% vs chemotherapy alone, with a median overall survival of 14.0 months vs 11.7 months (hazard ratio [HR] = 0.77; 95% confidence interval [CI] = 0.65–0.92; P = .00304), and a median progression-free survival of 6.2 months vs 4.8 months (HR = 0.72; 95% CI = 0.60–0.86; P = .0003).
The durvalumab plus chemotherapy arm showed a hazard ratio for progression-free survival of 0.74 (95% CI = 0.62–0.89; P = .0009), with a median progression-free survival of 5.5 months vs 4.8 months for chemotherapy alone. A positive trend of overall survival for the comparison between these two arms did not reach statistical significance.
Updated Findings
At a median follow-up of 46.5 months, the triplet combination led to a median overall survival of 14 months vs 11.7 months with chemotherapy alone, representing a 25% improvement when tremelimumab and durvalumab were added to chemotherapy. The rate of overall survival at 36 months was 25% vs 13.6%, respectively—almost double for the triplet arm of the trial.
In the updated analysis, the triplet combination improved overall survival compared with chemotherapy alone in lung cancers associated with mutations that are considered more difficult to treat: STK11, KEAP1, and KRAS. KRAS mutations occur in approximately 25% of patients with NSCLC. Tumors that harbor KEAP1 and STK11 mutations are associated with poor outcomes; although KRAS-mutated tumors can respond to immunotherapy, they are also associated with poor outcomes when in conjunction with STK11 or KEAP1 co-mutations.
The use of durvalumab plus chemotherapy led to a median overall survival of 13.3 months vs 11.7 months with chemotherapy alone. In that comparison, the 36-month overall survival rate was 20.7% vs 13.6%, respectively.
Melissa L. Johnson, MD
“Metastatic NSCLC is a devastating diagnosis, particularly for patients whose cancers are less responsive to standard treatments such as chemotherapy and immunotherapy. These results support the addition of a limited course of tremelimumab to durvalumab plus chemotherapy as a potential new treatment option for patients with these harder-to-treat forms of lung cancer,” said lead author Melissa L. Johnson, MD, Director of Lung Cancer Research at the Sarah Cannon Research Institute, Tennessee Oncology, Nashville.
The updated analysis also showed that all subgroups had improved survival on the triplet combination arm compared with chemotherapy alone. A numerical trend favored the triplet in patients with low or no levels of PD-L1.
Histology and Mutational Analysis
Overall survival was also evaluated according to histology and mutational status, and in all subgroups, the benefit of the triplet combination was consistent with the overall analysis. The overall survival benefit was greater in patients with nonsquamous metastatic NSCLC compared with squamous histology when treated with the triplet regimen vs chemotherapy alone, reducing the risk for death by 32%.
Median overall survival was 17.2 months with the triplet combination vs 13.1% for chemotherapy alone. The 3-year overall survival rate for nonsquamous histology was 31.4% vs 17.3%, respectively.
Treatment with tremelimumab plus durvalumab and chemotherapy was favored over chemotherapy in patients whose cancers harbored STK11, KEAP1, and KRAS mutations. In the subset with an STK11 mutation, the triplet reduced the risk of death by 38%, and median overall survival was 15 months vs 10.7 months with chemotherapy alone. The 3-year rate of overall survival was 25.8% vs 4.5%, respectively.
Similarly, the triplet combination reduced the risk of death by 57% in those with a KEAP1 mutation, with a median overall survival of 13.7 months vs 8.7 months for chemotherapy alone. The 3-year overall survival rate was 30.0% vs 0.0%, respectively, in this small sample size.
Tremelimumab plus durvalumab and chemotherapy reduced the risk of death by 45% compared with chemotherapy alone in the subset of patients with a KRAS mutation, and median overall survival was 25.7 months vs 10.4 months for chemotherapy alone. The 3-year overall survival rate was 40.0% vs 15.8%, respectively.
These subsets of patients were fairly small: STK11 mutations were present in 31 patients in the triplet combination group and 22 in the chemotherapy alone group; KEAP1 mutations were present in 22 patients and 6 patients, respectively; and KRAS mutations were present in 60 and 53 patients, respectively.
Expert Point of View
Formal discussant Mary O’Brien, MD, Head of the Lung Unit, the Royal Marsden Hospital, NHS Foundation Trust, London, commented on the POSEIDON trial.
Mary O’Brien, MD
“The POSEIDON trial is the largest data set we have on KRAS-mutated NSCLC [non–small cell lung cancer], with a positive signal in picking up some patients who would derive the greatest benefit from chemotherapy/immunotherapy. KRAS, KEAP1, and STK11 appear to predict better outcomes for durvalumab/tremelimumab plus chemotherapy vs chemotherapy,” Dr. O’Brien said, but she added this was not found in two other recent trials of different regimens.
With tremelimumab, durvalumab, and chemotherapy, 25.8% of those with STK11 mutations were alive at 3 years; 30% of those with KEAP1 mutations were alive at 3 years; and 40% of those with KRAS mutations were alive at 3 years.
“The survival trends suggest that a limited course of tremelimumab plus durvalumab plus chemotherapy is beneficial in those patients with these harder-to-treat mutations,” she stated.
“I want to stress that the experimental regimen [in POSEIDON] included a short course of the CTLA-4 inhibitor [tremelimumab]. The survival curves and progression-free survival curves don’t separate early, but there is a dropoff of about 5% from 3 to 4 years.
“We need much more granularity on the toxicities. Patient-reported outcomes will help, but I still I think we need new tools, such as biomarkers for organ-specific toxicity,” Dr. O’Brien told the audience.
DISCLOSURE: Dr. Johnson has served as a consultant or advisor to and received research funding from Amgen, GNE, Mirati Therapeutics, and Revolution Medicines. Dr. O’Brien reported no conflicts of interest.
REFERENCES
1. Johnson ML, Cho BC, Luft A, et al: Durvalumab ± tremelimumab + chemotherapy in 1L metastatic NSCLC: Overall survival update from POSEIDON after median follow-up of approximately 4 years. ESMO Congress 2022. Abstract LBA59. Presented September 12, 2022.
2. Johnson ML, Cho BC, Luft A, et al: Durvalumab ± tremelimumab + chemotherapy as first-line treatment for metastatic NSCLC: Results from the phase 3 POSEIDON Study. Thorac Oncol 16:S844, 2021.
