Feb 27, 2023
In this JCO Article Insights episode, Emily Zabor summarizes two articles from the February 20th, 2023 Journal of Clinical Oncology issue: "Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study" by Johnson, et al and "The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?" by Remon, et al.
The Original Report by Johnson, et al describes results of the Phase III POSEIDON clinical trial. The accompanying editorial by Remon, et al discusses the findings of a significant progression-free survival and overall survival benefit for the combination of tremelimumab plus durvalumab plus chemotherapy as compared to chemotherapy alone, which were secondary endpoints in the trial.
TRANSCRIPT
Emily Zabor: Welcome to JCO Article Insights for the February 20, 2023, issue of JCO. I’m your host, Emily Zabor, JCO Biostatistics Editorial Fellow.
Today, I will be providing summaries for two articles. The first article, titled ‘Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study,’ by Dr. Melissa Johnson and colleagues, describes the results of the Phase III POSEIDON clinical trial. POSEIDON was a randomized Phase III clinical trial in patients with metastatic non-small cell lung cancer. The trial had a three-arm design to evaluate the efficacy of tremelimumab plus durvalumab plus chemotherapy; durvalumab plus chemotherapy; and chemotherapy alone in a first-line treatment setting. The two immunotherapies were selected for study because of their complementary mechanisms of action. Tremelimumab is an anti-CTLA-4 antibody which can diversify T-cell responses and lead to increased tumor infiltration. Durvalumab is an anti-PDL1 antibody which can enhance T-cell function. Chemotherapy is still an important treatment option for early disease control and potential for immune priming.
Patients in the POSEIDON trial were randomized to the three arms with equal allocation. The co-primary endpoints for the trial were progression-free survival and overall survival for the comparison of durvalumab plus chemotherapy vs. chemotherapy alone. Then, a hierarchical multiple-testing procedure with a gatekeeping strategy was used across the primary endpoints and key secondary endpoints. Gatekeeping procedures are a way of controlling the type I error rate across multiple groups of null hypotheses that have a hierarchical structure, meaning that some of the hypotheses are considered more important than others. In this case, the plan was to first test for differences in progression-free survival and overall survival between the durvalumab plus chemotherapy and chemotherapy alone arms. Then, if either of those tests had a significant p-value so that the null hypothesis of no difference between groups was rejected, tests for differences in progression-free survival and overall survival between the tremelimumab plus durvalumab plus chemotherapy and chemotherapy alone arms would be conducted. Additional levels of testing could be conducted for other secondary endpoints following significance at the previous level. These types of gatekeeping procedures are a rigorous way of controlling the type I error of the entire study at 5% while still allowing multiple tests to possibly be conducted.
The efficacy analyses were conducted in the intention-to-treat population, which included 338 patients on the tremelimumab plus durvalumab plus chemotherapy arm, 338 patients on the durvalumab plus chemotherapy arm, and 337 patients on chemotherapy alone. The median follow-up among those without an event was 10.3 months for progression-free survival and 34.9 months for overall survival. The findings for the co-primary endpoints were that progression-free survival was significantly improved with durvalumab plus chemotherapy versus chemotherapy alone, with 12-month progression-free survival rates of 24.4% versus 13.1%. There was no statistically significant difference in overall survival, with 24-month overall survival rates of 29.6% versus 22.1%.
Because progression-free survival was significantly different in the durvalumab plus chemotherapy versus chemotherapy alone arms comparison, according to the hierarchical testing procedure, the study proceeded to compare efficacy between the tremelimumab plus durvalumab plus chemotherapy and chemotherapy alone arms. Both progression-free survival and overall survival were significantly higher for the tremelimumab plus durvalumab plus chemotherapy arm, with 12-month progression-free survival rates of 26.6% versus 13.1% and 24-month overall survival rates of 32.9% versus 22.1%. The tremelimumab plus durvalumab plus chemotherapy arm had higher rates of grade III or IV treatment-related adverse events and immune-mediated adverse events as compared to the other two arms. The rates of grade III or IV treatment-related adverse events were 51.8%, 44.6%, and 44.4%, and the rates of immune-mediated adverse events were 33.6%, 19.2%, and 5.1% for the tremelimumab plus durvalumab plus chemotherapy; durvalumab plus chemotherapy; and chemotherapy alone arms, respectively.
This paper also reports on a number of subgroup analyses of overall survival comparing both the tremelimumab plus durvalumab plus chemotherapy and durvalumab plus chemotherapy arms to chemotherapy alone to examine consistency of effect across subgroups of patients. The results were found to be generally consistent across subgroups according to sex, age, tumor PD-L1 expression levels, histology, planned chemotherapy regimen, smoking history, race, ECOG Performance Status, and AJCC disease stage at diagnosis. Notably, patients with less than 1% PD-L1 tumor cells had no difference in hazard of death on durvalumab plus chemotherapy versus chemotherapy alone with a hazard ratio of 0.99, but had a reduced hazard of death on tremelimumab plus durvalumab plus chemotherapy versus chemotherapy alone with a hazard ratio of 0.77. But the study was not powered to conduct statistical tests for the subgroups, so no p-values are reported, and no strong conclusions can be drawn from the subgroup analyses.
Dr. Johnson and colleagues conclude that durvalumab plus chemotherapy significantly improved progression-free survival as compared to chemotherapy alone, and tremelimumab plus durvalumab plus chemotherapy significantly improved both progression-free survival and overall survival as compared to chemotherapy alone. The authors suggest that adding a limited course of tremelimumab to durvalumab and four cycles of chemotherapy provided long-term survival benefits to patients with metastatic non-small cell lung cancer and may represent a new first-line treatment option.
The second article, titled ‘The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?’ by Dr. Jordi Remon and colleagues, is an editorial related to the first article just described. In the editorial, the authors discussed the findings of a significant progression-free survival and overall survival benefit for the combination of tremelimumab plus durvalumab plus chemotherapy as compared to chemotherapy alone, which were secondary endpoints in the trial. Recall that the POSEIDON trial had two co-primary endpoints of progression-free survival and overall survival for the comparison of durvalumab plus chemotherapy to chemotherapy alone, and the secondary endpoints were only evaluated since the co-primary endpoint of progression-free survival was found to be significant.
Dr. Remon and colleagues note that while there was no head-to-head comparison of the durvalumab plus chemotherapy and tremelimumab plus durvalumab plus chemotherapy arms, the tremelimumab plus durvalumab plus chemotherapy regimen had only a modest increase in progression-free survival and overall survival rates, but much higher rates of immune-related adverse events as compared to the durvalumab plus chemotherapy regimen. The authors suggest that following this trial, we still don't know what subset of patients would benefit from a dual immunotherapy treatment approach or what is the optimal duration of such treatment protocols. Recall that in POSEIDON, while efficacy was estimated in pre-planned subgroups, the study was not powered to detect effects within subgroups, so no statistical comparisons were made, and therefore no definitive conclusions could be drawn about whether a particular subgroup did or did not benefit from either of the experimental arms.
The authors point out that many combinations of immunotherapies have been studied for patients with advanced non-small cell lung cancer, and that there is likely little benefit from further studies where new drugs are added to current protocols in unselected patients. The authors emphasize that new predictive markers are urgently needed, especially given the financial toxicity associated with the use of immunotherapies. They propose that the study of such markers should be at the forefront of future trials.
That concludes this episode on the articles ‘Durvalumab With or Without Tremelimumab in Combination with Chemotherapy as First Line Therapy for Metastatic Non-Small Cell Lung Cancer: Phase III POSEIDON Study’, and the associated editorial, ‘The POSEIDON Trial: Will Secondary Endpoints Change Our Clinical Practice?’
Thank you for listening, and please tune in for the next episode of JCO Article Insights.
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Articles
The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice?
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