The POSEIDON study was investigating a combination of chemotherapy of four cycles with durvalumab or durvalumab and tremelimumab compared to six cycles of chemotherapy alone in a large phase III environment in first line stage 4 non-small cell lung cancers without EGFR or ALK alterations. The study had this three-arm design and there were some particular aspects which should be mentioned in this context. First of all, there was a combination of four cycles of durvalumab and tremelimumab, not two cycles as compared to a previous other study. Second, tremelimumab was restricted to five applications only, four applications with chemotherapy and durvalumab and one application in the maintenance phase together with durvalumab. Then it was subsequently followed by only durvalumab maintenance, this therapy arm. Finally, there was a variety of chemotherapy combinations allowed in this protocol which was also unique compared to other studies.
The results were that the combination of chemotherapy plus immunotherapy was superior in regard to progression free survival and, and this was particularly pronounced in the combination of durvalumab and tremelimumab, also regarding overall survival in combination with chemotherapy versus chemotherapy alone. Also, the combination of durvalumab and tremelimumab with chemotherapy led to improved response rates, duration of response and, as I said earlier, progression free survival. Interestingly, if you look at subgroup analysis, in particular patients with non-squamous histology seemed to benefit from the combination of durvalumab, tremelimumab and chemotherapy.
Later, some exploratory analyses were done and looked for patients which may be hard to treat and have been associated with lack of efficacy with the addition of checkpoint inhibitors in retrospective studies such as patients with non-squamous histology and KRAS, KEAP1 or STK11 mutations. In the POSEIDON study 96% of patients had been evaluated with non-squamous non-small cell lung cancer regarding the efficacy with the analysis of KEAP1, KRAS or STK11 mutations. Indeed, the benefit of durvalumab and tremelimumab with chemotherapy versus chemotherapy alone was more pronounced in patients with mutations in these three factors so underlining that these hard to treat patients may see particular benefit from this kind of regimen.
At the ELCC I was proudly allowed to present on behalf of my co-authors some further exploratory analysis investigating the use of four versus two cycles of chemotherapy in the combination with checkpoint inhibitors. The majority of patients, 80% of patients, did receive at least four cycles of chemotherapy in the chemotherapy plus checkpoint inhibitor arms versus the chemotherapy only arm only 74% had four cycles or more. The response rates were superior in all histologies, in particular non-squamous histology versus the chemotherapy alone arm.
Interestingly, most patients did demonstrate a further benefit in the shrinkage of target lesions if you look from two versus four cycles of chemotherapy meaning that the two additional cycles of chemotherapy did result in a further shrinkage of the target lesion sizes. Moreover, about 26% of patients went from stable disease to partial response when treated with durvalumab, tremelimumab and chemotherapy. About 90% of patients who had a receipt of partial remission or complete remission after two cycles remained in partial remission or complete remission after four cycles.
Very finally, again in these patients with STK11, KEAP1 or KRAS mutations the response of chemotherapy was again more improved if you look from two versus four cycles when treated with durvalumab and tremelimumab with chemotherapy.
How might these results impact the future treatment of NSCLC?
The two additional cycles of chemotherapy did not result in higher toxicity meaning that if the patient is able to receive four cycles of chemotherapy with durvalumab and tremelimumab the patient has benefit from these two additional cycles and may also be able to stand these four cycles. Of course, if there is a major toxicity one may think about limitations but, nevertheless, these results demonstrate that four cycles is doable, at least in the study context, and also does result in higher efficacy as compared to two cycles only.
In summary, of course the durvalumab, tremelimumab and chemotherapy combination is a new, now approved, approach in stage 4 non-small cell lung cancer in Europe.