The PROCLAIMSM observational database informs upon the real-world use and outcome of high dose interleukin-2 (HD IL-2) therapy for metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC) patients in the era of targeted therapy (TT) and checkpoint inhibitory immunotherapy (CPI). This retrospective analysis of contemporary patients with mM and mRCC, treated with HD IL-2 between 2005 and 2012, reveals improved median overall survival (OS) compared to historical experience. Importantly, because patient demographics and dosing of HD IL-2 recorded in the PROCLAIMSM registry reflect prior reports of HD IL-2 treated populations and because the OS reported is consistent with that reported by recent single institution reports of IL-2-treated patients [1,2] and a prospective multi-institutional study in mRCC (SELECT) , the PROCLAIM observational database both solidified the conclusions of these studies and provides a richer picture of the benefits of high dose IL-2 [4,5,6].
A valuable aspect of the PROCLAIM database is that the enrolled patients were treated during a transition period when novel agents were being developed for the initial or follow-on treatment of mRCC and mM, and became commercially available for these indications in 2006 and 2011 respectively. This provides the opportunity to study the impact of sequencing of other therapies and IL-2. Indeed, there is a mix of registry patients who received HD IL-2 as their initial treatment for advanced disease and those who received prior systemic therapies (mM no prior systemic treatment, N=93; prior systemic treatment, N=77; mRCC no prior systemic treatment, N=162, prior systemic treatment, N=30). Clinical trials involving the newer TTs and more recent CPIs report improved survival of patients with mM and mRCC, perhaps in part relating to use of multiple sequential treatments with different mechanisms of action. Similarly, follow-on treatment with these drugs is likely to be additive to the survival of patients treated with HD IL-2.
One of the most important findings of the PROCLAIM database is that HD IL-2 uniformly appears to have a positive treatment effect on the survival of patients whose best response is SD, in addition to those achieving CR and PR. This is also suggested in the prospective IL-2 SELECT RCC trial . We hypothesize that SD is a clinically relevant drug effect that is related to HD IL-2, as has been demonstrated with TT, contributing to prolonged survival. Because the data presented here were collected retrospectively, we do not have information on specific treatment(s) that patients received upon experiencing post IL-2 disease progression. However, we have evaluated the potential impact of additional treatments by evaluating OS in the group treated with HD IL-2 from 2005-2009 versus from 2010-2012. We predicted that the latter group would have had superior access to the newer agents available outside the context of clinical trials, which had more strict eligibility criteria (including definite PD). However, surprisingly, there was no significant difference in OS between the two time periods. The impact of sequential therapies is currently being evaluated in the prospectively collected PROCLAIM database.
We believe that studies of combinations of IL-2 and TT or CPI should be performed, but in the meantime, the PROCLAIM database will provide important data regarding interactions between these therapies. Further, the database will continue to generate new insights into the efficacy and safety of high dose IL-2 in its continuing role in the treatment of mRCC and mM. The progress in tumor immunotherapy has offered new hope for patients with cancer and resulted in numerous new possible combination strategies for clinical investigation. Furthermore, the value proposition, including therapeutic effectiveness, toxicity and cost has not been fully determined for immunotherapy agents. The rapid access to a prospectively collected database, such as PROCLAIM, brings an important resource for developing better therapeutic strategies for patients and will help confirm the true value of IL-2 and other immunotherapy approaches for the treatment of cancer.
Written by: GA Daniels, MKK Wong, HL Kaufman, MA Morse, DF McDermott, JI Clark, H Hua T Rao, JP Dutcher ( PROCLAIM Steering Committee).
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