“If This Is True” – What Does This Mean for Clinical Trials?

On March 19, 2019, the FDA released an Impact Story with implications for nearly everyone in the biopharma industry, either professionally as we try to develop the miracle drug, or personally with loved ones who are fighting the ultimate fight against cancer. The “Impact Story: Determining the Clinical Benefit of Treatment Beyond Progression with Immune Checkpoint Inhibitors” was the result of CDER regulatory science researchers evaluating whether it is clinically beneficial to treat cancer patients with checkpoint inhibitors (CPIs) if their tumors do not immediately respond to treatment.

FDA conducted a retrospective analysis of pooled data from eight melanoma trials submitted to the Agency1. The eight studies encompassed 2,600 patients treated with CPIs (pembrolizumab or nivolumab). Half of those patients progressed while receiving CPI therapy. Within this subset of patients, approximately 600 patients received treatment beyond documented progression and approximately the same number of patients did not (although many of these patients received other types of concurrent treatment). The group who received treatment beyond progression achieved a longer, more than double, median overall survival than the group who did not (24.2 months compared with 11.2 months).

So, what does this mean? On its surface, this data is exciting – suggesting that the benefits of CPI-based regimens might extend well beyond an initial three-month disease assessment following treatment initiation. Hard conclusions cannot be drawn from a retrospective study at this point as so many of the usual various factors (prognostic factors, disease stage, prior therapies, etc.) influencing outcomes should be considered.  In addition, the state-of-the-art of evaluating CPI-based therapy and oncology treatment ranging from approaches to measuring the tumor response (radiographically, radiomics, and/or biopsy analysis), to clinical trial design considerations towards combination therapy approaches, and patient eligibly has evolved since those eight studies were conducted.  Despite these caveats, the analysis FDA presented remains intriguing to anyone working in the oncology space. A 13-month improvement in median survival in virtually all settings is a phenomenal success.

CPI treatment has been hailed as “game-changing” and the rapid adoption of CPI in early-stage treatment for Melanoma, Non-small Cell Lung Cancer, Head and Neck Squamous Cell Cancer, Classical Hodgkin’s Lymphoma, Primary Mediastinal Large-B Cell Lymphoma, Urothelial Carcinoma and more suggests it truly is offering hope to patients in a very broad sense. The industry has contended that CPI-based regimens could have the long-term impact on patients that current study designs and tools are insufficient to detect and measure.  Overall survival (OS) is still the gold standard as the most reliable and precise clinical endpoint, effectively immune from bias. FDA has focused on OS as the key endpoint for determining benefit following progression on CPI therapy knowing that at the end of a study, patients would ultimately move on to additional therapies or regimens. Does this analysis of long-term outcome post-CPI therapy impact the hierarchy of endpoints used in clinical trials evaluating a checkpoint inhibitor?  This is a topic for continued debate, as the prognostic factors (e.g. absence of rapidly progressing disease, ECOG status, life expectancy, and laboratory values) tumor type and available therapies will undoubtedly impact the evaluation of any primary clinical endpoint.

With respect to evaluating the potential for the clinical benefit of a CPI therapy following progression, how long should patients be followed? Could or should you do a long-term registry study for all patients so that the initial endpoint (Response Rate (RR), progression-free survival (PFS), or OS) of a study is only the first piece of data that shows the immediate effects of the CPI monotherapy or combination therapy?  This design might prove that disease control for some drugs does translate to increased OS over the life of the patient, even when tumors are not eradicated. This would be a long study but if the goal is as FDA says, “clinical benefit” and that is defined as survival, then overall improvement in life span, regardless of when it occurs (on study or 2 years later) should be equally important for approval.

Given the FDA’s mission to further evaluate and understand the clinical benefits of CPI therapy beyond progression, in addition to our quest to find the cure for cancer, we expect there to be more transparency and collaboration between the FDA and sponsors. In clinical trials evaluating CPI combination therapy, criteria to determine when a patient has progressed and the prognostic factors to determine if this patient should continue to receive combination therapy, or CPI monotherapy have recently emerged as critical issues. The potential to achieve a clinical benefit that is not measured solely by response rate or progression-free intervals requires a clearly described methodology in clinical protocols.

1 = These trials were in support of marketing applications for anti-programmed death receptor-1 (PD-1) antibodies alone or in combination for the treatment of patients with unresectable or metastatic melanoma that allowed for the continuation of the antibody beyond RECIST-defined progression in the anti-PD-1 group and were approved by FDA before Jan 1, 2017 (Beaver et al.,2018).

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