Defining the Most Appropriate Primary End Point in Phase 2 Trials of Immune Checkpoint Inhibitors for Advanced Solid Cancers

Abstract

In checkpoint-inhibitor trials, ORR correlated poorly with OS. For future phase 2 studies, 6-month PFS rate is recommended as an end point.

Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer

“…Of interest in this study is the finding of encouraging disease control and survival benefit without high objective response rates. As recently reported by others in a large meta analysis of 87 clinical trials of solid tumors treated with immune checkpoint inhibitors, there is a lack of correlation between response rate and survival (31). The reasons for this are uncertain, but it could be due to the triggering of a persistent immune response that maintains durable tumor growth control despite the absence of an immediate elimination of tumor cells.…”

Immune checkpoint inhibitors for head and neck squamous cell carcinoma: Current landscape and future directions

“…ORR is considered to be an important clinical endpoint for cancer clinical trials . However, several analyses showed that ORR may not be a reliable surrogate for OS . For example, two important anti‐PD1/PD‐L1 phase III combination studies were conducted based on their high ORR in earlier phase trials—epacadostat and pembrolizumab for melanoma, and atezolizumab‐cobimetinib for colon cancer .…”

“…These two studies showed the limitation of ORR as surrogates for OS benefits. Other surrogates for predicting OS benefits have been proposed, including 6‐month PFS rate, milestone survival analyses, or a high ORR (>30%) …”

“…79,80 However, several analyses showed that ORR may not be a reliable surrogate for OS. 81,82 For example, two important anti-PD1/PD-L1 phase III combination studies were conducted based on their high ORR in earlier phase trials-epacadostat and pembrolizumab for melanoma, 55,56 and atezolizumab-cobimetinib for colon cancer. 83 Both regimens showed encouraging ORR in early phase I/II trials 56,83 ; however, confirmatory phase III trials of both regimens reported a lower ORR than expected.…”

“…These two studies showed the limitation of ORR as surrogates for OS benefits. Other surrogates for predicting OS benefits have been proposed, including 6-month PFS rate, 82 milestone survival analyses, [84][85][86] or a high ORR (>30%). 79 As discussed earlier, the crossover on survival curves, reflecting delayed clinical effects, 86 is another unique feature of cancer immunotherapy studies.…”