Get your free personalized podcast brief
We scan new podcasts and send you the top 5 insights daily.
The adoption of Major Pathologic Response (MPR), defined as ≤10% viable tumor cells, as a primary endpoint in lung cancer trials was a pragmatic decision. It was proposed because early therapies were not effective enough to consistently induce Pathologic Complete Response (pCR), which remains the ideal gold standard.
Related Insights
Minimal Residual Disease (MRD) negativity is now recognized by regulators as a surrogate endpoint in oncology. Because it is considered 'reasonably likely to predict progression-free survival,' this shift allows drug developers to use MRD data to support accelerated approval pathways, expediting the availability of new therapies.
The trial's 57.1% pathologic complete response (pCR) rate is deceptively conservative. It categorized patients who responded well but declined surgery as non-responders, suggesting the treatment's true biological efficacy is even higher than the already impressive reported figure.
The PROTEUS trial used two pathologic endpoints. The investigator suggests Residual Cancer Burden (RCB), which measures cellularity, is a more meaningful reflection of response than just residual tumor size. The RCB endpoint showed a much larger treatment effect (30% vs. 11%) compared to the tumor size endpoint (9% vs. 1%).
In a pivotal neoadjuvant trial of cemiplimab for CSCC, none of the 40 patients who achieved a pathologic complete response (path CR) had relapsed at long-term follow-up. This suggests that path CR can be used as a powerful early indicator of long-term disease control and potential cure.
Data from trials like CheckMate 816 shows that achieving a Pathologic Complete Response (PCR) after neoadjuvant chemo-immunotherapy is a powerful early surrogate endpoint. Patients with PCR demonstrate markedly improved overall and event-free survival.
Unlike immunotherapy, neoadjuvant osimertinib yields poor pathologic complete response (pCR) rates. However, it significantly improves major pathologic response (MPR) and survival, suggesting pCR may be the wrong efficacy endpoint for cytostatic EGFR TKIs, which have a different mechanism of action than immunotherapy.
While depth of response strongly predicts survival for an individual patient, the FDA analysis concludes it cannot yet be used as a surrogate endpoint to replace overall survival in pivotal clinical trials. It serves as a measure of drug activity, similar to response rate, but is not sufficient for drug approval on its own.
The LEAP-010 trial showed a combination therapy improved tumor response and progression-free survival but failed to improve overall survival, the ultimate measure of benefit. This highlights the risk of relying on surrogate endpoints, which can be misleading, especially when a treatment adds significant toxicity.
Immunotherapies can be effective even without causing significant tumor shrinkage. Immunocore's drug KimTrack had a low 5-7% objective response rate (ORR) but demonstrated a massive overall survival (OS) benefit, challenging the reliance on traditional chemotherapy metrics for evaluating modern cancer treatments.
An expert oncologist identified a pathological complete response (pCR) rate over 50% as the benchmark that would fundamentally alter treatment. The EV Pembro trial's 57% pCR rate crossed this threshold, forcing a shift from a surgery-centric model toward bladder preservation strategies and systemic therapy.