KEY TAKEAWAYS
- The CheckMate 025 interventional phase 3 study aimed to validate HPD-based selection for improved PFS/OS in clinical trials and real-world settings.
- The result demonstrated that HPD-based ICB restriction doubles the median OS benefit, while high-risk patients should seek alternative therapies or ICB-combination trials.
The precise assessment of FOXC1, MKI67, and PDL1 expression, capturing plasticity, proliferation, and immune evasion, reliably forecasts the effectiveness of Immune Checkpoint Blockade (ICB) involving PD1/PDL1 inhibitors.
While uncommon, renal cell carcinoma can exhibit hyperprogressive disease after immunotherapy, with the potential for rapid, aggressive tumor growth. Dr. Partha S. Ray and his research team conducted a study that aimed to validate if patient selection, guided by the prediction of Hyperprogressive Disease (HPD) risk using this methodology, could enhance Progression-free Survival (PFS) and/or Overall Survival (OS) in both clinical trials and real-world cohorts.
The interventional study analyzed pre-treatment tumor RNA-Seq data from advanced/metastatic melanoma (n=154,121), non-small cell lung cancer (NSCLC, n=82,140), and renal cell carcinoma (RCC, n=250,120), they assessed FOXC1, MKI67, and PDL1 expression, correlating with precise values for overall response rate (ORR), PFS, OS, and HPD. HPD, defined as time-to-treatment-failure (TTF) <= 2 months post-treatment initiation, guided the optimization of biomarker cutoff values through leave-one-out cross-validation based on model AUC. Subsequently, cancer-type specific (CTS) prediction algorithms were formulated and validated against independent CTS datasets.
In the context of advanced/metastatic conditions, clinical respondents (CR) predicted in advance demonstrated significant enhancement in PFS and OS compared to predicted non-responders with standard progressive disease (PD) or HPD. [a/m Melanoma OS HR=0.35 (0.187-0.666)95%CI, P=0.0004; a/m NSCLC OS HR=0.24 (0.119-0.499)95%CI, P<0.0001; a/m RCC OS HR= 0.45 (0.255-0.810)95%CI, P=0.008].
The study concluded that, in contrast to indiscriminate ICB administration, a refined approach targeting predicted CRs yields a striking twofold or greater enhancement in median OS benefits across diverse cancer types. Patients anticipated to carry heightened HPD risk merit consideration for non-ICB regimens or inclusion in clinical trials amalgamating ICB with alternative therapeutic agents. This study is sponsored by Bristol-Myers Squibb.
Source: https://cslide.ctimeetingtech.com/immuno23hybrid/attendee/confcal/show/session/34
Clinical Trial: https://clinicaltrials.gov/study/NCT01668784
Ray PS. “Patient selection based on hyperprogressive disease risk nearly doubles survival benefit of immune checkpoint blockade: validation of a pan-tumor tissue agnostic combined biomarker approach” Presented at ESMO IO 2023. (Abstract: 39P).
