PII-215 - EVALUATING THE EFFICACY OF COMBINATION OF CHECKPOINT INHIBITORS AND CHEMOTHERAPY IN LUNG CANCER USING A MECHANISTIC MODEL

K. Thiagarajan¹, A. Mohan², M. Channavazzala³, A. Sareen⁴, T. Ray³, M. Roy⁴, R. Kumar⁵; ¹Vantage Research Inc, Lewes, Delaware, USA, ²Vantage Research, Lewes, Delware, USA, ³Vantage Research, ⁴Vantage Research, Lewes, Delaware, USA, ⁵AbbVie Inc, North Chicago, IL, US.

Background: Checkpoint inhibitors (CITs) targeting programmed cell death receptor -1 (PD-1) have been approved for use in NSCLC without genetic driver alterations and PD-L1 tumor proportion score ≥ 50% in the first line setting. Approximately, 50-60 % of the patients drop out at the first clinical visit due to various reasons such as radiographic progression, treatment related adverse events [1]. Here, we propose to utilize a QSP model to evaluate the efficacy of sequential vs parallel administration of chemotherapy in combination with CITs and recommend trial designs where this combination is beneficial to the maximum number of patients.

Methods: An immune-oncology (IO) QSP model [2] was developed by incorporating intra-patient heterogeneity in lesions and inter-patient variability and calibrated to publicly available clinical data [3-5] (pembrolizumab monotherapy in KEYNOTE-024, chemotherapy in CHECKMATE-9LA, Nivolumab+ipilimumab in CHECKMATE-227) in patients with metastatic NSCLC. Model captures the waterfall, spider plot, objective response rate (ORR) and progression-free survival curves. A virtual phase III trial was then simulated with the following arms: PD-1 monotherapy(P), PD-1 + CTLA-4 combination therapy(P+I), Chemotherapy(C) and PD-1 + CTLA-4 + Chemotherapy (P+I+C) arm.

Results: Virtual patients in the P+I+C arm displayed deeper (number of patients with tumor reduction ≥ 30%) and longer duration (time on trial) than the other arms in this virtual clinical trial. Percentage of virtual patients displaying oligo-progression (some lesions exhibiting reduction ≥ 30%, while some lesions showing growth) was fewer in the P+I+C arm compared to other arms. We observed that chemotherapy followed by a combination of CITs yielded better outcomes among the 3 strategies that were evaluated.

Conclusion: The model developed was able to visualize trial outcomes, identify responder populations and provide recommendations for optimal trial designs. Simulations presented here show that there was modest improvement in the tumor dynamics as well as progression free survival with the P + I + C arm in comparison to other arms. Amongst the strategies investigated here, sequential administration of C for 4 cycles followed by P + I combination yielded deeper response and better improvement in PFS.