Authors
Sachdev P. Thomas, Ninah Achacoso, Chen Jiang, Elaine Chung, Aleyda V. Solorzano-Pinto, Pamela Tse, Benjamin J. Bulen, Nickolay A. Khazanov, Laura Elaine Lamb, Daniel H. Hovelston, Kat Kwiatkowski, D. Bryan Johnson, Daniel R. Rhodes, Scott A. Tomlins, Jennifer Marie Suga, Laurel A. Habel

Organizations
Kaiser Permanente, Vallejo, CA, Kaiser Permanente, Oakland, CA, Strata Oncology, Ann Arbor, MI, Strata Oncology (Ann Arbor, MI), Ann Arbor, MI, Division of Research, Kaiser Permanente Northern California, Oakland, CA

Research funding
Pharmaceutical/Biotech Company
Strata Oncology

Background
IRS is a multivariable biomarker algorithm combining tissue-based tumor mutation burden (TMB) with quantitative gene expression biomarkers, previously validated to predict anti-PD-1 and anti-PD-L1 monotherapy (mono) benefit in an observational clinical trial (PMID: 36750617). Herein, we evaluated IRS in pts with advanced solid tumors across the Kaiser Permanente Northern California (KPNC) health system following a pre-specified statistical analysis plan. 

Methods
KPNC pts with valid IRS results (from 2018 – 2022; specimen collection years 2011-2021) and electronic health record (EHR) documented > 1^st line systemic pembro mono treatment were included; pts with gliomas or previous immunotherapy were excluded. All oncologic treatments were obtained from the EHR and standardized to determine time to next treatment (TTNT) as a real-world progression free survival endpoint. A within-pt evaluation was performed, comparing pembro TTNT to the pt’s immediate prior therapy line (prior) TTNT. The primary objective was to determine if IRS status (-H vs. Low [-L]) predicts pembro clinical benefit in Cox proportional hazards models through testing for interaction between IRS status and pembro/prior therapy TTNT. 

Results
With a data cutoff of 06/15/2022, 211 KPNC pts (142 2^nd line and 69 > 2^nd line pembro) were eligible and included (from 24 solid tumor types). The median (m) pembro follow-up was 16.0 months. IRS-H pts (n = 77, 36%) had significantly longer pembro vs. prior TTNT (mTTNT 20.3 mo vs. 4.5 mo, log-rank p-value < 0.0001), whereas IRS-L pts (n = 134, 64%) did not (mTTNT 3.3 mo vs. 5.2 mo, log-rank p-value 0.75); the interaction between IRS status and pembro/prior treatment was significant (interaction test p-value < 0.0001). 

Conclusions
IRS predicted pan-solid tumor pembro mono benefit compared to prior therapy and may be a potential marker for pembro mono treatment decisions. Clinical trial information: NCT03061305.

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