Germline biomarkers predict toxicity to anti-PD1/PDL1 checkpoint therapy.

BACKGROUND: There is great interest in finding ways to identify patients who will develop toxicity to cancer therapies. This has become especially pressing in the era of immune therapy, where toxicity can be long-lasting and life-altering, and primarily comes in the form of immune-related adverse effects (irAEs). Treatment with the first drugs in this class, anti-programmed death 1 (anti-PD1)/programmed death-ligand 1 (PDL1) checkpoint therapies, results in grade 2 or higher irAEs in up to 25%-30% of patients, which occur most commonly within the first 6 months of treatment and can include arthralgias, rash, pruritus, pneumonitis, diarrhea and/or colitis, hepatitis, and endocrinopathies. We tested the hypothesis that germline microRNA pathway functional variants, known to predict altered systemic stress responses to cancer therapies, would predict irAEs in patients across cancer types. METHODS: MicroRNA pathway variants were evaluated for an association with grade 2 or higher toxicity using four classifiers on 62 patients with melanoma, and then the panel's performance was validated on 99 patients with other cancer types. Trained classifiers included classification trees, LASSO-regularized logistic regression, boosted trees, and random forests. Final performance measures were reported on the training set using leave-one-out cross validation and validated on held-out samples. The predicted probability of toxicity was evaluated for its association, if any, with response categories to anti-PD1/PDL1 therapy in the melanoma cohort. RESULTS: A biomarker panel was identified that predicts toxicity with 80% accuracy (F1=0.76, area under the curve (AUC)=0.82) in the melanoma training cohort and 77.6% accuracy (F1=0.621, AUC=0.778) in the pan-cancer validation cohort. In the melanoma cohort, the predictive probability of toxicity was not associated with response categories to anti-PD1/PDL1 therapy (p=0.70). In the same cohort, the most significant biomarker of toxicity in RAC1, predicting a greater than ninefold increased risk of toxicity (p<0.001), was also not associated with response to anti-PD1/PDL1 therapy (p=0.151). CONCLUSIONS: A germline microRNA-based biomarker signature predicts grade 2 and higher irAEs to anti-PD1/PDL1 therapy, regardless of tumor type, in a pan-cancer manner. These findings represent an important step toward personalizing checkpoint therapy, the use of which is growing rapidly.

Real World Experience With Pembrolizumab in Recurrent or Advanced Prostate Cancer.

INTRODUCTION: Phase II trials have shown activity with pembrolizumab against prostate cancer. However, the clinical factors predictive of a response to pembrolizumab in men with prostate cancer are unknown. PATIENTS AND METHODS: A total of 54 consecutive men with progressive, recurrent, or advanced prostate cancer were treated with 1 to 12 cycles of pembrolizumab 200 mg every 3 weeks with or without stereotactic body radiotherapy (SBRT). RESULTS: For the 31 men evaluable for response, the median age, prostate-specific antigen (PSA) level, and Gleason score were 75 years, 30 ng/mL, and 8 (4 + 4), respectively, which were similar to those for the 23 nonevaluable patients. The treatments received before pembrolizumab were enzalutamide in 26, abiraterone in 18, and sipuleucel-T in 23. All but 4 men had had castrate-resistant disease. Of the 54 men, 31 had completed ≥ 4 cycles of pembrolizumab and were evaluable for the response. Ten men had undergone SBRT to an isolated metastasis shortly before or during pembrolizumab treatment, with the goal of inducing an abscopal effect. The clinical characteristics of the 17 men with a response or stable disease were compared with those of the 14 men with progressive disease. Grade ≥ 2 toxicity occurred in 16 men (30%). PSA stabilization or a response occurred in slightly more than one half (55%) of the men treated with ≥ 4 cycles of pembrolizumab. Five patients had a notable PSA decline of > 50%, which were sustained as long as they had continued receiving pembrolizumab. A PSA response or stabilization was more common for men who had begun taking pembrolizumab with a lower PSA level, fewer bone metastases, and fewer mutations and without previous chemotherapy. A statistically nonsignificant trend toward stabilization or a response was observed in men who had undergone concomitant SBRT. CONCLUSION: Pembrolizumab showed modest anticancer activity against metastatic castrate-resistant prostate cancer. A PSA response or stabilization occurred more frequently in men with less-advanced disease.