RESUMO
LESSONS LEARNED: Disease control with signals of response were demonstrated, which should lead to future validating clinical trials using checkpoint inhibitors in this underserved rare malignancy population. Although the study of single types of rare cancers is practically challenging, clinical trial designs that aggregate such patients into cohorts treated similarly are feasible, even in the community setting. BACKGROUND: Patients with rare cancers are an underserved population with limited access to clinical trials aside from phase I trials in the refractory setting. Treatment of these patients is often based on collections of anecdotes and small denominator review articles. Despite broad evidence of efficacy of combined immune checkpoint blockade across multiple tumor types, patients with rare tumors have not been afforded the opportunity for these therapies. METHODS: A phase II, investigator-initiated, single institution trial using durvalumab (1,500 mg every [Q]4 weeks × 13) and tremelimumab (75 mg Q4 weeks × 7, then Q12 weeks × 2) is reported. The population included 50 patients with advanced rare solid tumors (incidence <6/100,000 per year). The phase II dose and safety profile were defined in prior phase I trials. All patients had exhausted standard therapy options and all had received at least one prior line of systemic therapy (n = 49) unless a standard treatment option did not exist (n = 1). RESULTS: A complete response was demonstrated in one patient with anal cancer. Striking partial responses were seen in four patients. Prolonged disease stability was noted in 18 patients. Thirteen patients experienced disease progression. Patients were considered unevaluable if unable to initiate therapy (n = 6) or unable to complete two cycles of therapy (n = 8). In all cases, patients were unevaluable because of clinical deterioration. The toxicity profile paralleled prior published studies. Toxicities were manageable and without new signals. There were two events of grade 4 immune-mediated hepatitis and one death from pneumonitis. CONCLUSION: This single-cohort basket trial demonstrated clinical activity from combined checkpoint blockade in 23 of the 36 evaluable patients. Patients with rare cancers, not eligible for immunotherapy via conventional clinical trial mechanisms, should be considered for this therapy through compassionate use, further clinical trials, and national registry programs.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias , Anticorpos Monoclonais , Anticorpos Monoclonais Humanizados , Humanos , Neoplasias/tratamento farmacológicoRESUMO
BACKGROUND: Anti-PD-1 and PD-L1 (collectively PD-[L]1) therapies are approved for many advanced solid tumors. Biomarkers beyond PD-L1 immunohistochemistry, microsatellite instability, and tumor mutation burden (TMB) may improve benefit prediction. METHODS: Using treatment data and genomic and transcriptomic tumor tissue profiling from an observational trial (NCT03061305), we developed Immunotherapy Response Score (IRS), a pan-tumor predictive model of PD-(L)1 benefit. IRS real-world progression free survival (rwPFS) and overall survival (OS) prediction was validated in an independent cohort of trial patients. RESULTS: Here, by Cox modeling, we develop IRS-which combines TMB with CD274, PDCD1, ADAM12 and TOP2A quantitative expression-to predict pembrolizumab rwPFS (648 patients; 26 tumor types; IRS-High or -Low groups). In the 248 patient validation cohort (248 patients; 24 tumor types; non-pembrolizumab PD-[L]1 monotherapy treatment), median rwPFS and OS are significantly longer in IRS-High vs. IRS-Low patients (rwPFS adjusted hazard ratio [aHR] 0.52, p = 0.003; OS aHR 0.49, p = 0.005); TMB alone does not significantly predict PD-(L)1 rwPFS nor OS. In 146 patients treated with systemic therapy prior to pembrolizumab monotherapy, pembrolizumab rwPFS is only significantly longer than immediately preceding therapy rwPFS in IRS-High patients (interaction test p = 0.001). In propensity matched lung cancer patients treated with first-line pembrolizumab monotherapy or pembrolizumab+chemotherapy, monotherapy rwPFS is significantly shorter in IRS-Low patients, but is not significantly different in IRS-High patients. Across 24,463 molecularly-evaluable trial patients, 7.6% of patients outside of monotherapy PD-(L)1 approved tumor types are IRS-High/TMB-Low. CONCLUSIONS: The validated, predictive, pan-tumor IRS model can expand PD-(L)1 monotherapy benefit outside currently approved indications.
Therapies activating the immune system (checkpoint inhibitors) have revolutionized the treatment of patients with advanced cancer, however new molecular tests may better identify patients who could benefit. Using treatment data and clinical molecular test results, we report the development and validation of Immunotherapy Response Score (IRS) to predict checkpoint inhibitor benefit. Across patients with more than 20 advanced cancer types, IRS better predicted checkpoint inhibitor benefit than currently available tests. Data from >20,000 patients showed that IRS identifies ~8% of patients with advanced cancer who may dramatically benefit from checkpoint inhibitors but would not receive them today based on currently available tests. Our approach may help clinicians to decide which patients should receive checkpoint inhibitors to treat their disease.