Michal Yalon-Oren

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion-deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10-100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in 'immunologically cold' tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy.

Abstract Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair–deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. Significance: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction. This article is highlighted in the In This Issue feature, p. 995

10525 Background: In the phase 1 portion of KEYNOTE-051 (NCT02332668), the 2-mg/kg-Q3W dose of pembro was identified as the pediatric recommended phase 2 dose. We provide an update on the safety and efficacy of this dose by tumor type in the ongoing phase 2 trial. Methods: Pts aged 6 mo to < 18 y with advanced melanoma or a PD-L1–positive, advanced relapsed/refractory solid tumor or lymphoma and measurable disease per RECIST v1.1 received pembro 2 mg/kg Q3W until confirmed disease progression per irRECIST by investigator review, intolerable toxicity, or pt/investigator decision to discontinue. Key efficacy end points were ORR and PFS per RECIST v1.1 by investigator and OS (data cutoff Oct 10, 2017). Results: 689 of 748 prescreened pts had PD-L1–evaluable tumors. Of these, 229 (33.2%) were PD-L1–positive; 125 pts (median age, 13 y [range, 1-17]) were enrolled and treated (10 Hodgkin lymphoma [HL]; 115 other tumors). Median follow-up was 5.7 mo (range, 0.2-29). Primary diagnoses were other non–central nervous system (CNS) solid tumors (46%), sarcoma (19%), CNS tumors (26%), and lymphoma (9%). Seven (6%) pts experienced grade 3-5 treatment-related AEs; of these, 2 (1.6%) discontinued (1 due to increased aspartate aminotransferase; 1 with renal medullary carcinoma died of treatment-related pulmonary edema). No major untoward effects on the developing immune system were observed. One pt (10.0%) with HL achieved CR and 5 (50%) achieved PR. Six (5.2%) pts with other tumors achieved prolonged PR (2 adrenocortical carcinoma and 1 each epithelioid sarcoma, mesothelioma, malignant ganglioglioma, and lymphoepithelial carcinoma). ORR was 60.0% (95% CI, 26.2-87.8) in pts with HL and 5.2% (95% CI, 1.9-11.0) in pts with all other tumor types. Median PFS was 12.2 mo in HL and 1.9 mo in any other tumor type; 12-mo PFS was 56.3% and 8.3%, respectively. Four (40.0%) pts with HL and 19 (16.5%) with any other tumor type survived ≥12 months. Conclusions: Pembro was well tolerated and showed response in HL and in a few rare tumor types, which warrants further study. Enrollment in KEYNOTE-051 is ongoing. Clinical trial information: NCT02332668.