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Purpose: The prevalence and clinical characteristics of small bowel adenocarcinomas (SBA) in the setting of Lynch syndrome have not been well studied. We characterized SBA according to DNA mismatch repair and/or microsatellite instability (MMR/MSI) and germline mutation status and compared clinical outcomes. Experimental Design: A single-institution review identified 100 SBAs. Tumors were evaluated for MSI via MSIsensor and/or corresponding MMR protein expression via IHC staining. Germline DNA was analyzed for mutations in known cancer predisposition genes, including MMR (MLH1, MSH2, MSH6, PMS2, and EPCAM). Clinical variables were correlated with MMR/MSI status. Results: Twenty-six percent (26/100; 95% confidence interval, 18.4–35.4) of SBAs exhibited MMR deficiency (MMR-D). Lynch syndrome prevalence was 10% overall and 38.5% among MMR-D SBAs. Median age at SBA diagnosis was similar in non-Lynch syndrome MMR-D versus MMR-proficient (MMR-P) SBAs (65 vs. 61; P = 0.75), but significantly younger in Lynch syndrome (47.5 vs. 61; P = 0.03). The prevalence of synchronous/metachronous cancers was 9% (6/67) in MMR-P versus 34.6% (9/26) in MMR-D SBA, with 66.7% (6/9) of these in Lynch syndrome (P = 0.0002). In the MMR-P group, 52.2% (35/67) of patients presented with metastatic disease, compared with 23.1% (6/26) in the MMR-D group (P = 0.008). In MMR-P stage I/II patients, 88.2% (15/17) recurred, compared with 18.2% (2/11) in the MMR-D group (P = 0.0002). Conclusions: When compared with MMR-P SBA, MMR-D SBA was associated with earlier stage disease and lower recurrence rates, similar to observations in colorectal cancer. With a 38.5% prevalence in MMR-D SBA, germline Lynch syndrome testing in MMR-D SBA is warranted.

Background The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC). Methods Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided. Results In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P Conclusions EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.

Initial treatment with either neoadjuvant chemoradiation (CRT) or induction FOLFOX (5-Fluorouracil, leucovorin, and oxaliplatin) chemotherapy followed by CRT is considered standard treatment for locally advanced rectal cancer. We compared patient-reported outcomes (PRO) during CRT in patients who had received induction chemotherapy versus those who did not.We reviewed records of patients with locally advanced rectal cancer who were treated with CRT between September 2009 and October 2014, and who had completed ≥ 4 PRO assessments during treatment. Clinician- and patient-reported toxicities were collected each week during treatment. We fit binomial generalized linear models to maximum toxicity scores across all patients' visits.Of 123 patients with ≥ 4 PRO assessments, 87 (71%) patients reported a clinically meaningful PRO score of 3 or higher for diarrhea, and 91 (74%) patients reported a PRO score of ≥ 3 for urgency, during 1 or more weeks of treatment, corresponding to 'very frequent' or worse. Of 116 patients who had also completed ≥ 4 clinician-reported assessments for descriptive analysis, clinically significant diarrhea (Common Terminology Criteria for Adverse Events grade ≥ 2) was reported in 9% of patients, and grade 2 proctitis and cystitis were reported in 20% and 4%, respectively. Eighty-four (68%) patients had undergone induction chemotherapy prior to CRT. Patients who received induction chemotherapy had 68% lower odds of experiencing significant urgency (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.11-0.95; P = .04), 76% lower odds of bleeding (OR, 0.24; 95% CI, 0.1-0.62; P .01), and 75% lower odds of tenesmus (OR, 0.25; 95% CI, 0.11-0.6; P .01) versus those treated with upfront CRT.Based on PROs, a high proportion of patients experienced clinically significant symptoms during pelvic CRT, with diarrhea and urgency being most commonly reported. This appears to be under-reported on clinician-reported assessments. Delivery of induction chemotherapy was associated with lower odds of experiencing urgency, bleeding, and tenesmus on PROs during subsequent CRT, with no significant impact on diarrhea and rectal pain.

Following initial successes in melanoma treatment, immunotherapy has rapidly become established as a major treatment modality for multiple types of solid cancers, including a subset of colorectal cancers (CRCs). Two programmed cell death 1 (PD1)-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in patients with metastatic CRC that is mismatch-repair-deficient and microsatellite instability-high (dMMR–MSI-H), and have been granted accelerated FDA approval. In contrast to most other treatments for metastatic cancer, immunotherapy achieves long-term durable remission in a subset of patients, highlighting the tremendous promise of immunotherapy in treating dMMR–MSI-H metastatic CRC. Here, we review the clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR–MSI-H CRC. We focus on new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR–MSI-L) and discuss emerging approaches for targeting the immune microenvironment, which might complement immune checkpoint inhibition.

Background Treatment of advanced anal squamous cell cancer (SCC) is usually with the combination of cisplatin and 5-fluorouracil, which is associated with heterogeneous responses across patients and significant toxicity. We examined the safety and efficacy of a modified schedule, FOLFCIS (leucovorin, fluorouracil, and cisplatin), and performed an integrated clinical and genomic analysis of anal SCC. Patients and Methods We reviewed all patients with advanced anal SCC receiving first-line FOLFCIS chemotherapy – essentially a FOLFOX (leucovorin, fluorouracil, and oxaliplatin) schedule with cisplatin substituted for oxaliplatin – in our institution between 2007 and 2017, and performed deep sequencing to identify genomic markers of response and key genomic drivers. Results Fifty-three patients with advanced anal SCC (48 metastatic; 5 unresectable, locally advanced) received first-line FOLFCIS during this period; all were platinum-naive. The response rate was 48% (95% confidence interval [CI], 32.6%-63%). With a median follow-up of 41.6 months, progression-free survival and overall survival were 7.1 months (95% CI, 4.4-8.6 months) and 22.1 months (95% CI, 16.9-28.1 months), respectively. Among all patients with advanced anal SCC that underwent sequencing during the study period, the most frequent genomic alterations consisted of chromosome 3q amplification (51%) and mutations in PIK3CA (29%) and KMT2D (22%). No genomic alteration correlated with response to platinum-containing treatment. Although there were few cases, patients with human papillomavirus-negative anal SCC did not appear to benefit from FOLFCIS, and all harbored distinct genomic profiles with TP53, TERT promoter, and CDKN2A mutations. Conclusions FOLFCIS appears effective and safe as first-line chemotherapy in patients with advanced anal SCC and represents an alternative treatment option for these patients.

PURPOSE Microsatellite instability (MSI) and/or mismatch repair deficiency (MMR-D) testing has traditionally been performed in patients with colorectal (CRC) and endometrial cancer (EC) to screen for Lynch syndrome (LS)–associated cancer predisposition. The recent success of immunotherapy in high-frequency MSI (MSI-H) and/or MMR-D tumors now supports testing for MSI in all advanced solid tumors. The extent to which LS accounts for MSI-H across heterogeneous tumor types is unknown. Here, we establish the prevalence of LS across solid tumors according to MSI status. METHODS MSI status was determined using targeted next-generation sequencing, with tumors classified as MSI-H, MSI-indeterminate, or microsatellite-stable. Matched germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM). In patients with LS with MSI-H/I tumors, immunohistochemical staining for MMR-D was assessed. RESULTS Among 15,045 unique patients (more than 50 cancer types), LS was identified in 16.3% (53 of 326), 1.9% (13 of 699), and 0.3% (37 of 14,020) of patients with MSI-H, MSI-indeterminate, and microsatellite-stable tumors, respectively ( P < .001). Among patients with LS with MSI-H/I tumors, 50% (33 of 66) had tumors other than CRC/EC, including urothelial, prostate, pancreas, adrenocortical, small bowel, sarcoma, mesothelioma, melanoma, gastric, and germ cell tumors. In these patients with non-CRC/EC tumors, 45% (15 of 33) did not meet LS genetic testing criteria on the basis of personal/family history. Immunohistochemical staining of LS-positive MSI-H/I tumors demonstrated MMR-D in 98.2% (56 of 57) of available cases. CONCLUSION MSI-H/MMR-D is predictive of LS across a much broader tumor spectrum than currently appreciated. Given implications for cancer surveillance and prevention measures in affected families, these data support germline genetic assessment for LS for patients with an MSI-H/MMR-D tumor, regardless of cancer type or family cancer history.

Purpose:Immune checkpoint inhibition (ICI) alone is not active in mismatch repair–proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models.Patients and Methods:In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles.Results:We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9–26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0–27.0]. The median progression-free survival was 1.8 (95% CI, 1.7–1.9) months, median overall survival was 11.4 (95% CI, 10.1–17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3–4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response.Conclusions:This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.

Background The MORPHEUS platform comprises multiple randomized Phase Ib/II trials to identify early safety and efficacy signals for treatment combinations across cancers. Seli interacts with CD40 on antigen presenting cells, resulting in activation and priming of CD8 T-cells. Atezo (anti-PD-L1)+seli (CD40 agonist) was evaluated with gem+nabP for pancreatic ductal adenocarcinoma (PDAC), or with bev for triple-negative breast cancer (TNBC) and colorectal cancer (CRC). Methods MORPHEUS-PDAC, MORPHEUS-TNBC and MORPHEUS-CRC enrolled 1L metastatic (m) PDAC, 2L locally advanced or mTNBC or 3L mCRC patients, respectively. Experimental arm patients received atezo (840 mg IV q2w) and seli (16 mg SC on D1 every 28-day cycle for C1-4 and every third cycle thereafter). Patients also received gem (1000 mg/m2) and nabP (1000 mg/m2, 125 mg/m2 respectively, IV on D1, 8, 15 every 28-day cycle) in PDAC or bev (10 mg/kg IV q2w) in TNBC and CRC. Control treatments were gem+nabP in PDAC, capecitabine in TNBC, and regorafenib in CRC. Primary endpoints were safety and objective response rate (ORR; investigator-assessed RECIST 1.1). PD-L1 and CD8/panCK IHC were tested in all biopsies. Results All treated patients were safety evaluable. MORPHEUS-PDAC (20-week interim analysis): 9 patients received atezo+seli+gem+nabP and 4 received control. Treatment-related adverse events (TRAEs) were seen in all. Treatment-related serious AEs (SAEs) occurred in 6 patients (67%) receiving atezo+seli+gem+nabP and 1 (25%) receiving control. Confirmed ORRs: 44% (95%CI:14–79) and 25% (95%CI:6–81), respectively. MORPHEUS-TNBC (27-week interim analysis): 6 patients received atezo+seli+bev and 24 received control. TRAEs were seen in 5 patients (83%) receiving atezo+seli+bev and 18 (75%) receiving control. Treatment-related SAEs occurred in 1 patient in each arm (17% and 4%, respectively). Confirmed ORRs: 17% (95%CI:0.4–64) and 21% (95%CI:7–42), respectively. All 6 patients receiving atezo+seli+bev were PD-L1 negative (SP142 IHC assay) at baseline; the only patient with partial response (PR) showed upregulation of PD-L1 expression at week 3. MORPHEUS-CRC (18-week interim analysis): 6 patients received atezo+seli+bev and 13 received control. TRAEs were seen in all patients receiving atezo+seli+bev and 12 (92%) receiving control. Treatment-related SAEs occurred in 3 patients (50%) receiving atezo+seli+bev and 1 (8%) receiving control. No responses occurred in either study arm. Paired biopsies for 3 patients (60%) receiving atezo+seli+bev suggest on-treatment increases in CD8 T-cell infiltration into tumors. Conclusions Toxicities related to the atezo+seli combinations were consistent with individual study treatments. Preliminary efficacy was observed for atezo+seli+gem+nabP in PDAC. Together with preliminary evidence of on-treatment pharmacodynamic effects in CRC and TNBC tumor samples, CD40 agonist strategies warrant further investigation. Trial Registration MORPHEUS-PDAC: NCT03193190; MORPHEUS-TNBC: NCT03424005; MORPHEUS-CRC: NCT03555149. Ethics Approval The trial was conducted according to the principles of the Declaration of Helsinki. All patients provided written informed consent. Protocol approval was obtained from independent review boards or ethics committees at each site.

Background Data on drug-induced liver injury (DILI) and acute liver failure (ALF) in modern phase 1 oncology trials are limited, specifically with respect to the incidence and resolution of DILI and the safety of drug rechallenge. Methods This study reviewed all patients who were recruited to phase 1 oncology trials between 2013 and 2017 at Memorial Sloan Kettering Cancer Center. Clinicopathologic data were extracted to characterize DILI, and attribution was assessed on the basis of data prospectively generated during the studies. Logistic regression models were used to explore factors related to DILI and DILI recurrence after drug rechallenge. Results Among 1670 cases recruited to 85 phase 1 trials, 81 (4.9%) developed DILI. The rate of DILI occurrence was similar for patients in immune-based trials and patients in targeted therapy trials (5.0% vs 4.9%), as was the median time to DILI (5.5 vs 6.5 weeks; P = .48). Two patients (0.12%) met the criteria of Hy's law, although none developed ALF. The DILI resolved in 96% of the patients. Pretreatment factors were not predictive for DILI development. Thirty-six of the 81 patients underwent a drug rechallenge, and 28% of these patients developed DILI recurrence. Peak alanine aminotransferase during the initial DILI was associated with DILI recurrence (odds ratio, 1.04; 95% confidence interval, 1.0-1.09; P = .035). Conclusions In modern phase 1 oncology trials, DILI is uncommon, may occur at any time, and often resolves with supportive measures. Rechallenging after DILI is feasible; however, the high rate of DILI recurrence suggests that clinicians should consider the severity of the DILI episode and treatment alternatives.

Purpose: Evaluate response of mismatch repair–deficient (dMMR) rectal cancer to neoadjuvant chemotherapy. Experimental Design: dMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (pMMR) rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity. Results: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), six (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable with 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome with enrichment of germline MSH2 and MSH6 mutations when compared with 193 patients with Lynch syndrome–associated colon cancer (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P < 0.003). Conclusions: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for Lynch syndrome in patients with dMMR rectal cancer.

The utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced cancers receiving immunotherapy is uncertain. We therefore analyzed pretreatment (n = 978) and on-treatment (n = 171) ctDNA samples across 16 advanced-stage tumor types from three phase I/II trials of durvalumab (± the anti-CTLA4 therapy tremelimumab). Higher pretreatment variant allele frequencies (VAF) were associated with poorer overall survival (OS) and other known prognostic factors, but not objective response, suggesting a prognostic role for patient outcomes. On-treatment reductions in VAF and lower on-treatment VAF were independently associated with longer progression-free survival and OS and increased objective response rate, but not prognostic variables, suggesting that on-treatment ctDNA dynamics are predictive of benefit from immune checkpoint blockade. Accordingly, we propose a concept of “molecular response” using ctDNA, incorporating both pretreatment and on-treatment VAF, that predicted long-term survival similarly to initial radiologic response while also permitting early differentiation of responders among patients with initially radiologically stable disease.Significance:In a pan-cancer analysis of immune checkpoint blockade, pretreatment ctDNA levels appeared prognostic and on-treatment dynamics predictive. A “molecular response” metric identified long-term responders and adjudicated benefit among patients with initially radiologically stable disease. Changes in ctDNA may be more dynamic than radiographic changes and could complement existing trial endpoints.This article is highlighted in the In This Issue feature, p. 1775

PURPOSE Adrenocortical carcinomas (ACC) are rare and aggressive malignancies with limited treatment options. This study was undertaken to evaluate the immunogenicity of ACC. PATIENTS AND METHODS Patients with advanced ACC were enrolled in a phase II study to evaluate the clinical activity of pembrolizumab 200 mg every 3 weeks, without restriction on prior therapy. The primary end point was objective response rate. Efficacy was correlated with tumor programmed death-ligand 1 expression, microsatellite-high and/or mismatch repair deficient (MSI-H/MMR-D) status, and somatic and germline genomic correlates. RESULTS We enrolled 39 patients with advanced ACC and herein report after a median follow-up of 17.8 months (range, 5.4 months to 34.7 months). The objective response rate to pembrolizumab was 23% (nine patients; 95% CI, 11% to 39%), and the disease control rate was 52% (16 patients; 95% CI, 33% to 69%). The median duration of response was not reached (lower 95% CI, 4.1 months). Two of six patients with MSI-H/MMR-D tumors responded. The other seven patients with objective responses had microsatellite stable tumors. The median progression-free survival was 2.1 months (95% CI, 2.0 months to 10.7 months), and the median overall survival was 24.9 months (95% CI, 4.2 months to not reached). Thirteen percent of patients (n = 5) had treatment-related grade 3 or 4 adverse events. Tumor programmed death-ligand 1 expression and MSI-H/MMR-D status were not associated with objective response. CONCLUSION MSI-H/MMR-D tumors, for which pembrolizumab is a standard therapy, are more common in ACC than has been recognized. In advanced ACC that is microsatellite stable, pembrolizumab provided clinically meaningful and durable antitumor activity with a manageable safety profile.

Purpose: Utomilumab (PF-05082566) is an agonistic mAb that engages the immune costimulatory molecule 4-1BB/CD137. In this first-in-human, phase I, open-label, multicenter, multiple-dose study (NCT01307267) we evaluated safety, tolerability, pharmacokinetics, preliminary clinical activity, and pharmacodynamics of single-agent utomilumab in patients with advanced malignancies. Experimental Design: Dose escalation was based on a standard 3+3 design for doses of utomilumab from 0.006 to 0.3 mg/kg every 4 weeks and a time-to-event continual reassessment method for utomilumab 0.6 to 10 mg/kg every 4 weeks. The primary study endpoint was dose-limiting toxicity (DLT) in the first two cycles. Results: Utomilumab demonstrated a well-tolerated safety profile (N = 55). None of the patients experienced a DLT at the dose levels evaluated. The most common treatment-related adverse events were fatigue, pyrexia, decreased appetite, dizziness, and rash ( Conclusions: The favorable safety profile and preliminary antitumor activity demonstrated by utomilumab warrant further evaluation in patients with advanced malignancies. Clin Cancer Res; 24(8); 1816–23. ©2018 AACR.

Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

Immunotherapy is rapidly becoming a standard of care for many cancers. However, colorectal cancer had been generally resistant to immunotherapy, despite features in common with sensitive tumors. Observations of substantial clinical activity for checkpoint blockade in colorectal cancers with defective mismatch repair (microsatellite instability–high tumors) have reignited interest in the search for immunotherapies that could be extended to the larger microsatellite stable (MSS) population. The Cancer Research Institute and Fight Colorectal Cancer convened a group of scientists, clinicians, advocates, and industry experts in colorectal cancer and immunotherapy to compile ongoing research efforts, identify gaps in translational and clinical research, and provide a blueprint to advance immunotherapy. We identified lack of a T-cell inflamed phenotype (due to inadequate T-cell infiltration, inadequate T-cell activation, or T-cell suppression) as a broad potential explanation for failure of checkpoint blockade in MSS. The specific cellular and molecular underpinnings for these various mechanisms are unclear. Whether biomarkers with prognostic value, such as the immunoscores and IFN signatures, would also predict benefit for immunotherapies in MSS colon cancer is unknown, but if so, these and other biomarkers for measuring the potential for an immune response in patients with colorectal cancer will need to be incorporated into clinical guidelines. We have proposed a framework for research to identify immunologic factors that may be modulated to improve immunotherapy for colorectal cancer patients, with the goal that the biomarkers and treatment strategies identified will become part of the routine management of colorectal cancer. Cancer Immunol Res; 5(11); 942–9. ©2017 AACR.

BACKGROUND Ovarian metastases from colorectal cancer (OM-CRC) often are unresponsive to chemotherapy and are associated with poor survival. To the authors' knowledge, the clinicopathologic and genomic predictors of OM-CRC are poorly characterized and optimal clinical management remains unclear. METHODS Women with a histopathological diagnosis of OM-CRC who were treated at Memorial Sloan Kettering Cancer Center from 1999 to 2015 were identified. Next-generation somatic mutation profiling (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT]) was performed on 38 OM-CRC cases, including 21 matched tumor pairs/trios. Regression models were used to analyze variables associated with progression-free survival and overall survival (OS). RESULTS Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), SMAD family member 4 (SMAD4), and neurotrophic receptor tyrosine kinase 1 (NTRK1) mutations were more frequent in cases of OM-CRC than in instances of CRC occurring without OM. SMAD4 and lysine methyltransferase 2D (KMT2D) mutations were associated with reduced OS. Matched multisite tumor sequencing did not identify OM-specific genomic alterations. Of the 195 patients who underwent oophorectomy for OM-CRC (median age, 49 years with a progression-free survival of 9.4 months and an OS of 23 months from oophorectomy), 76% had extraovarian metastasis (EOM). In multivariable analysis, residual disease after surgery (R2 resection) was associated with worse survival. Patients with EOM were less likely to achieve R0/R1 surgical resection status (complete macroscopic resection without clinical/radiological evidence of disease) (48% vs 94%). However, if R0/R1 resection status was achieved, both patients with (35.9 months vs 12 months) and without (43.2 months vs 14.5 months) EOM were found to have better OS. Among 114 patients with R0/R1 resection status, 23 (20%) had no disease recurrence, including 10 patients (9%) with > 3 years of follow-up. CONCLUSIONS Loss-of-function alterations in SMAD4 are frequent and predictive of worse survival in patients with OM-CRC. Similar to oligometastatic CRC to the lung or liver, surgical resection of OM-CRC is associated with a better outcome only if all macroscopic metastatic disease is resected. Cancer 2016. © 2016 American Cancer Society.

Introduction Two clinical studies (Study 1108 and ATLANTIC) were analyzed to evaluate the prognostic value of baseline liver metastases (LMs) in advanced/metastatic non–small-cell lung cancer patients treated with durvalumab 10 mg/kg every 2 weeks. Patients and Methods A multivariate Cox proportional hazards analysis was conducted; covariates included performance status, tumor stage, histology, sex, age, smoking status, and programmed cell death ligand 1 (PD-L1) status. Results In all, 569 patients were included. LMs were present in 31.6% (96/304) of Study 1108 patients and 17.9% (47/263) of ATLANTIC patients. Median overall survival (OS) was shorter in patients with LMs than in those without in both studies. In both studies, LMs were an independent negative prognostic factor for OS and progression-free survival. Objective response rates were also significantly lower. PD-L1 independently predicted benefit across all patients. Conclusion Liver metastases were associated with worse outcomes irrespective of PD-L1 status, but PD-L1 status predicted benefit from durvalumab irrespective of LMs.

Background Microsatellite-stable metastatic colorectal cancer is typically unresponsive to immunotherapy. This phase 3 study was designed to assess atezolizumab plus cobimetinib in metastatic colorectal cancer. Here, we report the comparison of atezolizumab plus cobimetinib or atezolizumab monotherapy versus regorafenib in the third-line setting. Methods IMblaze 370 is a multicentre, open-label, phase 3, randomised, controlled trial, done at 73 academic medical centres and community oncology practices in 11 countries. Patients aged at least 18 years with unresectable locally advanced or metastatic colorectal cancer, baseline Eastern Cooperative Oncology Group performance status of 0–1, and disease progression on or intolerance to at least two previous systemic chemotherapy regimens were enrolled. We used permuted-block randomisation (block size four) to assign patients (2:1:1) via an interactive voice and web response system to atezolizumab (840 mg intravenously every 2 weeks) plus cobimetinib (60 mg orally once daily for days 1–21 of a 28-day cycle), atezolizumab monotherapy (1200 mg intravenously every 3 weeks), or regorafenib (160 mg orally once daily for days 1–21 of a 28-day cycle). Stratification factors were extended RAS status (wild-type vs mutant) and time since diagnosis of first metastasis (

INTRODUCTION: Durvalumab is a selective, high-affinity human immunoglobulin G1 monoclonal antibody that blocks programmed cell death ligand 1 (PD-L1) binding to programmed death 1. Here we report safety and clinical activity in the NSCLC cohort of a phase I/II trial that included multiple tumor types (Study 1108; NCT01693562). METHODS: Patients with stage IIIB-IV NSCLC (squamous or nonsquamous) received durvalumab 10 mg/kg every 2 weeks for 12 months or until confirmed progressive disease or unacceptable toxicity. Primary objectives were safety and antitumor activity. Tumoral PD-L1 expression was assessed using the VENTANA SP263 Assay. Responses were assessed by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1). Adverse events were graded according to National Cancer Institute's Common Terminology Criteria for Adverse Events (v4.03). RESULTS: Of 304 patients, 79.0% were previously treated. Confirmed objective response rate was 21.8% in patients with greater than or equal to 25% PD-L1 expression and 6.4% in those with less than 25%; 25.9% in first-line patients and 12.7% in previously treated patients; and 14.0% in squamous and 16.7% in nonsquamous disease. Median overall survival was 12.4 months and median progression-free survival was 1.7 months; both were numerically longer in the PD-L1 greater than or equal to 25% group than in the PD-L1 less than 25% group (overall survival 16.4 versus 7.6 months, respectively; progression-free survival 2.6 versus 1.4 months, respectively). Treatment-related adverse events occurred in 57.2%, were grade 3/4 in 10.2%, and led to discontinuation in 5.6%. One patient (0.3%) died of treatment-related pneumonia with underlying pneumonitis. CONCLUSIONS: Durvalumab was clinically active irrespective of histology in this mostly pretreated population, with a manageable safety profile. Response rates and survival appeared to be enhanced in patients with greater tumoral PD-L1 expression. ispartof: JOURNAL OF THORACIC ONCOLOGY vol:14 issue:10 pages:1794-1806 ispartof: location:United States status: published

82 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations across tumor types. Isatuximab (isa; anti-CD38) targets CD38 receptors expressed on immunosuppressive cells in the tumor microenvironment. We hypothesized atezolizumab (atezo; anti–PD-L1) + isa would induce an anti-tumor response beyond that of regorafenib (rego), a multi-kinase inhibitor, in patients (pts) with tx-refractory metastatic colorectal cancer (mCRC). Methods: This randomized Phase Ib/II trial (NCT03555149) enrolled pts with microsatellite stable/mismatched repair proficient mCRC who had received ≤ 2 prior tx lines (fluoropyrimidine-, oxaliplatin- or irinotecan-containing chemotherapy plus a biologic agent). Pts received atezo (1200 mg intravenously [IV] every 3 weeks [q3w]) + isa (10 mg/kg IV q3w) or control tx with rego (160 mg orally days 1–21; dose escalation to 160 mg during Cycle 1 allowed per institutional guidelines). The primary endpoint was objective response rate (ORR; investigator-assessed RECIST 1.1); secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: Data cutoff date was March 3, 2020. Fifteen pts received atezo + isa and 13 pts received rego. Fourteen atezo + isa pts (93.3%) and 11 control arm pts (84.6%) had received 2 prior lines of tx; 9 atezo + isa pts (60.0%) and 9 control pts (69.2%) had liver metastases at enrollment. No responses were seen in either arm; 3 pts receiving atezo + isa (20.0%) and 8 control pts (61.5%) had stable disease as their best response. DCR (response and/or stable disease ≥ 12 weeks) was 6.7% with atezo + isa and 15.4% with control. One pt treated with atezo + isa beyond progression had prolonged disease stabilization. Median PFS was 1.4 mo (95% CI: 1.4, 1.8) with atezo + isa and 2.8 mo (95% CI: 1.6, 3.1) in the control arm; median OS was 5.1 mo (95% CI: 3.1, 7.8) with atezo + isa and 10.2 mo (95% CI: 4.8, not reached) with control. Tx-related adverse events (AEs, Grade 1-4) occurred in 13 atezo + isa pts (86.7%), and 12 control pts (92.3%). The most common tx-related AEs with atezo + isa were infusion-related reaction (73.3%), nausea (26.7%) and fatigue (20.0%). No Grade 5 AEs occurred in the atezo + isa arm, 1 (7.7%) was reported in the control arm (sepsis, considered unrelated to study tx). No atezo + isa pts and 1 control-arm pt (7.7%) withdrew from treatment due to a tx-related AE. Biomarker analyses did not identify any significant trends related to efficacy. Conclusions: In this trial, superior efficacy of atezo + isa vs rego was not shown. However, the atezo + isa combination was well tolerated, with a manageable safety profile. Clinical trial information: NCT03555149.

Background Imprime PGG (β(1,6)-[poly-(1,3)-D-glucopyranosyl]-poly-β(1,3)-D-glucopyranose) is an innate immune cell modulator that primes neutrophils and monocytes/macrophages to exert antitumor activity against complement opsonized tumor cells. In patients with KRAS-mutant colorectal cancer (CRC), cetuximab alone is ineffective; however, it can bind to tumor cells and induce opsonization for recognition by Imprime PGG-bound innate immune cells. The primary objective of this study was to determine the antitumor activity of Imprime PGG in combination with cetuximab in patients with KRAS-mutant metastatic CRC. Patients and Methods The study had a 2-stage Simon optimal design with 80% power to detect a target objective response rate (ORR) of ≥10% at a 10% significance level. Patients received weekly Imprime PGG (4 mg/kg) and cetuximab (loading dose, 400 mg/m2, then 250 mg/m2) intravenously. The primary end point was ORR; secondary end points included duration of response (DOR), time to progression (TTP), overall survival (OS), disease control rate, progression-free survival, and safety. Stage 1 of the study was to enroll 17 evaluable patients. Results One partial response (5.6%) was observed among 18 patients enrolled into stage 1. Median DOR was 4.2 months, TTP 2.7 months, and OS 6.6 months. Overall, observed toxicity was as expected from cetuximab alone. The most common (≥20%) adverse events related to Imprime PGG were fatigue (7 patients; 38.9%), infusion reaction (4 patients; 22.2%), and headache (4 patients; 22.2%). There was no Grade 4 toxicity nor treatment-related deaths. Conclusion Imprime PGG in combination with cetuximab treatment in patients with KRAS-mutant CRC showed compelling, albeit modest, clinical activity. This study provides proof of principle that Imprime PGG, in combination with complement-activating antibodies, is associated with clinical activity.

Importance Treatment of locally advanced rectal (LARC) cancer involves chemoradiation, surgery, and chemotherapy. The concept of total neoadjuvant therapy (TNT), in which chemoradiation and chemotherapy are administered prior to surgery, has been developed to optimize delivery of effective systemic therapy aimed at micrometastases. Objective To compare the traditional approach of preoperative chemoradiation (chemoRT) followed by postoperative adjuvant chemotherapy with the more recent TNT approach for LARC. Design, Setting, and Participants A retrospective cohort analysis using Memorial Sloan Kettering Cancer Center (MSK) records from 2009 to 2015 was carried out. A total of 811 patients who presented with LARC (T3/4 or node-positive) were identified. Exposures Of the 811 patients, 320 received chemoRT with planned adjuvant chemotherapy and 308 received TNT (induction fluorouracil- and oxaliplatin-based chemotherapy followed by chemoRT). Main Outcomes and Measures Treatment and outcome data for the 2 cohorts were compared. Dosing and completion of prescribed chemotherapy were assessed on the subset of patients who received all therapy at MSK. Results Of the 628 patients overall, 373 (59%) were men and 255 (41%) were women, with a mean (SD) age of 56.7 (12.9) years. Of the 308 patients in the TNT cohort, 181 (49%) were men and 127 (49%) were women. Of the 320 patients in the chemoRT with planned adjuvant chemotherapy cohort, 192 (60%) were men and 128 (40%) were women. Patients in the TNT cohort received greater percentages of the planned oxaliplatin and fluorouracil prescribed dose than those in the chemoRT with planned adjuvant chemotherapy cohort. The complete response (CR) rate, including both pathologic CR (pCR) in those who underwent surgery and sustained clinical CR (cCR) for at least 12 months posttreatment in those who did not undergo surgery, was 36% in the TNT cohort compared with 21% in the chemoRT with planned adjuvant chemotherapy cohort. Conclusions and Relevance Our findings provide additional support for the National Comprehensive Cancer Network (NCCN) guidelines that categorize TNT as a viable treatment strategy for rectal cancer. Our data suggest that TNT facilitates delivery of planned systemic therapy. Long-term follow-up will determine if this finding translates into improved survival. In addition, given its high CR rate, TNT may facilitate nonoperative treatment strategies aimed at organ preservation.

Immune checkpoint inhibitor (ICI) treatments benefit some patients with metastatic cancers, but predictive biomarkers are needed. Findings in select cancer types suggest that tumor mutational burden (TMB) may predict clinical response to ICI.To examine this association more broadly, we analyzed the clinical and genomic data of 1662 advanced cancer patients treated with ICI, and 5371 non-ICI treated patients, whose tumors underwent targeted next-generation sequencing (MSK-IMPACT). Among all patients, higher somatic TMB (highest 20% in each histology) was associated with better OS (HR 0.52; p=1.6 ×10(−6)). For most cancer histologies, an association between higher TMB and improved survival was observed. The TMB cutpoints associated with improved survival varied markedly between cancer types. These data indicate that TMB is associated with improved survival in patients receiving ICI across a wide variety of cancer types, but that there may not be one universal definition of high TMB.

O1 Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumab #### Sonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1, Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia

4112 Background: Adrenocortical carcinomas (ACC) are rare and aggressive. Treatment options are limited and marked by poor efficacy and substantial toxicity. In this phase II single-center study, the efficacy and safety of pembrolizumab was assessed in patients (pts) with advanced ACC. Methods: Enrolled pts were aged ≥18 y with advanced ACC, ECOG ≤ 1, available tumor samples for biomarker analysis. Pts received pembrolizumab 200 mg Q3W for 2 y or until disease progression, intolerable toxicity, physician/patient decision to stop treatment. Imaging was performed every 9 wks. Tumor PD-L1 positivity (modified proportion score ≥ 1% or presence of stromal interface) was evaluated. Primary endpoint was ORR (by RECIST v1.1). Secondary endpoints included DOR, PFS, OS, safety. Somatic and germline next-generation sequencing was performed. Results: 39 pts were treated. Median age 62 (range, 19-87), 28% ECOG 0, 72% received ≥ 1 therapy. In available samples to date, 7/31 (23%) PD-L1+. At time of analysis, median follow-up among survivors was 17.8 mo (range, 5.4-34.7). ORR was 23.1% (95% CI, 11.1-39.3); 0 CR, 9PR. Seven pts (17.9%) had SD as best response. Among the 9 PRs, median time to PR was 4.1 mo (range, 1.7-10.5) and median DOR was not reached (95% CI, 4.1-not reached). Three pts achieving PR have completed 2 y of treatment with ongoing response noted. Tumor PD-L1 status is currently available in 6 pts with PR, 2/6 (33%) PD-L1+. Median PFS was 2.1 mo (95% CI, 2.0-10.7). Median OS was 24.9 mo (95% CI, 4.2-not reached); 2-year OS rate was 50% (95% CI, 36-69%). In the 34 tested tumors, germline testing identified 2 PR pts with Lynch syndrome; the remaining 7 PRs were MSS. Median tumor mutation burden for all PRs was 4.1 mutations/megabase (range, 0-31.5). There was no significant relationship between somatic alterations and response to treatment. Grade 3/4 treatment-related AEs occurred in 7/39 (17.9%) pts. Two pts discontinued therapy due to AEs; both pts achieved PRs and continue to respond. All pts with PRs had LFT elevation ≥ grade 2. Conclusions: Pembrolizumab demonstrated antitumor activity and was well tolerated in advanced ACC. Durable responses were noted. Complete evaluation of tumor PD-L1 and microsatellite status will be reported at the meeting. Clinical trial information: NCT02673333.

3585 Background: We assembled a large series of consecutive patients with unresectable metastatic colorectal cancer (mCRC) to identify genomic biomarkers of response and survival. Methods: Patients with unresectable mCRC treated at Memorial Sloan Kettering with genomic tumor profiling between 2014 and 2017 were included. Patients who underwent upfront metastasectomy or received neoadjuvant/conversion chemotherapy were excluded. Clinical information was retrieved from electronic medical records, and we evaluated associations between genomic profiles with progression free survival (PFS) on first-line chemotherapy and overall survival (OS). Categorical data were analyzed by Fisher exact test and time-to-event data were analyzed by Cox proportional hazards models. Results: Of 1453 mCRCs profiled in this period, 471 patients met the study criteria. Median age was 59 years (range, 18 to 95), and 73% of patients were stage IV at diagnosis. Most tumors (91%) were microsatellite stable (MSS). The most frequent first-line regimen was FOLFOX +/- bevacizumab (66%). Among MSS patients treated with oxaliplatin-containing regimens (n = 305), 7% harbored alterations in genes associated with DNA damage response (DDR) (BRCA1, BRCA2, ATM, PALB2). DDR gene alterations were not associated with PFS (P = 0.94) nor were different quartiles of large-state transitions (P = 0.54). Genomic alterations that significantly varied by duration of response included BRAF (16%, 10%, and 5% for PFS < 6 months, 6-12 months, and > 12 months, respectively) and APC (62%, 74%, and 80% for PFS < 6 months, 6-12 months, and > 12 months, respectively). APC mutation, single or dual, was associated with significantly longer PFS (HR 0.67) and OS (HR 0.59) in multivariate analysis versus no WNT pathway alteration or alterations in other WNT pathway genes (RNF43, AXIN2, CTNNB1). Conclusions: In unresectable mCRC patients, mutations in APC were associated with better outcomes; absence of an APC alteration or the occurrence of other WNT pathway alterations was associated with shorter survival. Somatic alterations in DDR genes were not associated with outcomes in mCRC patients receiving oxaliplatin-containing regimen.

TPS467 Background: CIT has significant survival benefits across multiple tumor types, but durable response is experienced by only subsets of patients (pts). To extend clinical benefit to more pts, efficacious CIT combinations (combos) targeting multiple cancer immune escape mechanisms need to be identified. The MORPHEUS platform includes multiple ph Ib/II trials designed to identify early signals of safety and efficacy of CIT combos. Using a randomized trial design, multiple treatment (tx) arms are compared with a single control arm in each pt cohort. We present three GI-specific MORPHEUS trials, each assessing CIT combos that could concurrently enhance multiple aspects of the cancer immune response. Methods: The MORPHEUS trials described here are global, open-label, randomized, Ph Ib/II trials enrolling pts with pancreatic ductal adenocarcinoma (PDAC), gastric or gastroesophageal junction cancers or colorectal cancer (CRC). New arms with novel CIT combos (table) are opened as new txs become available, and arms with minimal efficacy or unacceptable toxicity are closed. Studies include multiple cohorts for pts receiving different lines of tx (1L and 2L PDAC and gastric; 3L CRC). Pts with loss of clinical benefit or unacceptable toxicity may be eligible to enroll in a different CIT combo arm. Primary endpoints include safety and investigator-assessed ORR (RECIST v1.1); secondary endpoints: PFS, OS, DCR and DOR. Clinical trial information: NCT03193190, NCT03281369, NCT03555149. [Table: see text]

Background: During DNA replication, there is an increased risk for base substitution due to replicative errors caused by DNA polymerases, which have error rates of approximately 10-5 per base pair per cell division. One of the mechanisms to counteract these errors involves real-time proofreading via exonuclease activity present in both DNA polymerase ε, which synthesizes the leading strand and is encoded by POLE, and DNA polymerase δ, which is involved in lagging strand synthesis and encoded by POLD1. Mutations in POLE or POLD1 are associated with an increase in DNA replication error rates and high tumor mutational burden (TMB). High TMB may confer sensitivity to immunotherapy with checkpoint inhibitors. The prevalence of POLE/POLD1 mutations is 5-10% across a wide assortment of tumor types, and POLE/POLD1 mutations can be identified through plasma circulating free DNA (cfDNA) testing. Therefore, POLE/POLD1 mutated tumors present an attractive target for treatment with the immune checkpoint inhibitors nivolumab and ipilimumab. Methods: This is an international multicenter, open-label, randomized phase II noncomparative trial of nivolumab alone or in combination with ipilimumab for the treatment of patients with advanced hypermutated solid tumors detected by a blood-based assay. While the intent is to expand this study into a platform to test additional liquid biomarker assays, the biomarker selection of eligible patients will initially be based on detection of either POLE or POLD1 mutations by cfDNA. Patients with POLE or POLD1 mutations identified on previous tumor tissue testing via the CLIA certified testing platform are also eligible. Patients will be randomized 1:1 to receive either nivolumab monotherapy (240mg IV every 2 weeks) or in combination with ipilimumab (1mg/kg IV every 6 weeks) until progression. Stratification factors are ECOG performance status (0,1) and number of prior treatments (0, 1-2,3 or more). Other key eligibility criteria include: histologically confirmed metastatic or unresectable solid tumors (except primary CNS tumors), tissue block (or minimum 20 slides) available from primary or metastatic tumor, measurable disease per RECIST 1.1, ≥ 18 years of age, received at least 1 standard cancer therapy (unless patient refused) for their tumor type and progressed on most recent regimen, and received no prior immunotherapy. A sample size of 50 evaluable patients in each arm will achieve 90% power to show a clinically meaningful objective response rate (ORR). These calculations assume nivolumab monotherapy p0 < 13%, p1 > 30%, and in combination with ipilimumab therapy p0 < 30%, p1 >50%. Objectives: The primary objective is to evaluate the ORR of nivolumab monotherapy and of nivolumab + ipilimumab in randomized patients with detectable POLE or POLD1 mutations as determined by plasma cfDNA. Secondary objectives are to evaluate efficacy by ORR and duration of response in all treated patients with detectable POLE or POLD1 mutations in either plasma cfDNA or tumor tissue as well as to assess correlation between POLE/D1 mutations in tumor and POLE/D1 mutations in blood. Exploratory endpoints include determining progression-free survival and overall survival, correlation between POLE/POLD1 mutations occurring within or outside of the exonuclease domain and TMB as determined by whole exome and RNA sequencing, and correlation between TMB assessed in plasma cfDNA and assessed directly in tumor tissue. NCT03461952. Citation Format: Naiyer Rizvi, Patricia Tang, Nina Bhardwaj, Timothy A. Chan, Jeffrey S. Weber, Michael Vickers, Sofya Pintova, Holger Hirte, Neil H. Segal, Neesha Dhani, Daniel Cho, Stephen Chia, Caitlin Burns, Donsheng Tu, Laura Pearce, Alison Urton, Martin Smoragiewicz, Janet Dancey. Nivolumab +/- Ipilimumab in patients with hypermutated cancers detected in blood: NIMBLE [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B207.

Background: This study evaluated the addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinoma first-line therapy. Methods: Patients with advanced biliary adenocarcinomas received gemcitabine 1000 mg m−2 and cisplatin 25 mg m−2 on a 2 weeks on/1 week off cycle and sorafenib 400 mg twice daily. After the initial 16 patients were enrolled, the chemotherapy doses were amended in view of grade 3 and 4 hand–foot skin reaction and haematologic toxicity. Subsequently, 21 patients received gemcitabine 800 mg m−2, cisplatin 20 mg m−2 and sorafenib 400 mg. The primary end point was an improvement in 6-month progression-free survival (PFS6) from historical 57–77% (90% power, type I error of 10%). Pretreatment pERK, evaluated by immunostaining, was correlated with clinical outcome. Results: A total of 39 patients were accrued. The most common grade 3–4 toxicities noted in >10% of patients were fatigue, elevated liver function tests and haematologic toxicities including thromboemboli, hyponatraemia and hypophosphataemia. Six-month progression-free survival was 51% (95% confidence interval (CI) 34–66%). Median PFS and overall survival were 6.5 (95% CI: 3.5–8.3) and 14.4 months (95% CI: 11.6–19.2 months), respectively. No correlation was observed between pERK and outcomes. Conclusion: The addition of sorafenib to gemcitabine and cisplatin in biliary adenocarcinomas did not improve efficacy over historical data, and toxicity was increased.

Purpose Pneumonitis is an uncommon but potentially fatal toxicity of anti–programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. Methods Patients who received anti–PD-1/PD-L1 monotherapy or in combination with anti–cytotoxic T-cell lymphocyte associated antigen-4 mAb were identified at two institutions (Memorial Sloan Kettering Cancer Center: advanced solid cancers, 2009 to 2014, and Melanoma Institute of Australia: melanomas only, 2013 to 2015). Pneumonitis was diagnosed by the treating investigator; cases with confirmed malignant lung infiltration or infection were excluded. Clinical, radiologic, and pathologic features of pneumonitis were collected. Associations among pneumonitis incidence, therapy received, and underlying malignancy were examined with Fisher’s exact test as were associations between pneumonitis features and outcomes. Results Of 915 patients who received anti–PD-1/PD-L1 mAbs, pneumonitis developed in 43 (5%; 95% CI, 3% to 6%; Memorial Sloan Kettering Cancer Center, 27 of 578 [5%]; Melanoma Institute of Australia, 16 of 337 [5%]). Time to onset of pneumonitis ranged from 9 days to 19.2 months. The incidence of pneumonitis was higher with combination immunotherapy versus monotherapy (19 of 199 [10%] v 24 of 716 [3%]; P < .01). Incidence was similar in patients with melanoma and non–small-cell lung cancer (overall, 26 of 532 [5%] v nine of 209 [4%]; monotherapy, 15 of 417 v five of 152 [ P = 1.0]; combination, 11 of 115 v four of 57 [ P = .78]). Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. Conclusion Pneumonitis associated with anti–PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti–PD-1/PD-L1 mAbs are combined with anti–cytotoxic T-cell lymphocyte associated antigen-4 mAb. Most events are low grade and improve/resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.

Purpose To assess the impact on acute toxicity of replacing 5-fluorouracil (5-FU) with capecitabine in definitive chemoradiation for patients with anal squamous cell carcinoma (ASCC). Methods and Materials We retrospectively reviewed the records of 107 consecutive patients with nonmetastatic ASCC treated with definitive chemoradiation from January 2009 to May 2014. In 2011, based on the noninferiority of capecitabine versus 5-FU, our institutional practice shifted to use capecitabine instead of 5-FU for ASCC. Of 107 patients, 63 were treated with infusional 5-FU (1000 mg/m 2 /day for 4 days) and mitomycin C (MMC) (10 mg/m 2 ) during weeks 1 and 5, and 44 patients were treated with capecitabine (825 mg/m 2 twice daily) Monday through Friday throughout radiation therapy (RT) and MMC (10 mg/m 2 ) during weeks 1 and 5. The incidence of grade 3 to 4 acute toxicity was compared between the 2 groups. Results The median age at diagnosis was 59 years, and 78 patients (73%) were female. The patient characteristics were similar between the 2 treatment groups. All patients in both groups were treated with intensity modulated RT (median dose, 56 Gy). In the 5-FU group, 52% experienced grade 3 to 4 neutropenia compared with 20% in the capecitabine group ( P =.001). Treatment breaks resulting from toxicity, primarily related to grade 3+ hematologic toxicity, were necessary for 42% of patients treated with 5-FU versus 16% of those treated with capecitabine ( P =.006). Conclusions Pelvic radiation therapy with MMC plus capecitabine was well tolerated and appeared to have less grade 3+ acute hematologic toxicity and fewer treatment interruptions than in a population of ASCC patients undergoing definitive chemoradiation with MMC and 5-FU.

Purpose To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC). Methods A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1–positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1. Results A total of 61 patients (40 PD-L1–positive, 21 PD-L1–negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1–positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1–negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks). Conclusion Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1–positive patients with UBC, many of whom were heavily pretreated.

Purpose Tumor screening for Lynch syndrome is recommended in all or most patients with colorectal cancer (CRC). In metastatic CRC, sequencing of RAS/BRAF is necessary to guide clinical management. We hypothesized that a next-generation sequencing (NGS) panel that identifies RAS/BRAF and other actionable mutations could also reliably identify tumors with DNA mismatch repair protein deficiency (MMR-D) on the basis of increased mutational load. Methods We identified all CRCs that underwent genomic mutation profiling with a custom NGS assay (MSK-IMPACT) between March 2014 and July 2015. Tumor mutational load, with exclusion of copy number changes, was determined for each case and compared with MMR status as determined by routine immunohistochemistry. Results Tumors from 224 patients with unique CRC analyzed for MMR status also underwent MSK-IMPACT. Thirteen percent (n = 28) exhibited MMR-D by immunohistochemistry. Using the 341-gene assay, 100% of the 193 tumors with < 20 mutations were MMR-proficient. Of 31 tumors with ≥ 20 mutations, 28 (90%) were MMR-D. The three remaining tumors were easily identified as being distinct from the MMR-D tumors with > 150 mutations each. Each of these tumors harbored the P286R hotspot POLE mutation consistent with the ultramutator phenotype. Among MMR-D tumors, the median number of mutations was 50 (range, 20 to 90) compared with six (range, 0 to 17) in MMR-proficient/POLE wild-type tumors (P < .001). With a mutational load cutoff of ≥ 20 and < 150 for MMR-D detection, sensitivity and specificity were both 1.0 (95% CI, 0.93 to 1.0). Conclusion A cutoff for mutational load can be identified via multigene NGS tumor profiling, which provides a highly accurate means of screening for MMR-D in the same assay that is used for tumor genotyping.

4032Background: PD-(L)1 checkpoint blockade has shown clinical benefits in gastroesophageal (GE) cancers. Durvalumab, a selective, high-affinity, engineered human immunoglobulin G1 anti-PD-(L)1 mon...

8518Background: SCLC is an aggressive lung cancer with high rate of relapse following initial treatment; immunotherapy holds potential as a novel treatment option for this disease. The anti-PD-L1 a...

1577Background: Although universal screening of all colorectal tumors for Lynch syndrome (LS) is recommended, the prevalence of other germline mutations, with potential clinical implications, in co...

8517Background: Treatment options for ED-SCLC are limited, with standard first-line platinum and etoposide and second-line topotecan having limited clinical activity. Beyond these agents, no approv...

3520Background: The incidence of CRC in patients (pts) under the age of 50 has been rising over the past decade. Little is known about the biologic differences between early and AO (over the age of...

169 Background: Single-agent durvalumab is being evaluated in patients with advanced squamous and non-squamous NSCLC in an ongoing Phase 1/2 study (NCT01693562). Here we present updated survival and safety data in NSCLC patients. Methods: Treatment-naïve (1L) and previously treated (2L or 3L+) stage IIIB/IV NSCLC patients received durvalumab 10 mg/kg Q2W for up to 12 months. Patients were stratified by tumor PD-L1 expression (Ventana PD-L1 [SP263] Assay [PD-L1 high: ≥25% of tumor cells with membrane staining]), treatment line, and histology. Results: As of 05 September 2017, 304 NSCLC patients received durvalumab monotherapy. Median duration of follow-up was 35.6 (0.3–50.9) months. Investigator-assessed ORR ranged between 23.2% and 30.0% among PD-L1 high patients, and between 3.6% and 8.3% among PD-L1 low/negative patients. Median PFS and median OS were longer in PD-L1 high vs PD-L1 low/negative patients (Table). Any-grade treatment-related AEs (TRAEs) were reported in 57.2% of pts (including fatigue, 17.4%, decreased appetite, 9.2%, diarrhea, 8.9%); in 10.2% of pts these were Grade 3 or 4. TRAEs resulting in treatment discontinuation were reported in 17 patients (5.6%); 1 patient had a Grade 5 TRAE (pneumonia). Conclusions: In this ongoing phase 1 study, OS and safety profile appear encouraging in treatment-naïve and previously treated NSCLC patients, particularly among PD-L1 high patients. Further investigation regarding PD-L1 expression for selection of patients who most likely benefit from durvalumab is needed. Clinical trial information: NCT01693562. [Table: see text]

Higher serum 25-hydroxy vitamin D [25(OH)D] levels are associated with decreased colorectal cancer (CRC) incidence. In this retrospective study of Stage IV CRC patients, we evaluate whether 25(OH)D levels at diagnosis correlate with survival. Stored sera from carcinoembryonic antigen (CEA) measurements obtained between February 2005 and March 2006 were screened. The first 250 patients with CEA ± 30 days of Stage IV CRC diagnosis were included. Serum 25(OH)D levels were determined and categorized as adequate ≥ 30 ng/mL, or deficient

We performed an integrated clinical and bioinformatic analysis of colorectal cancers (CRCs) genotyped at our institution from 4/2014-7/2016 to comprehensively characterize genomic alterations in metastatic CRC (mCRC). We analyzed 1008 samples (474 primaries, 534 metastases) from 985 mCRC patients and 128 early stage CRCs sequenced with MSK-IMPACT, a hybridization capture next generation sequencing assay. Metastatic CRCs were divided into 3 groups by mutation burden and MSIsensor algorithm score: microsatellite stable (MSS) (n=939; 95%), microsatellite-high (MSI-H) (n=41; 4%), and ultra-mutated (n=5; 1%). Early stage CRC were enriched for MSI-H due to clinical selection and were 53% MSS, 44% MSI-H, and 4% ultra-mutated. Ultra-mutated tumors exhibited >100 mutations and harbored hotspot mutations in POLE in 8 cases and a potential novel POLE alteration in 1 case. We evaluated the frequency of oncogenic alterations in MSI-H and MSS mCRCs. The frequency of the resistance biomarkers KRAS and NRAS did not vary between MSI-H and MSS mCRCs (46% v 41%, p=0.6). Potentially actionable alterations were enriched in MSI-H tumors (78% v 33%, p Analysis of mutation frequencies in 3 MSS CRC disease states - early stage resected primary (The Cancer Genome Atlas, TCGA), primary site of mCRC, and metastatic site - found significant depletion of FBXW7 mutations in metastases. We also found significant and progressive enrichment of TP53 alterations (58% TCGA, 73% primaries of mCRC, 79% metastases) and BRAF mutations (4% TCGA, 9% primaries of mCRC, 10% metastases) in advanced disease, suggesting a role of these genes in aggressive disease. One third of the BRAF mutations in our cohorts were not V600 but known to be oncogenic. In this large dataset, we identified markers of advanced CRC and found that while MSI-H and MSS CRC have a similar frequency of resistance biomarkers, MSI-H CRC more commonly harbor actionable alterations. Citation Format: Marla Lipsyc, Walid Chatila, Jaclyn F. Hechtman, Francisco Sanchez-Vega, Sumit Middha, Andrea Cercek, Zsofia Stadler, Ritika Kundra, Aijazuddin Syed, David M. Hyman, Ahmet Zehir, Armin Shahrokni, Anna Varghese, Diane Reidy, Neil H. Segal, Efsevia Vakiani, David B. Solit, Marc Ladanyi, Michael F. Berger, Nancy Kemeny, Leonard Saltz, Nikolaus Schultz, Rona Yaeger. Integrative genomics analysis of metastatic colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4380. doi:10.1158/1538-7445.AM2017-4380

3534 Background: Metastatic colorectal cancers (mCRCs) with a right-sided primary site are associated with shorter survival and insensitivity to EGFR inhibitors compared to those originating in the left side of the colon or rectum. Methods: We performed targeted gene sequencing of 928 consecutive MSS mCRCs. Primary tumor site was divided into right-sided for cecum to distal transverse colon (n = 242), left-sided for splenic flexure to rectum (n = 673), or unknown colonic location (n = 13). Histologic subtypes were conventional (adenocarcinoma not otherwise specified), conventional with mucinous features ( < 50% mucinous), mucinous, signet ring, and poorly differentiated. To evaluate receptor tyrosine kinase (RTK) signaling, we analyzed ligand mRNA expression in TCGA. Results: Overall survival from time of metastasis was shorter for right-sided than left-sided primary site (survival at 5 years: 45% v 67%, p < 0.001). Right-sided tumors had more mutations (5.60 v 4.62 per MB, p < 0.001) but fewer copy-number changes (0.18 v 0.22 fraction genome altered, p = 0.001) compared to left-sided tumors. Alterations of KRAS, BRAF, PIK3CA, PTEN, AKT1, RNF43, and SMAD4 were significantly enriched in right-sided tumors, and of APC and TP53 in left-sided tumors. In a multivariate model, APC (HR = 0.7, p = 0.03), BRAF (HR = 3.7, p < 0.001), and KRAS (HR = 1.7, p < 0.01) alterations predicted for survival, but primary site did not (HR = 0.74, p = 0.07). Amphiregulin, epiregulin, neuregulin, and HGF expression was significantly higher in left-sided tumors. We found a higher proportion of conventional histology (83% v 63%) and moderate differentiation (82% v 69%) for left versus right-sided cases. Conclusions: We find that within MSS mCRC there are significantly more oncogenic mutations in right-sided tumors, and the difference in survival between right- and left-sided mCRC is primarily driven by differences in mutations. Left-sided tumors more commonly exhibit a “simpler” conventional histology that is lower grade and may rely on native RTK signaling, such as EGFR, for growth, providing a potential mechanism for the differential sensitivity to EGFR inhibitors seen by primary tumor site.

3002 Background: CEA CD3 TCB (RG7802, RO6958688) is a novel T-cell bispecific antibody targeting CEA on tumor cells and CD3 on T cells. In preclinical models, CEA CD3 TCB displays potent anti-tumor activity, leads to increased intra-tumoral T cell infiltration and activation and upregulates PD-1/PD-L1. Methods: Intwo ongoing dose-escalation phase I studies, RO6958688 is given as monotherapy (S1) i.v. QW or in combination (QW) with atezolizumab 1200 mg Q3W (S2) in adult patients (pts) with advanced CEA+ solid tumors. In S1, 80 pts (mCRC: 68) were treated at dose levels from 0.05 mg to 600 mg; in S2, 38 pts (mCRC: 28) from 5 mg to 160 mg. In S1, a Bayesian logistic regression model with overdose control guided dose escalation. Data cutoff 25.01.17. Results: At doses ≥60mg (36 pts in S1; 10 in S2), CT scans revealed tumor inflammation within days of first dose, consistent with the mode of action of RO6958688. 2 (5%) pts in S1 (both microsatellite stable (MSS) and 2 (20%; 1 MSS) in S2 had a partial response (RECIST v1.1). Preliminary tumor size reduction ( > -10% and < -30% [stable disease]) was observed in 4 (11%) additional pts in S1 and 5 (50%) in S2. At week 4-6 FDG PET scan assessment, 10 (28%) pts with mCRC in S1 and 6 (60%) in S2 had a metabolic partial response (EORTC criteria). At all doses in S1, the most common related AEs were pyrexia (56.3%), infusion related reaction (IRR, 50%) and diarrhea (40%). The most common grade ≥ 3 (G3) related AEs were IRR (16.3%) and diarrhea (5%). 5 patients experienced DLTs: G3 dyspnea, G3 diarrhea, G3 hypoxia, G4 colitis and G5 respiratory failure (G4-5 at 600mg). DLT events were likely associated with tumor lesion inflammation. In S2, there was no evidence of new or additive toxicities, with 1 DLT at 160 mg (G3 transient increase of ALT in a patient with liver metastases). PK/PD data are reported separately. Conclusions: Evidence of antitumor activity was observed with RO6958688 monotherapy in ongoing dose escalation. Activity appeared to be enhanced with doses in combination with atezolizumab, with a manageable safety profile. Updated data will be presented. Clinical trial information: NCT02324257 and NCT02650713.