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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: Adding trastuzumab to first-line chemotherapy improves overall survival in patients with HER2-positive metastatic gastric cancer. We assessed the safety and efficacy of pembrolizumab in combination with trastuzumab and chemotherapy in first-line HER2-positive metastatic esophagogastric (EG) cancer. METHODS: This was an open-label, non-randomized, single-arm, investigator-initiated single center phase 2 trial in patients aged 18 years or older with HER2-positive mEG cancer. Eligible patients had measurable or evaluable non-measurable disease at baseline, Eastern Cooperative Oncology Group performance status of 0, 1, or 2, and baseline left ventricular ejection fraction of ≥ 53%. Patients were eligible to receive an initial induction cycle of intravenous (IV) pembrolizumab (200 mg flat dose) and IV trastuzumab 8 mg/kg loading dose. For subsequent cycles, patients received IV oxaliplatin 130 mg/m(2) or cisplatin 80 mg/m(2) on day 1, oral capecitabine 850 mg/m(2) twice a day for 2 weeks followed by 1 week off, or IV 5-FU 800 mg/m(2)/day on day 1 to 5, and IV pembrolizumab 200 mg flat dose and trastuzumab 6 mg/kg, both administered on day 1 of each 3-week cycle. The primary endpoint was 6-month progression-free survival (PFS). Pre-treatment tumor and plasma samples were collected for confirmation of HER2 status and exploratory biomarker analysis by targeted and whole exome sequencing. This trial is registered with Clinicaltrials.gov, number NCT02954536 (ongoing, closed to enrollment). FINDINGS: Between Nov 11, 2016, and Jan 23, 2019, 37 patients were enrolled. At the time of data cutoff on Aug 6, 2019, the median follow-up among survivors was 13 months (range 6–31). The primary endpoint was achieved; 26 of 37 (70%, 95% CI 54–83%) patients were progression-free at 6 months. The overall response rate among 35 patients with measurable disease was 91% (32 patients, 95% CI 78–97%), including 6 (17%) complete responses, 26 (74%) partial responses, and 3 (8%) stable disease. The median PFS was 13.0 months (95% CI 8.6–NA), median overall survival (OS) was 27.2 months (95% CI 18.8–NA), and the 12-month OS rate was 80% (95% CI 68–95%). The most common treatment-related adverse event of any grade was neuropathy, which affected 36 (97%) of the 37 patients. Treatment-related grade 3 or 4 adverse events occurred in 21 (67%) patients, and serious adverse events occurred in 2. Two patients discontinued treatment due to treatment-related adverse events, and 4 discontinued pembrolizumab due to immune-related adverse events. ERBB2 amplification or focal gain was detected in 21 of 32 patients (66%) patients who had tumor sequencing and in 18 of 33 patients (54%) whose circulating tumor DNA (ctDNA) was sequenced. Tissue and ctDNA sequencing were concordant for presence or absence of ERBB2 amplification in 27 of 29 patients (93%). A decline in tumor-matched ctDNA was observed after the first dose of pembrolizumab and trastuzumab in 13 of the 16 patients with tumor-matched pre-treatment ctDNA. Patients with ERBB2 amplification in both tumor and ctDNA had longer PFS; median 16.4 (n = 14, 95% CI 13.0–NA) versus 6.2 months (n = 12, 95% CI 5.9–NA) in those who did not (p = 0.013). INTERPRETATION: Pembrolizumab can be safely combined with trastuzumab and chemotherapy and has promising activity in HER2-positive mEG cancer irrespective of PD-L1 status. Plasma-based ctDNA should be explored in future randomized studies as a predictive biomarker. A randomized phase 3 clinical trial assessing the efficacy and safety of pembrolizumab versus placebo in combination with trastuzumab and chemotherapy in first-line HER2-positive mEG cancer is currently underway.

// Yassine Ridouane 1 , Gilberto Lopes 2 , Geoffrey Ku 3 , Hasan Masud 1 and Benjamin Haaland 1, 4 1 H. Milton Stewart School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA, USA 2 Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, FL, USA 3 Memorial Sloan Kettering Cancer Center, New York, NY, USA 4 Population Health Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA Correspondence to: Benjamin Haaland, email: ben.haaland@hsc.utah.edu Keywords: Bayesian, colorectal cancer, decision analysis, meta-analysis, targeted therapy Received: May 10, 2017 Accepted: August 03, 2017 Published: August 11, 2017 ABSTRACT Background: Colorectal cancer is common and deadly. First-line treatments for patients with metastatic disease include FOLFIRI and FOLFOX, which have been combined with anti-EGFR or anti-VEGF antibodies to achieve benefit in selected populations. However, optimal therapy remains unclear. Results: Fifteen publications on 10 trials were identified. There was a lack of decisive evidence that FOLFIRI or FOLFOX impact efficacy of either anti-EGFR or anti-VEGF, across mutational status groups. On the other hand, evidence suggests both anti-EGFR and anti-VEGF may be more effective for KRAS WT than MT patients. KRAS WT results provided evidence that anti-EGFR treatments may be more effective than anti-VEGF treatments when combined with FOLFIRI or FOLFOX . Further, evidence suggests that both anti-EGFR and anti-VEGF therapies, when combined with FOLFIRI or FOLFOX , may be harmful as compared to chemotherapy for KRAS MT patients. Materials and Methods: Literature was searched for randomized trials comparing anti-EGFR or anti-VEGF antibodies, paired with FOLFIRI or FOLFOX, as first-line therapy for advanced colorectal cancer. Meta-estimates were generated via Bayesian hierarchical log-linear model. The primary endpoint was overall survival. Conclusions: Further studies examining impact of all- RAS mutation status, left or right side location of primary tumor, and combination anti-VEGF with modern bolus fluoropyrimidine are needed.

Background Angiogenesis is critical to gastroesophageal adenocarcinoma growth and metastasis. Regorafenib is a multikinase inhibitor targeting angiogenic and stromal receptor tyrosine kinases. We evaluated whether regorafenib augments the antitumor effect of first-line chemotherapy in metastatic esophagogastric cancer. Materials and methods Patients with previously untreated metastatic gastroesophageal adenocarcinoma received 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) every 14 days and regorafenib 160 mg daily on days 4 to 10 of each 14-day cycle. The primary endpoint was 6-month progression-free survival (PFS). To identify predictive biomarkers of outcome, we examined correlations between genomic characteristics of sequenced pretreatment tumors and PFS. Results Between August 2013 and November 2014, 36 patients with metastatic esophagogastric cancer were accrued to this single-center phase II study (NCT01913639). The most common grade 3-4 treatment-related adverse events were neutropenia (36%), leucopenia (11%) and hypertension (8%). The 6-month PFS was 53% (95% confidence interval [CI], 38%-71%), the objective response rate was 54% (95% CI, 37%-70%), and the disease control rate was 77% (95% CI, 67%-94%). Next-generation sequencing did not identify any genomic alterations significantly correlated with response, and there was no association between homologous recombination deficiency and PFS with platinum-based chemotherapy. Conclusion Regorafenib (one week on-one week off schedule) is well tolerated in combination with first-line FOLFOX but does not improve 6-month PFS relative to historical control. Implications for practice Prognosis for metastatic esophagogastric cancer remains poor despite modern systemic therapy regimens. This phase II trial indicates that the combination of regorafenib and FOLFOX is well tolerated but does not add to the efficacy of first-line chemotherapy in metastatic esophagogastric cancer. Notably, recently reported data suggest potential synergy between regorafenib and the PD-1 inhibitor nivolumab. As this study demonstrates that regorafenib plus FOLFOX is safe, and combined chemotherapy and immunotherapy show favorable toxicity profiles, future studies combining immunotherapy with regorafenib and chemotherapy may be feasible.

Esophageal carcinoma is an aggressive malignancy and outcomes remain poor. Immune checkpoint inhibitors are a standard-of-care in the third-line and beyond settings, although benefit is modest. Herein, we report the case of a patient who achieved a partial response to salvage chemotherapy following treatment with an immune checkpoint inhibitor despite having chemo-refractory disease. A 41-year-old male, with a history of Crohn's disease, was diagnosed with Her2-positive metastatic esophageal adenocarcinoma to lungs and lymph nodes. The patient received multiple lines of systemic therapy including: first-line modified DCF (docetaxel/cisplatin/5-fluorouracil) with trastuzumab, second-line trastuzumab/afatinib on a clinical study, third-line carboplatin/irinotecan/ramucirumab and fourth-line treatment with a Her2 antibody-drug conjugate, DS-8201A, on a phase I study. While the patient was not a candidate for clinical trials evaluating immune checkpoint inhibitors due to his history of Crohn's disease, the latter was well controlled. Thus, the patient commenced pembrolizumab as fifth-line of treatment 2 years since diagnosis. After 3 cycles of therapy, the patient developed grade 3 immune-related colitis and treatment was discontinued. The patient maintained a good performance status and commenced a sixth-line of carboplatin/irinotecan/ramucirumab. Subsequent imaging demonstrated a partial response which was maintained over a 6-month period. This case demonstrates a response to previously administered chemotherapy following immune checkpoint inhibitor therapy, despite prior progression on this chemotherapy regimen. To our knowledge, this has not been previously reported in esophagogastric carcinoma (EGC). Post-immune checkpoint inhibitor chemotherapy may be a feasible treatment strategy. Research is needed to evaluate the role of post-immune checkpoint inhibitor chemotherapy in patients with metastatic EGC.

Immune checkpoint inhibitors have transformed treatment paradigms in several cancers, many of which were previously associated with a poor prognosis, including melanoma and lung cancer. Given the poor outcomes from treatment with chemotherapy and targeted therapies in this disease, there has been strong interest in the evaluation of immunotherapy.

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of EGFR and ERBB2. Heterogeneous 89Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplification or with acquisition of MET amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplified EG cancer. Significance: Analysis of patients with ERBB2-amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with EGFR/ERBB2 coamplification and MET amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones. See related commentary by Klempner and Catenacci, p. 166. This article is highlighted in the In This Issue feature, p. 151

OBJECTIVE: Esophageal squamous cell carcinoma (ESCC-R) is a rarely encountered sequela of chest radiation. Treatment is limited by toxicity with reirradiation and complex surgical dissection in a previously radiated field. The clinical presentation, prognosis and treatment selection of ESCC-R remains undefined. METHODS: A retrospective review was performed of patients with esophageal squamous cell carcinoma at a single institution between 2000 to 2017 to identify patients with previous radiation therapy (≥ 5 years delay). Clinicopathologic characteristics, treatment and outcomes of ESCC-R (n=69) patients were compared to patients with primary esophageal squamous cell carcinoma (ESCC) (n=827). Overall survival (OS) and cumulative incidence of recurrence (CIR) were compared using log rank and Gray’s tests, respectively. RESULTS: Median time from radiation to ESCC-R was 18.2 years. The majority of ESCC-R patients was female, and presented with earlier disease and decreased behavioral risk factors. ESCC-R treated with surgery alone had worse OS than ESCC (5-year 15% vs 33, p=0.045). Patients with ESCC-R that received neoadjuvant treatment had higher risk of postoperative in-house mortality (16.7% vs 4.2, p=0.032). Patients with ESCC-R treated with surgery alone and definitive chemoradiation had higher recurrence risk than neoadjuvant+surgery (5-year recurrence 55% and 45 vs 15%, p=0.101). CONCLUSION: Neoadjuvant chemotherapy or chemoradiation should be used whenever possible for ESCC-R as it is associated with lower risk of recurrence. The improved survival benefits of aggressive treatment must be weighed against the higher associated postoperative risks.

Variability in surgical and pathological techniques in Western centers may lead to inconsistency in lymph node staging in patients with gastric adenocarcinoma. We hypothesize that ex vivo dissection (EVD) after gastrectomy for adenocarcinoma increases lymph node yield. We retrospectively reviewed 222 consecutive patients who underwent gastrectomy with curative intent for adenocarcinoma between November 2010 and June 2014. In August of 2012, we began performing EVD of nodes in surgical specimens (EVD group, N = 111), as opposed to submitting specimens en bloc with lymph node basins attached to the specimen (No EVD group, N = 111). Primary end point was lymph node yield. The median number of lymph nodes procured was significantly higher in the EVD compared to that in the No EVD group (30 vs. 21 lymph nodes, respectively; P

Clinical trials of agents targeting the vascular endothelial growth factor A (VEGF-A) pathway in gastric adenocarcinoma (GA) suggest that these therapies may have varying efficacy in different races. VEGF-A in serum and/or VEGF receptor 2 (VEGFR-2) in CD31-positive tumor vessels (VEGFR-2/CD31) were measured in 118 Caucasians and 263 Asians who underwent gastric resection at two institutions and correlated with overall survival (OS). Blood was drawn before any treatment. Patients receiving neoadjuvant treatment were excluded from VEGFR-2 analysis. Compared with Asians, Caucasians were older (mean age 66–73 vs 59–62 years), had more proximal tumors, and had more advanced TNM stage. In the VEGF-A cohort, Caucasians had a median VEGF-A level that was 95 % higher than that of Asians and a much higher standard deviation (88 ± 6.206 vs 45 ± 76 pg/ml, p

Background Prior studies show that intramuscular injection and particle-mediated epidermal delivery of xenogeneic melanosomal antigens (tyrosinase or Tyr, gp100) induce CD8+ T cell responses to the syngeneic protein. To further define the optimal vaccination strategy, we conducted a phase I study of in vivo electroporation (EP) of a murine Tyr DNA vaccine (pINGmuTyr) in malignant melanoma patients. Methods Human leukocyte antigen (HLA)-A1, A2, A24 or B35 stage IIb-IV melanoma patients received up to five doses of the mouse tyrosinase DNA vaccine by EP every three weeks at dose levels of 0.2 mg, 0.5 mg, or 1.5 mg per injection. Peripheral blood mononuclear cells (PBMC) were collected, cultured with a peptide pool containing eight HLA class I-restricted Tyr-specific T-cell epitopes, and analyzed by HLA-A*0101-restricted tetramers and intracellular cytokine staining (ICS). Results Twenty-four patients received ≥1 dose of the pINGmuTyr vaccine; PBMCs from 21 patients who completed all five doses were available for Tyr immune assays. The only common toxicity was grade 1 injection site reaction. Six of 15 patients (40%) in the 1.5 mg dose cohort developed Tyr-reactive CD8+ T cell responses following stimulation, defined as a ≥3 standard deviation increase in baseline reactivity by tetramer or ICS assays. No Tyr-reactive CD8+ T cell response was detected in the 0.2 mg and 0.5 mg dose cohort patients. Epitope spreading of CD8+ T cell response to NY-ESO-1 was observed in one patient with vitiligo. One patient subsequently received ipilimumab and developed an enhanced Tyr-reactive response with polyfunctional cytokine profile. After a median follow-up of 40.9 months, median survival has not been reached. Conclusions A regimen of five immunizations with pINGmuTyr administered by EP was found to be safe and resulted in Tyr-reactive immune responses in six of 15 patients at 1.5 mg dose cohort. Trial registration ClinicalTrials.gov NCT00471133