Immunotherapy induces durable responses in a subset of patients with cancer. High TMB may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free and overall survival (PFS, OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.0001); median PFS, 12.8 vs. 3.3 months (P = <0.0001); median OS, not reached vs. 16.3 months (P = 0.0036). Results were similar when anti-PD-1/PD-L1 monotherapy was analyzed (N = 102 patients), with a linear correlation between higher TMB and favorable outcome parameters; the median TMB for responders vs. non-responders treated with anti-PD-1/PD-L1 monotherapy was 18.0 vs. 5.0 mutations/mb (P < 0.0001). Interestingly, anti-CTLA4/anti-PD-1/PD-L1 combinations vs. anti-PD-1/PD-L1 monotherapy was selected as a factor independent of TMB for predicting better RR (77% vs. 21%) (P = 0.004) and PFS (P = 0.024). Higher TMB predicts favorable outcome to PD-1/PD-L1 blockade across diverse tumors. Benefit from dual checkpoint blockade did not show a similarly strong dependence on TMB.

The resurgence of cancer immunotherapy stems from an improved understanding of the tumor microenvironment.

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Purpose Checkpoint inhibitors demonstrate salutary anti-cancer effects including long-term remissions. PD-L1 expression/amplification, high mutational burden and mismatch repair-deficiency correlate with response. We have, however, observed a subset of patients who appear to be “hyper-progressors,” with a greatly accelerated rate of tumor growth and clinical deterioration compared to pre-therapy, which was also recently reported by Institut Gustave Roussy. The current study investigated potential genomic markers associated with “hyper-progression” after immunotherapy. Method Consecutive stage IV cancer patients who received immunotherapies (CTLA-4, PD-1/PD-L1 inhibitors or other [investigational] agents) and had their tumor evaluated by next-generation sequencing were analyzed (N=155). We defined hyper-progression as time-to-treatment failure (TTF) <2 months, >50% increase in tumor burden compared to pre-immunotherapy imaging, and >2-fold increase in progression pace. Results Amongst 155 patients, TTF <2 months was seen in all six individuals with MDM2/MDM4 amplification. After anti-PD1/PDL1 monotherapy, four of these patients showed remarkable increases in existing tumor size (55% to 258%), new large masses, and significantly accelerated progression pace (2.3-, 7.1-, 7.2- and 42.3-fold compared to the two months before immunotherapy). In multivariate analysis, MDM2/MDM4 and EGFR alterations correlated with TTF<2 months. Two of 10 patients with EGFR alterations were also hyper-progressors (53.6% and 125% increase in tumor size; 35.7- and 41.7-fold increase). Conclusion Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent checkpoint (PD-1/PD-L1) inhibitors. Genomic profiles may help to identify patients at risk for progression on immunotherapy. Further investigation is urgently needed.

Purpose: Pancreatic cancer is almost always lethal, and the only U.S. Food and Drug Administration^approved therapies for it, gemcitabine and erlotinib, produce objective responses in <10% of patients.We evaluated the clinical biological effects of curcumin (diferuloylmethane), a plant-derived dietary ingredient with potent nuclear factor-nB (NF-nB) and tumor inhibitory properties, against advanced pancreatic cancer. Experimental Design: Patients received 8 g curcumin by mouth daily until disease progression, with restaging every 2 months. Serum cytokine levels for interleukin (IL)-6, IL-8, IL-10, and IL-1 receptor antagonists and peripheral blood mononuclear cell expression of NF-nB and cyclooxygenase-2 were monitored. Results:Twenty-five patients were enrolled, with 21evaluable for response. Circulating curcumin was detectable as drug in glucuronide and sulfate conjugate forms, albeit at low steady-state levels, suggesting poor oral bioavailability. Two patients showed clinical biological activity. One had ongoing stable disease for >18 months; interestingly, one additional patient had a brief, but marked, tumor regression (73%) accompanied by significant increases (4-to 35-fold) in serum cytokine levels (IL-6, IL-8, IL-10, and IL-1 receptor antagonists). No toxicities were observed. Curcumin down-regulated expression of NF-nB, cyclooxygenase-2, and phosphorylated signal transducer and activator of transcription 3 in peripheral blood mononuclear cells from patients (most of whom had baseline levels considerably higher than those found in healthy volunteers). Whereas there was considerable interpatient variation in plasma curcumin levels, drug levels peaked at 22 to 41ng/mL and remained relatively constant over the first 4 weeks. Conclusions: Oral curcumin is well tolerated and, despite its limited absorption, has biological activity in some patients with pancreatic cancer.

Background Dabrafenib (GSK2118436) is a potent ATP-competitive inhibitor of BRAF kinase and was highly selective for mutant BRAF in kinase panel screening, cell lines, and xenografts. Methods A Phase I trial of dabrafenib was conducted to evaluate safety and tolerability in patients with incurable solid tumours. Efficacy at the recommended Phase II dose (RP2D) was studied in patients with BRAF-mutant tumours, including those with non-V600E mutations, in three cohorts: (1) metastatic melanoma, (2) melanoma with untreated brain metastases, and (3) non-melanoma solid tumours. Findings 184 patients enrolled, and 150 mg twice daily was chosen as the RP2D, based on safety, pharmacokinetic, and pharmacodynamic data. At the RP2D in patients with V600 BRAF-mutant melanoma, a response rate of 69% (a confirmed response rate of 50%) was observed overall and a 78% response rate (a confirmed response rate of 56%) in V600E BRAF-mutant melanoma. In V600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months and a median progression-free survival (PFS) of 5·5 months. Responses were observed in patients with non-V600E BRAF mutations, including V600K and V600G. In the RP2D expansion of melanoma with untreated brain metastases, nine of ten patients (90%) showed reduction in brain lesion size and the median PFS was 4.2 months. Among BRAF-mutant non-melanoma solid tumours, antitumour activity was observed in gastrointestinal stromal tumour, papillary thyroid, non-small cell lung, ovarian, and colorectal cancer. Interpretation Dabrafenib is a highly active inhibitor of V600-mutant BRAF with a high response rate in V600E melanoma, and is the first drug of its class to demonstrate activity in melanoma brain metastases. Funding This study was funded and sponsored by GlaxoSmithKline

Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples. The criteria require multicentric lymphadenopathy with defined histopathology, ≥2 clinical/laboratory changes, and exclusion of iMCD mimics.

The Wnt/beta-catenin pathway is a family of proteins that is implicated in many vital cellular functions such as stem cell regeneration and organogenesis. Several intra-cellular signal transduction pathways are induced by Wnt, notably the Wnt/beta-catenin dependent pathway or canonical pathway and the non-canonical or beta-catenin-independent pathway; the latter includes the Wnt/Ca2+ and Planar Cell Polarity pathway (PCP). Wnt activation occurs at the intestinal crypt floor, and is critical to optimal maintenance of stem cells. Colorectal cancers show evidence of Wnt signaling pathway activation and this is associated with loss of function of the tumor regulator APC. Wnt activation has been observed in breast, lung, and hematopoietic malignancies and contributes to tumor recurrence. The Wnt pathway cross talks with the Notch and Sonic Hedgehog pathways, which has implications for therapeutic interventions in cancers. There are significant challenges in targeting the Wnt pathway, including finding agents that are efficacious without damaging the system of normal somatic stem cell function in cellular repair and tissue homeostasis. Here, we comprehensively review the Wnt pathway and its interactions with the Notch and Sonic Hedgehog pathways. We present the state of the field in effectors and inhibitors of Wnt signaling, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic Hedgehog.