Background

Malnutrition frequently affects gastrointestinal (GI) cancer patients. It is known how protein supplementation could prevent loss of lean body mass and sarcopenia. Therefore, we present a placebo-controlled study, to explore the effect and safety of whey proteins in GI cancer patients.

Methods

Patients with GI cancer referred for 5-fluorouracil based chemotherapy, without metabolic alteration, were considered eligible. After informed consent was obtained, they were blind-randomized 1:1 to whey protein (PROLYOTIN®) (arm A) vs placebo (arm B). Patients were assessed, before chemotherapy, after 3 and 6 months, on a physical-nutritional examination, Body Impedance Assessment, MNA® and MUST questionnaire. At the same time frames, tumor characteristics, dietary practices and laboratory values were collected by a specialist team of medical oncologists and dieticians.

Results

Forty subjects with a median age of 65.53 years old were included in this preliminary analysis. Baseline patients characteristics were well balanced between the two arms (A and B) for age, sex, localization and stage of disease, clinical status, nutritional condition and laboratory values (Vitamin D proved to be insufficient in both groups:17,3 ng/ml in A and 15,4 ng/ml in B). After three months of chemotherapy, 32 patients were reevaluated. Overall, no patient was found underweight or malnourished, nor were any differences in blood analysis. Meanwhile, clinical and anthropometric parameters (PS ECOG= 0: 89% A vs 59% B; lean body mass 69,7 % to 71,8% A vs 67,6% to 63,6% B, p value=0,013), nutritional status (MNA>27=34% to 100% A vs 42% to 65% B, p value=0,001) and toxicity (hematological: no adverse effects 86% A vs 29% B, p value 0,005; gastrointestinal: 94% A vs 29% B, p value 0,001) resulted to be significantly different between the two groups.

Conclusions

The nutritional counselling and whey proteins intake during chemotherapy showed a significant benefit in nutrition, performance status and treatment tolerability in GI cancer patients. However, further studies are needed to improve the knowledge of whey protein protective role against chemotherapy toxicity and to select more accurately those patients who may benefit from a preventive whey protein supplements.

Clinical trial identification

EudraCT number: 2018-000122-64.

Legal entity responsible for the study

Sapienza University.

Funding

Has not received any funding.

Editorial Acknowledgement

None

Disclosure

All authors have declared no conflicts of interest.

Background

MpBCs are morphologically heterogeneous, frequently triple-negative and resistant to chemotherapy. To better understand why MpBCs are resistant to chemotherapy, we investigated associations between response to NAST and clinical, morphologic, as well as molecular characteristics in a cohort of MpBC patients (pts).

Methods

19 MpBC pts were identified from a prospective cohort of 242 triple-negative breast cancer (TNBC) pts treated with anthracycline-based NAST. Histologic subtype of MpBC was determined by light microscopy. TNBC subtypes were determined using the Vanderbilt gene expression signatures (GES). Residual cancer burden (RCB) was assessed after surgery.

Results

Of the 19 MpBCs, 37% (7/19) were matrix producing and 63% (12/19) were not. Analysis of GES revealed the following subtype distributions: mesenchymal (M)=32% (6/19), mesenchymal stem-like (MSL)=11% (2/19), basal-like 2 (BL2)=32% (6/19), immunomodulatory (IM)=11% (2/19), unstable (UNS)=11% (2/19), basal-like 1 (BL1)=5% (1/19). Fifty-seven percent (4/7) and 33% (4/12) of the matrix producing and non-matrix producing MpBCs were of the M/MSL subtype, respectively. Twenty-one percent (4/19) of pts had a pathologic complete response (pCR)/minimal residual disease (RCB-I) following NAST. MpBCs that were matrix producing or of the M/MSL subtype were associated with worse response to NAST as none (0/11) of the pts with MpBC that was matrix producing and/or of the M/MSL subtype had a pCR/RCB-I, compared with 50% (4/8) of the remaining pts (p = 0.018).Table: 228P

Associations between response to NAST and clinical, morphological as well as molecular characteristics

Conclusions

Analysis of GES suggest that MpBC is enriched for subtypes less likely to achieve pCR/RCB-I with NAST (BL2, M, MSL). Matrix-producing (light microscopy) and the M/MSL subtypes (GES) appear to be associated with resistance to anthracycline-based NAST in MpBC.

Legal entity responsible for the study

The University of Texas MD Anderson Cancer Center.

Funding

National Comprehensive Cancer Network (NCCN) Oncology Research Program, The MD Anderson Cancer Center Moonshots Program, CPRIT Multi-Investigator Research Award (MIRA).

Disclosure

All authors have declared no conflicts of interest.

Background

Inhibition of the TGF-β pathway, which promotes tumor immunosuppression, may enhance the clinical response to PD-(L)1 monoclonal antibodies (mAbs). M7824 is an innovative first-in-class bifunctional fusion protein composed of a human anti–PD-L1 IgG1 mAb fused with 2 extracellular domains of the TGFβ receptor II to function as a TGF-β “trap”. We report on the safety and efficacy of M7824 in a cohort of Asian patients (pts) with ESCC. Esophageal cancer is the sixth most common type of cancer in Eastern Asia, with ESCC accounting for ≈90% of cases. ESCC represents an area of high unmet need. Additionally, no immunotherapies have been yet approved for this patient population, and monochemotherapy with a taxane or irinotecan remains the 2L standard of care (ORRs, ≤16%).

Methods

In this expansion cohort of the ongoing, phase 1 trial NCT02699515, Asian pts with ESCC unselected for PD-L1 expression, for which no standard therapy exists or has failed, received M7824 1,200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal. The primary objective is safety and tolerability; secondary objectives include best overall response per RECIST v1.1.

Results

As of January 4, 2018, 30 pts received M7824 for a median of 6.1 (range, 2.0–44.1) weeks; 4 pts remained on treatment. 76.7% of patients had received ≥2 prior lines of treatment. The most common TRAEs were hypothyroidism, maculopapular rash (both 16.7%), rash (13.3%), and interstitial lung disease (ILD; 10.0%). Grade 3 TRAEs occurred in 4 pts (13.3%; eczema, increased amylase, lip SCC, maculopapular rash, rash); 2 grade 4 TRAEs were observed (6.7%; ILD, increased blood creatine phosphokinase). 3 treatment discontinuations, but no deaths, due to TRAEs occurred. 6 pts (confirmed ORR, 20.0%; unconfirmed ORR, 26.7%) had a partial response (duration of response, 1.4+, 2.8+, 4.2+, 4.2+, 5.8, and 7.0 months); 5 pts had stable disease (disease control rate, 36.7%) by investigator read.

Conclusions

M7824 had a manageable safety profile and promising preliminary efficacy in heavily pretreated Asian pts with ESCC and no/limited treatment options.

Clinical trial identification

NCT02699515.

Legal entity responsible for the study

Merck KGaA, Darmstadt, Germany.

Funding

Merck KGaA.

Editorial Acknowledgement

Medical writing support was provided by ClinicalThinking, and was funded by Merck KGaA, Darmstadt, Germany.

Disclosure

T. Doi: Consultancy: Lilly Japan, Chugai Pharma, Kyowa Hakko Kirin, Merck Sharp and Dohme Corp, Daiichi Sankyo, Amgen, Sumitomo Dainippon, Taiho Pharmaceutical; Research funding: Taiho Pharmaceutical, Novartis, Merck Serono, Astellas Pharma, Merck Sharp and Dohme Corp, Janssen, Boehringer Ingelheim, Takeda, Pfizer, Lilly Japan, Sumitomo Group, Chugai Pharma, Kyowa Hakko Kirin, Daiichi Sankyo, Celgene, Bristol-Myers Squibb, Abbvie Quintiles. M-M. Hou: Employee: Chang Gung Memorial Hospital. H. Hara: Honoraria: Chugai Pharma, Taiho Pharmaceutical, Merck Serono, Yakult Honsha, Lilly, Ono Pharmaceutical, Takeda; Consulting or advisory role: Ono Pharmaceutical, Chugai Pharma, Merck Serono, Merck Sharp & Dohme Corp; Research funding: AstraZeneca, Chugai Pharma, Merck Serono, Merck Sharp & Dohme Corp, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Boehringer Ingelheim, Dainippon Sumitomo Pharma, Daiichi Sankyo, Lilly, Pfizer, LSK BioPharma, Eisai, Incyte. H-C. Chung: Employee: Yonsei University College of Medicine; Consultancy: Taiho, Celltrion, Merck Sharp and Dohme Corp, Lilly, Quintiles, Bristol-Myers Squibb, Merck-Serono; Research funding: Lilly, GlaxoSmithKline, Merck Sharp and Dohme Corp, Merck-Serono, Bristol-Myers Squibb/Ono, Taiho; Speakers bureau: Merck-Serono, Lilly, Foundation Medicine. M. Osada: Employee: Merck Serono. C. Helwig: Employee: Merck KGaA. All other authors have declared no conflicts of interest.

Background

In situ dying and just died tumor cells after irradiation give danger signals and release tumor-specific antigens which are sequentially incorporated into dendritic cells (DCs). Our previous studies on a murine subcutaneous tumor model showed that injection of bone marrow derived DCs (BM-DCs) after X-ray therapy significantly delayed tumor growth. As compared to X-rays, the unique biological and physical benefits of proton beam therapy may prove superior in the systemic immune effect. In addition, usage of DCs induced from iPS cells (iPS-DCs) may overcome practical problems of BM-DCs such as a limited number of applicable cells and an induction period of 7 days. The purpose of this study is to investigate: 1) whether proton beam therapy are superior in induction of anti-tumor immune response compared to X-ray therapy. 2) whether the function of induced iPS-DCs is superior to that of BM-DCs.

Methods

DCs were induced by using GM-CSF and IL-4 from autologous bone marrow cells or iPS cells of C57BL/6 mice. Syngeneic B16 melanoma cells subcutaneously implanted at the thighs of C57BL/6 mice were treated with X-ray or proton beam 5 days after inoculation. After 1, 3, 5, 7 days from irradiation, induced BM-DCs or iPS-DCs were injected directly into the tumor site. Tumor growth was monitored, and survival analyses were performed.

Results

Proton beam therapy induced superior immunogenicity of cancer cell comparing to X-ray therapy. Also, iPS-DCs showed an excellent ability to incorporate antigens in vitro comparing to BM-DCs. The combination treatment of proton beam and iPS-DCs significantly delayed tumor growth in vivo.

Conclusions

iPS-DCs should overcome the practical problems of BM-DCs in cancer treatment. The combination therapy of proton beam and iPS-DCs administration can offer a promising novel cancer therapy.

Legal entity responsible for the study

Koji Tsuboi.

Funding

Japan Society for the Promotion of Science.

Disclosure

All authors have declared no conflicts of interest.

Background

Whether somatic or germline, biallelic BRCA1/2 loss of function (LOF) results in homologous recombination deficiency (HRD) and is associated with sensitivity to PARP inhibitors (PARPi) in ovarian and breast cancer. We evaluate the pan-cancer landscape of BRCA1/2 GAs in tissue and ctDNA.

Methods

Hybrid capture-based CGP was performed in a CLIA/CAP lab using a tissue-based assay (FoundationOne) of 315 cancer-related genes or a blood-based ctDNA assay of 62 genes (FoundationACT), including the complete exonic regions of BRCA1 and BRCA2. Genomic profiles were available for >90,000 tissue and >5,000 ctDNA samples.

Results

We identified pathogenic BRCA GAs in 5% of tissue and 6% of ctDNA specimens, with BRCA GAs most frequently identified in ovarian carcinoma (15%), prostate (11%), breast (9%), endometrial (6%), and colorectal [CRC] (4%). Somatic-like BRCA GAs were most frequent in CRC (85%), non-small cell lung cancer [NSCLC] (64%), and prostate cancer (56%), but were also frequent in breast (32%) and ovarian cancers (42%). In tissue-based testing, we observe high frequencies of BRCA loss-of-heterozygosity (LOH) in ovarian and breast carcinomas (94% and 82% of BRCA point GAs), intermediate levels in prostate and pancreatic carcinomas (69% and 66%), and low levels in NSCLC, melanoma, and CRC (40%, 20%, 18%). BRCA LOF was associated with an elevated % genomic LOH in most tumor types (ovarian, breast, pancreatic, NSCLC, CRC, melanoma, and prostate; p < 1e-10). An index case of a prostatic carcinoma with homozygous BRCA alteration, and a genomic LOH score in the top quintile, showed a robust response to a PARPi. Comparison of tissue versus ctDNA revealed highly similar BRCA alteration frequencies (r = 0.94) across disease groups. ctDNA concordance with BRCA-altered tissue (n = 56) was 73% (41/56) overall, and concordance was associated with ctDNA fraction.

Conclusions

The frequencies of BRCA GAs observed here suggest HRD-targeted therapies warrant further investigation in carcinomas beyond ovarian, breast, and prostate. CGP of ctDNA may be a convenient and highly sensitive method for identifying such cases although it may need to be complemented with tissue testing for bi-allelic assessment of BRCA loci.

Legal entity responsible for the study

Huntsman Cancer Institute.

Funding

Has not received any funding.

Disclosure

N. Agarwal: Consultant or advisor: Pfizer, Exelixis, Cerulean Pharma, Medivation/Astellas, Eisai, Merck, Novartis, EMD Serono, Clovis Oncology, Genentech/Roche, Bristol-Myers Squibb, AstraZeneca, and Nektar; Research funding: Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Medivation, Takeda, Novartis, Pfizer, BN ImmunoTherapeutics, Exelixis, Tracon Pharma, Rexahn Pharmaceuticals, Amgen. E.S. Sokol: Employment: Foundation Medicine, Inc. P. Lara Jr.: Consultant or advisor: Exelixis, Pfizer, Novartis, AstraZeneca, Bayer, Genentech/Roche, Celgene, Janssen Biotech, Bristol-Myers Squibb, Abbvie, Turnstone Bio; Research funding: Millennium, Polaris, GlaxoSmithKline, Genentech/Roche, Aragon Pharmaceuticals, Janssen Biotech, Heat Biologics, Tracon Pharma, Merck, Pharmacyclics, Incyte; Honoraria: Pfizer. J.S. Ross: Employment, leadership, stock, other ownership interests, research funding: Foundation Medicine, Inc. V.A. Miller: Employment, leadership, stock, other ownership interests: Foundation Medicine, Inc.; Patents, royalties, other intellectual property: Periodic royalties related to T790M patent awarded to Memorial Sloan Kettering Cancer Center. A.W. Welsh: Employment, travel, accommodations, expenses, stock, other ownership interests: Foundation Medicine, Inc. J.P. Gregg: Consultant or advisor: AstraZeneca, Bristol-Myers Squibb, Abbvie, Roche; Speakers' bureau: AstraZeneca, Foundation Medicine, Inc. G.M. Frampton: Employment, stock, other ownership interests: Foundation Medicine, Inc. S.M. Ali: Employment, patents, royalties, other intellectual property: Foundation Medicine, Inc.; Stock, other ownership interests: Exelixis, Blueprint Medicines, Agios; An immediate family member: Patent royalties: Seres Health. J. Chung: Employment, stock, other ownership interests: Foundation Medicine, Inc.

Background

Identification of clinically actionable mutations in cancer is essential for catalyzing precision oncology based on risk stratification. Currently, little is known about the mutation profile of high-risk acute lymphoblastic leukemia (ALL) in Korean patients. We aimed to develop a multigene panel for ALL and to investigate clinically actionable mutations in the Korean patients with high-risk ALL.

Methods

We developed a multigene panel targeting 102 genes with diagnostic, prognostic, or therapeutic significance in ALL and validated it using reference materials and clinical samples. The mutation analyses were done in a total of 18 patients with high-risk ALL {T lymphoblastic leukemia (T-ALL, n = 7), B lymphoblastic leukemia in relapse (relapsed B-ALL, n = 5), and Philadelphia chromosome-positive ALL (Ph+ ALL, n = 6)}. High-risk ALL was categorized based on clinical findings and laboratory tests including immunophenotyping, chromosome analyses, fluorescence in situ hybridization, and RT-PCR. Clinically actionable mutations were selected based on a four-tiered system recommended by Association for Molecular Pathology in 2017.

Results

A total of 28 clinically actionable mutations including 6 novel mutations were identified in 83% of the patients. The most frequent alterations in Korean patients were loss of function mutations of KMT2C (78%), followed by mutations of NOTCH1 (17%) and SUZ12 (11%). There is no difference in the frequency of KMT2C mutation among T-ALL, relapsed B-ALL, and Ph+ ALL, while mutations in NOTCH1 and SUZ12 were observed only in T-ALL. Additional 8 genes including NT5C2 and KRAS were mutated. Furthermore, potential germline pathogenic variants were discovered in 3 patients including one previously diagnosed as neurofibromatosis type 1.

Conclusions

This study showed that KMT2C mutations were recurrently observed in Korean patients with high-risk ALL. The KMT2C mutation status could be an effective risk stratification strategy for Korean patients with ALL. This study provides clinically actionable mutational portrait of high-risk ALL, albeit in a limited number of patients and gives novel insight into genetic heterogeneity of the disease.

Legal entity responsible for the study

Pusan National University Yangsan Hospital Institutional Review Board.

Funding

Biomedical Research Institute in Pusan National University Yangsan Hospital.

Disclosure

All authors have declared no conflicts of interest.

Background

Neoadjuvant Chemotherapy (NACT) followed by Interval Debulking Surgery (IDS) is an alternative frontline treatment in patients with advanced Epithelial Ovarian Cancer (EOC). Histopathologic assessment of tumor post NACT is an ideal mean of response to treatment. The present study aims to characterize the pathological response and to examine its prognostic significance in these patients.

Methods

Medical records of women with EOC treated at Alexandra Hospital from 2011 to 2016 were retrospectively identified. Clinicopathological data, treatment and survival data were analyzed. IDS specimens were reviewed by study pathologist and Chemotherapy Response Score (CRS), lymphocytic infiltration, necrosis and mitosis were assessed. Survival differences were estimated using the long-rank test.

Results

55 patients with EOC treated with NACT were identified, 48 had complete clinical and pathological data. Median age was 63 years. All patients had high grade disease and 45 of them had serous carcinoma. At baseline 38 patients had stage IIIc disease and 10 stage IV. All patients received Paclitaxel-Carboplatin combination for 3 cycles. 20 patients had complete debulking (no macroscopic residual disease), 18 had optimal (macroscopic disease <1cm) and 7 suboptimal. 22 patients received also bevacizumab as part of their treatment post IDS. CRS assessed at omentum predicted PFS when adjusted for age, stage, debulking status (complete, optimal, suboptimal) and post IDS bevacizumab administration (mPFS CRS 1vs2vs3: 11.9-14-19.5 months 95% CI [7.4-18.3], [12.2-20.7], [13.5-31.3]). Lymphocytic invasion was associated with improved OS (log-rank test p = 0.022). Presence of necrosis and mitosis per HPF did not predict either PFS or OS. BRCA status was known for 19 patients and presence of BRCA1/2 mutations was strongly correlated with lymphocytic infiltration (P = 0.011) but not CRS (p = 0.801).

Conclusions

Our study confirms the predictive value of CRS in EOC patients treated with NACT and IDS, but also demonstrates the prognostic significance of lymphocytic infiltration in IDS specimens. The later was associated with presence of BRCA mutations with obvious therapeutic implications.

Legal entity responsible for the study

Michalis Liontos.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Cabo is approved for mccRCC based on trials in which the vast majority of patients were ICB-naive. We analyzed the activity of cabo in mccRCC patients who had progressed on ICB.

Methods

We included 69 patients with mccRCC who received cabo after progression on ICB alone or in combination with VEGF or other therapies. Baseline characteristics, best response (BR, investigator-assessed), time to treatment failure (TTF) and overall survival (OS) were analyzed.

Results

Median age was 62 years (range 37-78). Median number of prior therapies was 2 (range 1-10). Median time on prior ICB was 3.9 months (range 0.5-38). Type of prior therapy was ICB single agent (54%) or in combination with a VEGF inhibitor (35%) or other therapies (12%). At time of cabo initiation, IMDC risk groups were 6% good, 67% intermediate and 27% poor. BR was 33% PR, 46% SD, 17% PD, 3% unevaluable. Median follow up after cabo initiation was 12 months. At time of analysis, 35% (n = 24) remained on cabo and median TTF was 6.6 (95%CI: 5.3-8.5) months. Of those discontinuing cabo, 58% (n = 26) received additional therapy. At time of analysis, 62% (n = 43) were alive with 1-year OS rate of 53% (95%CI: 37%-66%).Table: 879P

Conclusions

Cabo is active in patients treated after PD-1/PD-L1 based ICB independent of prior combination therapy with VEGF inhibitors, with 79% achieving disease control at minimum. These results support the continued use of cabo irrespective of ICB timing. Equal contribution: BAM, AAL.

Legal entity responsible for the study

Dana Farber Cancer institute.

Funding

Has not received any funding.

Disclosure

B.A. McGregor: Consulting: Exelixis, Genentech, Astellas, Seattle-Genetics, Bayer, Jannsen, AstraZeneca, Pfizer Institutional research: Bristol-Myers-Squibb. L.C. Harshman: Advisory: Bayer, Genentech, Dendreon, Pfizer, Medivation/ Astellas, Kew Group, Theragene, Corvus, Merck, Exelixis; Novartis; Research to the institution: Bayer, Sotio, Bristol-Myers Squib, Merck, Takeda, Dendreon/Valient, Jannsen, Medivation/Astellas, Genentech, Pfizer. M.A. Bilen: Consulting: Exelixis. T.K. Choueiri: Research funding: AstraZeneca, B Bristol-Myers-Squibb MS, Exelixis, Genentech, GSK, Merck, Novartis, Peloton, Pfizer, Roche, Tracon, Eisai; Consulting and Advisory role: AstraZeneca, Bayer, Bristol-Myers-Squibb, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Ipsen. All other authors have declared no conflicts of interest.