Gut microbiome is associated with the clinical response to anti-PD-1 based immunotherapy in hepatobiliary cancers

BackgroundThe gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims to investigate the relationship between the gut microbiome and the clinical response to anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced hepatobiliary cancers.MethodsPatients with unresectable hepatocellular carcinoma or advanced biliary tract cancers who have progressed from first-line chemotherapy (gemcitabine plus cisplatin) were enrolled. Fresh stool samples were collected before and during anti-PD-1 treatment and analyzed with metagenomic sequencing. Significantly differentially enriched taxa and prognosis associated taxa were identified. The Kyoto Encyclopedia of Genes and Genomes database and MetaCyc database were further applied to annotate the differentially enriched taxa to explore the potential mechanism of the gut microbiome influencing cancer immunotherapy.ResultsIn total, 65 patients with advanced hepatobiliary cancers receiving anti-PD-1 treatment were included in this study. Seventy-four taxa were significantly enriched in the clinical benefit response (CBR) group and 40 taxa were significantly enriched in the non-clinical benefit (NCB) group. Among these taxa, patients with higher abundance of Lachnospiraceae bacterium-GAM79 and Alistipes sp Marseille-P5997, which were significantly enriched in the CBR group, achieved longer progression-free survival (PFS) and overall survival (OS) than patients with lower abundance. Higher abundance of Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 enriched in the CBR group was also observed in patients with better PFS. In contrast, worse PFS and OS were found in patients with higher abundance of Veillonellaceae, which was significantly enriched in the NCB group. Functional annotation indicated that the taxa enriched in the CBR group were associated with energy metabolism while the taxa enriched in the NCB group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy in hepatobiliary cancers. In addition, immunotherapy-related adverse events were affected by the gut microbiome diversity and relative abundance.ConclusionsWe demonstrate that the gut microbiome is associated with the clinical response to anti-PD-1 immunotherapy in patients with hepatobiliary cancers. Taxonomic signatures enriched in responders are effective biomarkers to predict the clinical response and survival benefit of immunotherapy, which might provide a new therapeutic target to modulate the response to cancer immunotherapy.

Survival outcomes associated with fewer combination ipilimumab/nivolumab doses in advanced-stage melanoma.

9549 Background: Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma. While many patients receive less than 4 doses due to treatment-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and if fewer doses of I/N can achieve similar survival outcomes. Methods: We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2020 who were treated with standard I/N. Cox regression of progression free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response assessment after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging or physical examination. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 3 or 4 vs 1 or 2 doses of I/N adjusted by age, gender, pre-treatment LDH level, BRAF mutation status, primary melanoma site, time to initial assessment, brain metastasis, and liver metastasis. Results: 199 patients were identified and considered evaluable in our study. Median follow up was 28.8 months. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.23, 95% CI 0.14-0.39; p<0.001) and OS (HR: 0.19, 95% CI 0.10-0.38; p<0.001) compared to progressive disease (PD) [Table]. Patients with CBR (vs PD) after 2 doses of I/N also had improved PFS (HR: 0.17, 95% CI 0.11-0.26; p<0.001) and OS (HR: 0.13, 95% CI 0.07-0.23; p<0.001) [Table]. The survival risk comparing 3 or 4 vs 1 or 2 doses of I/N were HR 0.82 (95% CI 0.45-1.53; p=0.540) for PFS and HR 0.56 (95% CI 0.24-1.30; p=0.175) for OS. Conclusions: Clinical benefit response (CBR) after 1 or 2 doses of I/N may be predictive of long-term survival in advanced stage melanoma. Patients who have CBR after 1 or 2 doses of I/N may achieve a similar survival benefit with fewer doses of I/N. Longer follow up and prospective studies are warranted to validate our findings.[Table: see text]

Clinical performance of blood-based RNA signatures (GemciTest) for the gemcitabine response in advanced pancreatic cancer.

e16238 Background: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal often presents at a later stage. Gemcitabine is still an important component in PDAC treatment however there is no routine biomarker to predict its efficacy. We had previously performed a discovery cohort of two separate RNA-blood signatures in 60 patients (NCT00789633) showing an association with PFS and OS. Called GemciTest, this CE-IVD molecular test requires 2.5ml whole blood sample before starting the patient's 1st line chemotherapy. From this liquid biopsy, IVD measures the expression levels of nine genes using real-time PCR processes. This abstract presents the clinical validation of GemciTest. Methods: In this study, clinical validations were done on 214 patients (mean 68.7-year-old; 37-88) from 3 distinct cohorts with the University of Wisconsin Biobank, GemciPANC trial (NCT03599154), and BACAP (NCT02818829). These cohorts included first-line treatment,with either a gemcitabine or fluoropyrimidine based regimen. Results: Patients with a clinical benefit response identified by GemciTest (31.5%) had a significantly longer progression free survival (PFS) (5.4 months vs. 3.1 months p = 0.0032) and a longer overall survival (OS) (13.1 months vs. 5.4, p < 0.0003). In multivariate analyses including tumor localization and performance status, this signature continued to be associated with PFS (HR = 0.52 (0.34–0.81) p = 0.003) and OS (HR = 0.44 (0.28 – 0.69) p = 0.0002).Conclusions: GemciTest validation was performed, showing a strong association with PFS and OS.[Table: see text]

Phase 2 study of cetuximab (Erbitux) in patients with progressive or recurrent endometrial cancer

IntroductionOverexpression of the epidermal growth factor receptor (EGFR) found in common subtypes of endometrial cancer has been associated with advanced stage disease and a poor prognosis. The purpose of this phase 2 study was to evaluate the efficacy and safety of cetuximab in patients with recurrent endometrial cancer.MethodsThe study was an open-label phase 2 clinical trial conducted at two institutions. Patients with recurrent or progressive endometrial cancer of any histologic type with the exception of uterine sarcoma received cetuximab at an initial dose of 400 mg/m2 IV followed by weekly doses of 250 mg/m2. One cycle was considered 4 weeks of treatment. The primary efficacy endpoint was clinical benefit response, defined as a complete or partial response or prolonged stable disease (>8 weeks) by RECIST 1.0 criteria.ResultsA total of 30 patients were enrolled with a median age of 64 years (range 42–83). Of the 20 evaluable patients, three (15%) had clinical benefit response (one complete response, two stable disease). The patient with a clinical benefit response received a total of 27 cycles and the two patients with stable disease were taken off the study due to progression after four and six cycles, respectively. Of the 10 inevaluable patients, nine received ≤1 cycle due to clinical deterioration and one had an anaphylactic reaction. One patient had a grade 3 rash which resolved after a delay in treatment. No dose reduction was reported.ConclusionsIn this cohort, single agent therapy with cetuximab was well tolerated and had a 15% clinical benefit response. Further studies are required to better identify patients who may respond to this treatment.

DKN-01 in combination with pembrolizumab in patients with advanced gastroesophageal adenocarcinoma (GEA): Tumoral DKK1 expression as a predictor of response and survival.

357 Background: Dickkopf-1 (DKK1) modulates Wnt signaling and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody + pembrolizumab (P) has demonstrated safety and clinical activity in advanced GEA. We report response and survival outcomes in anti-PD-1/anti-PD-L1 naïve GEA patients by high/low tumoral DKK1 expression. Methods: We enrolled advanced anti-PD-1/PD-L1 naïve GEA patients (pts) in a Phase 1b/2a study of D + P (NCT02013154). Tumoral DKK1 mRNA expression was assessed by an in situ hybridization RNAscope assay. Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS) were compared between DKK1 high and low groups. Kaplan-Meier method and Cox-PH model was used for survival analysis and logistic regression was used for clinical benefit/response outcome. Results: 34 GEA pts were enrolled to receive 300 mg D + P. 31 GEA pts had DKK1 expression available (25 response-evaluable/RE) and 27 had both DKK1 and PD-L1 expression available (22 RE). In RE pts, DKK1 high (H-score ≥ upper-tertile [≥35]) had an ORR of 50% (5 PR/10), DCR of 80% (8/10) while DKK1 low ( < upper-tertile) had an ORR of 0% (0/15) and DCR of 20% (3/15); DKK1 high (vs. low) had an OR of 16 (95%CI: 2.2, 118.3; n = 25) and adjusted (for PD-L1 CPS ≥10 vs. < 10) OR of 17.6 (95%CI:1.6, 194.4; n = 22) for clinical benefit/response (PR/SD vs. PD). Median PFS was 22.1 weeks in DKK1 high (n = 11) vs. 5.9 weeks in DKK1 low (n = 20); HR of 0.23 (95%CI: 0.082, 0.66; n = 31). Adjusted (for PD-L1 expression) HR for DKK1 high was 0.20 (95%CI: 0.061,0.68; n = 27) for PFS. DKK1 high (n = 11) had a median OS of 31.6 weeks vs. 17.4 weeks in DKK1 low (n = 20); HR of 0.45 (95%CI: 0.16, 1.3; n = 31) and adjusted HR of 0.62 (95%CI: 0.2,1.9; n = 27). Conclusions: High levels of tumoral DKK1 expression identify advanced anti-PD-1/PD-L1 naïve GEA pts with the greatest benefit from D + P. Improvements in response/clinical benefit and PFS were observed independent of PD-L1 expression. Tumoral DKK1 as a potential predictive biomarker for DKN-01 treated GEA pts will be evaluated in future studies. Overall survival follow-up is ongoing. Clinical trial information: NCT02013154.

An Outpatient, Dose-Intense, Intravenous Cisplatin and Oral Etoposide Regimen for the Treatment of Advanced, Platinum-Resistant Ovarian Cancer

ObjectivesAdvanced-stage, platinum-resistant, ovarian cancer can be treated with dose-intense chemotherapy; one such regimen includes intravenous cisplatin and oral etoposide. To minimize the toxicity associated with weekly cisplatin, pretreatment and posttreatment hydration is required, often necessitating inpatient, overnight admission. We report a shorter, within-day regimen for delivering weekly cisplatin.MethodsThis was a retrospective study to assess the use of standard (inpatient; treatment time of 12 hours) versus modified (outpatient; treatment time of 4 hours) regimens. The primary outcome included all-grade and grade 3/4 adverse events. Secondary outcomes included clinical benefit response and, median progression-free survival and overall survival.ResultsBetween January 2012 and December 2014, 66 women with metastatic ovarian cancer received dose-intense weekly cisplatin and oral etoposide (n = 45 standard, n = 21 modified). The commonest all-grade adverse events were anemia (96% vs 90%, standard and modified, respectively), fatigue (73% vs 67%), neutropenia (71% vs 76%), hypocalcemia (51% vs 43%), and thrombocytopenia (49% vs 57%). There were no statistically significant differences in the incidence or grades of adverse events. The clinical benefit response was 53% in the standard group and 62% in the modified group (P = 0.9). The median progression-free survival was 4.2 and 6.5 months (incidence rate ratio, 1.22; 95% confidence interval, 0.71–2.15; P = 0.29), and median overall survival was 6.6 and 8.4 months (incidence rate ratio, 1.83; 95% confidence interval, 1.04–3.35; P = 0.03), in favor of the modified regimen.ConclusionsOur shorter, within-day regimen for delivering dose-intense weekly cisplatin and oral etoposide to treat platinum-resistant metastatic ovarian cancer is safe and efficacious.

Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study

Background: Based on a model suggesting leukemia can be driven by combined effect of mutations in an epigenetic gene (DNMT3) and Ras, the combination of a hypomethylating agent (HMA) such as azacitidine (AZA) and a Ras mimetic such as rigosertib (RIG) may have enhanced activity in both MDS and AML. The mechanism of action for RIG (Athuluri-Divakar et al, Cell 2016) documents its interference with the RAS-binding domains of RAF kinases and inhibition of the RAS-RAF-MEK and the PI3Ks pathways. In vitro, the combination of RIG with AZA was found to act synergistically to inhibit growth and to induce apoptosis of leukemic cells in a sequence-dependent manner (exposure to RIG first, followed by AZA) (Skidan et al, AACR 2006). Rigosertib's low bone marrow toxicity in pre-clinical assays, effective inhibition of human hematopoietic tumor cell lines, and its synergy with AZA suggests the potential value of combination treatment for patients (pts) with MDS. Phase I results of the current clinical study in pts with MDS or AML showed the combination of oral RIG and standard-dose AZA to be well-tolerated with evidence of efficacy (Navada et al, Blood 2014). The phase II portion of the study was initiated to further evaluate the combination in pts with MDS. Methods: Phase II results are presented for HMA-treatment-naïve MDS pts and for those with MDS failing to respond to or progressed on a prior HMA. Oral RIG was administered twice daily on Day 1-21 of a 28-day cycle at the recommended Phase II dose (RPTD: 560 mg qAM and 280 mg qPM). AZA 75 mg/m2/d SC or IV was administered for 7 days starting on Day 8. A CBC was performed weekly and a bone marrow aspirate and/or biopsy were performed at baseline, D29, and then every 8 weeks thereafter. Results: The combination of oral RIG and injectable AZA has been administered to a total of 54 pts, of whom 40 were pts with MDS including HMA-treatment-naïve (N=23) and previously HMA treated pts (N=17). Median age was 66 years (range 25-85); 73% of pts were male; and ECOG performance status was 0, 1, and 2 in 23%, 73%, and 5%, respectively. 17 pts received prior HMA therapy: 12 AZA, 4 decitabine, and 1 both. Patients have received 1-36+ cycles of treatment (median, 6 cycles), with a median duration of treatment of 25 weeks (range 4 to 145+ weeks). 8 (20%) and 2 (5%) of pts have been treated for more than 1 and 2 years, respectively. Table 1 shows the response per IWG 2006 criteria (Cheson, Blood 2006) among 33 evaluable patients. The response per IWG 2006 was complete remission (CR) in 8 (24%), concurrent marrow CR and hematologic improvement (HI) in 9 (27%), marrow CR alone in 7 (21%), and HI alone in 1 (3%). When overall response is defined as CR plus PR plus HI - responses with improvement in marrow function and thus either normalization of the peripheral blood count or lineage improvement - defined here as Clinical Benefit Response - 55% of all evaluable pts and 70% of the evaluable HMA-treatment-naïve patients showed responses meeting these criteria. Median time to initial response was 2 cycles (2.2 months), and median time to best response was 3 cycles (3.3 months). Median duration of response was 8 months for CR, 14.3 months for marrow CR, 7.4 months for erythroid response, 8 months for platelet response, and 6.2 months for neutrophil response. Clinical response is classified by IPSS-R risk categories below. The most frequently reported adverse events are nausea (41%), fatigue (39%), diarrhoea (37%), constipation (37%), dysuria (28%), decreased appetite (28%), haematuria (24%, 8% Grade 3), pyrexia (24%), dizziness (22%), thrombocytopenia (20%), back pain (20%), dyspnoea (20%), and cough (20%). Eight deaths were reported on study with most common causes including infection and progression of disease. Conclusions: The combination oforalRIG and standard-dose AZA was well tolerated in repetitive cycles in pts with MDS. Response per IWG 2006 criteria was observed both in HMA-treatment-naïve patients (85%) and in patients after failure of prior HMA therapy (62%); employing Clinical Benefit Response as the criteria, these groups had 70% and 31% response, respectively. These clinical results confirm the preclinical synergistic interaction with the combination of RIG and AZA reported by Skidan et al, and suggest that the combination can overcome clinical resistance to HMAs. Based on these results, a Phase III study of the combination of oral RIG and AZA in patients with MDS is planned. Disclosures Navada: Onconova Therapeutics, Inc.: Research Funding. Daver:Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Ariad: Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; BMS: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Petrone:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova: Employment. Silverman:Onconova Therapeutics, Inc.: Patents & Royalties: Co-Patent holder for the combination of azacitidine and rigosertib, Research Funding.

Phase II trial of target-guided personalized chemotherapy in first-line metastatic colorectal.

3543 Background: Chemotherapy (Ch) options for patients (pts) with colorectal cancer (CRC) have increased in the last years. However, there are no validated prospective molecular markers in CRC to select which agents are better to treat any individual case. The aim of this study was to determine the efficacy in terms of progression free survival (PFS) of a biomarker panel to guide treatment selection in this setting. Methods: Treatment naive, ECOG 0-1, metastatic CRC pts were accrued. Pts were prospectively analyzed with a predefined set of 10 molecular targets, including: KRAS, BRAF, and PI3K mutations and Topoisomerase-1(Top-1), ERCC-1, Thymidylate synthase (TS) and Thymidine phosphorylase (TP) expression by inmunohistochemistry ( IHC) performed in a tumor biopsy. Ch combination schema plus Cetuximab (C) or Bevacizumab (B) at standard doses was customized based on: Topo-1 +:Irinotecan (I). Topo-1- and ERCC-1 -:Oxaliplatin(O). Topo-1- and ERCC1 +:investigator option (I or O). TS -:Fluoropyrimidines (FP).TS +:No FP. TP -:5-FU, TP +:Capecitabine. Maintenance C or B treatment was allowed. Primary outcome measure was PFS. Results: 74 pts were accrued and all of them received biomarker guide treatment. All of them began personalized. Interim analysis on 61 pts (38 males, median age 65) showed.Topo-1 + in 33 pts (54%),ERCC-1- in 36( 59%) TS + in 44 (73%), TP – in 61 ( 100%), K-ras nativein 34 ( 55%), BRaf mutated in 2 (3,2%). With a median follow up time of 9,1 months (m). Median PFS (95% CI) is 8,6 (6,2-10,9) m, with a 41,3% (27,4-55,2) 12mPFS . Overall clinical benefit (Response + Stabilizations) was 74,5% (65,6-83,4).Toxicities Grade ≥ 3 included 18% neutropenia, 4,9% asthenia and 3,3% anemia. 12 pts (23%) received loco-regional treatment ( surgery or radiosurgery). Median Overall survival has not been reached. Conclusions: Target- Guided Personalized Ch in first line CRC pts is feasible and results in promising PFS with low toxicity. Update of final results and more detailed data will be presented. Clinical trial information: NCT01453257.

Phase I trial of obatoclax mesylate in combination with bortezomib for treatment of relapsed multiple myeloma.

8013 Background: Obatoclax mesylate (GX15-070MS) is a BH3 mimetic that inhibits Bcl-2 protein family members including MCL-1, a dominant target in myeloma (MM). Obatoclax (OBX) inhibited viability of 14 MM cell lines (mean IC50 215 nM) and primary MM samples while exhibiting pre clinical synergy with bortezomib (BTZ). Sensitivity correlated with basal levels of Mcl-1 and Bcl-XL, but not Bcl2, Bim, Bax or Bak expression. Methods: We report a phase I trial of OBX in combination with BTZ. Eligibility required measureable disease, > 1 prior MM therapy, ≤10 cycles of prior BTZ and did not progress on prior BTZ therapy, creatinine ≤2 ULN. Starting dose level 1 was OBX 14 mg/m2 24-hour continuous iv. infusion days 1, 8, 15 of a 21-day cycle. BTZ given at 1.3mg/m2 iv. days 1, 4, 8 and 11. After protocol amendment OBX level 1 dosing was 30 mg/m2, level 2 was 40 mg/m2 IV both by continuous 3 hour infusion days 1, 8 and 15 on a 21 day schedule. Pre med. with famotidine was required. Results: Eleven patients were accrued, median age 62 (range: 46-77), median time from diagnosis was 4.7 years. Median of 2.5 cycles (range: 1-10). Median follow-up for patients still alive is 11.6 months (range: 0.9-35.5). At dose level 1, there were 2 DLTs. After amendment 8 patients were accrued (3 hour infusion): 4 at amended dose level 1 and 4 at dose level 2. All patients are now off treatment. 10 patients are evaluable for response: 2 patients at original dose level 1 (2 PR), 3 patients at dose level 1 (2 PR, 1 MR), no patients at dose level 2 responded: overall PR of 40%, clinical benefit response in 50% (95% CI: 19-81%). 6 patients had disease progression and 2 patients died. 4 DLTs were seen: at original dose level 1 grade 4 thrombocytopenia and delay of therapy > 15 days. At dose level 2, 1 patient had grade 3 somnolence, a 2nd patient grade 3 euphoria and grade 4 thrombocytopenia. No DLTs were seen at amended dose level 1. Common adverse events of any grade included GI, hematologic and neurologic e.g. euphoria, decreased level of consciousness, psychosis, speech. Conclusions: In summary MTD is OBX 30mg/m2 by 3 hour iv infusion once weekly, BTZ 1.3 mg/m2 days 1,4,8, and 11. Major toxicities were central neurologic and hematologic. This P2C consortium study was supported by NCI N01-CM62205.