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Immune-checkpoint inhibitors (ICI) have revolutionized the therapeutic landscape of cancer. However, optimal patient selection is still an unmet need. One-hundred-forty-six patients with metastatic cancer candidates to ICI at the Hospital Clinic of Barcelona Clinical Trials Unit were prospectively recruited in this observational study. Blood samples were collected at different timepoints, baseline LIPI score calculated and pre-ICI archived tissues retrieved to evaluate PD-L1, tumor-infiltrating lymphocytes (TILs) and PD1 mRNA levels. Tumor assessments were centrally reviewed by RECIST 1.1 criteria. Associations with overall response rates (ORR), durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) were performed with univariable/multivariable logistic and Cox regressions, where appropriate. At a median follow-up of 26.9 months, median PFS and OS were 2.7 and 12.9 months. Response rates were 17.8% with duration of response (DOR) of 4.4 months. LIPI score was independently associated with PFS (p = 0.025) and OS (p p = 0.005). Time-to-best response (TTBR) and ORR (p p p = 0.028) and DCB (univariate p = 0.043). PD1 mRNA levels were strikingly associated to complete responses (p = 0.021). To resume, in our prospective observational pan-cancer study, baseline LIPI score, immunotherapy-naïve status, cancer type and RT before starting ICI were the most relevant clinical factors independently correlated with immunotherapy outcomes. Longer TTBR seemed to associate with better survival, while PD1 mRNA and PD-L1 protein levels might be tumor-agnostic predictive factors of response to ICI and should be furtherly explored.

ObjectiveSecond-line treatment of endometrial cancer is an unmet medical need. We conducted a phase I study evaluating lurbinectedin and doxorubicin intravenously every 3 weeks in patients with solid tumors. The aim of this study was to characterise the efficacy and safety of lurbinectedin and doxorubicin for patients with endometrial cancer.MethodsThirty-four patients were treated: 15 patients in the escalation phase (doxorubicin 50 mg/m2 and lurbinectedin 3.0–5.0 mg) and 19 patients in the expansion cohort (doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2). All histological subtypes were eligible and patients had received one to two prior lines of chemotherapy for advanced disease. Antitumor activity was evaluated every two cycles according to the Response Evaluation Criteria in Solid Tumors version 1.1. Adverse events were graded according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 4.ResultsMedian age (range) was 65 (51–78) years. Eastern Cooperative Oncology Group performance status was up to 1 in 97% of patients. In the escalation phase, 4 (26.7%) of 15 patients had confirmed response: two complete and two partial responses (95% CI 7.8% to 55.1%). Median duration of response was 19.5 months. Median progression-free survival was 7.3 (2.5 to 10.1) months. In the expansion cohort, confirmed partial response was reported in 8 (42.1%) of 19 patients (95% CI 20.3% to 66.5%). Median duration of response was 7.5 (6.4 to not reached) months, median progression-free survival was 7.7 (2.0 to 16.7) months and median overall survival was 14.2 (4.5 to not reached) months. Fatigue (26.3% of patients), and transient and reversible myelosuppression (neutropenia, 78.9%; febrile neutropenia, 21.1%; thrombocytopenia, 15.8%) were the main grade 3 and higher toxicities in the expanded cohort.ConclusionsIn patients with recurrent advanced endometrial cancer treated with doxorubicin and lurbinectedin, response rates (42%) and duration of response (7.5 months) were favorable. Further evaluation of doxorubicin and lurbinectedin is warranted in this patient population.

PURPOSE Pembrolizumab and pembrolizumab-chemotherapy demonstrated efficacy in recurrent/metastatic head and neck squamous cell carcinoma in KEYNOTE-048. Post hoc analysis of long-term efficacy and progression-free survival on next-line therapy (PFS2) is presented. METHODS Patients were randomly assigned (1:1:1) to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Efficacy was evaluated in programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 20, CPS ≥ 1, and total populations, with no multiplicity or alpha adjustment. RESULTS The median study follow-up was 45.0 months (interquartile range, 41.0-49.2; n = 882). At data cutoff (February 18, 2020), overall survival improved with pembrolizumab in the PD-L1 CPS ≥ 20 (hazard ratio [HR], 0.61; 95% CI, 0.46 to 0.81) and CPS ≥ 1 populations (HR, 0.74; 95% CI, 0.61 to 0.89) and was noninferior in the total population (HR, 0.81; 95% CI, 0.68 to 0.97). Overall survival improved with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.62; 95% CI, 0.46 to 0.84), CPS ≥ 1 (HR, 0.64; 95% CI, 0.53 to 0.78), and total (HR, 0.71; 95% CI, 0.59 to 0.85) populations. The objective response rate on second-course pembrolizumab was 27.3% (3 of 11). PFS2 improved with pembrolizumab in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.84) and CPS ≥ 1 (HR, 0.79; 95% CI, 0.66 to 0.95) populations and with pembrolizumab-chemotherapy in the PD-L1 CPS ≥ 20 (HR, 0.64; 95% CI, 0.48 to 0.86), CPS ≥ 1 (HR, 0.66; 95% CI, 0.55 to 0.81), and total (HR, 0.73; 95% CI, 0.61 to 0.88) populations. PFS2 was similar after pembrolizumab and longer after pembrolizumab-chemotherapy on next-line taxanes and shorter after pembrolizumab and similar after pembrolizumab-chemotherapy on next-line nontaxanes. CONCLUSION With a 4-year follow-up, first-line pembrolizumab and pembrolizumab-chemotherapy continued to demonstrate survival benefit versus cetuximab-chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma. Patients responded well to subsequent treatment after pembrolizumab-based therapy.

Quimioteràpia; Carcinoma de cèl·lules escamoses de cap i coll Quimioterapia; Carcinoma de células escamosas de cabeza y cuello Chemotherapy; Head and neck squamous cell carcinoma PURPOSE The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1 and CPS ≥ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS < 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS < 1 and CPS 1-19 subgroups were performed. RESULTS Of 882 participants enrolled, 128 had PD-L1 CPS < 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS < 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS < 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS < 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS ≥ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1–expressing HNSCC. Funding for this research was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ.

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response.METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031.FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], pINTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC.FUNDING: Merck Sharp & Dohme.

Immune checkpoint inhibitors directed against CTLA-4, PD-1 and PD-L1 have transformed the treatment of patients with cancer. Immunotherapy regimens have evolved from a single agent approach to the combination of immune checkpoint inhibitors like anti CTLA-4 and PD-1, immune checkpoint blockade combined with chemotherapy, anti-angiogenic agents and kinase inhibitors. These synergistic combinations were developed to heighten the potency and duration of immune responses against cancer cells. Hence, immunotherapy combinations have shaped the landscape of therapeutic options against a wide range of cancer types, and are current standard treatment regimens worldwide. In this review, we describe the clinical evidence supporting the use of immunotherapy combination regimens for the treatment of patients with solid tumors.

3060 Background: Genetic profiling (GP) is essential not only for understanding tumor biology but also helps to identify potential genes for targeted therapies. At the same time, selected CT provide an individual genomic profile panel during the pre-screening phase. Here, we demonstrate our experience using these panels. Methods: We selected 14 CT from our Early Drug Development Clinical Trial Unit at Hospital Clinic of Barcelona that included analysis of gene panels in tumor (Foundation One, ArcherDX, Therascreen and Sophia Genetics) or plasma (Resolution Bioscience ctDx). These panels analyzed mutations, fusions, amplifications, microsatellite instability (MSI) and tumor mutational burden (TMB), among others. We collected information about types of cancers, molecular alterations and therapies chosen according to the results of GP. The platform OncoKB (Chakravarty JCO PO, 2017) was used to define genes with potential target therapies and levels of evidence (LE) for those targets (from LE 1 –FDA-recognized biomarker predictive of response to an FDA-approved drug- to LE 4 –Compelling biological evidence supports the biomarker as being predictive of response to a drug). Descriptive statistics were used. Results: From March 2017 to January 2021 we analyzed samples from 410 patients (pts) with CNS (19.3%), urothelial (18.3%), prostate (17.6%), breast (15.4%), ovarian (9.3%), esophageal and gastric (5.4%), colorectal (4.4%), pancreas (2.7%), endometrial (2.4%), cholangiocarcinoma (1.2%), cervix (1%), HNSCC (1%), renal (1%), lung (0.5%), liver (0.2%) fallopian tube (0.2%) and paraganglioma (0.2%). 352 pts (85.8%) had at least 1 genetic alteration. The most frequently altered genes were TP53 (153 pts, 46.2%), INSR (19 pts, 22.8%), TERT (76 pts, 22%), CDKN2A (65 pts, 19.9%), FAM175A (11 pts, 19.3%), CDKN2B (54 pts, 18.1%), MLL2 (53 pts, 17.7%), PTEN (52 pts, 16%), MTAP (45 pts, 15.7%), PIK3CA (52 pts, 15%) and ATM (55 pts, 14.4%). TMB ranged from 0 to 76.9 mut/Mb (median 2.5 mut/Mb). MSI was found in 3 pts (1.5%). 196 pts (47.1%) had an OncoKB LE 1 alteration, 105 pts (25.6%) if we restrict the options to their specific cancer type. 16 pts (3.9%) received a matched therapy: 6 pts received an off-label drug, 6 pts were included in the same CT for which the pre-screening was performed and 4 pts were included in a different CT. Additionally, 13 pts (3.2%) received a matched therapy either with OncoKB LE 4 (5 pts received an off-label drug and 3 were included in a different CT) or not included in OncoKB (8 pts included in the same CT of the pre-screening). As a whole, 29 pts (7.1%) received a matched drug according to their genomic results. Conclusions: Comprehensive gene panel testing offered through CT allows the identification of targets to enroll pts, although the recruitment was 1.5%. However, 7.1% of the pts received a matched therapy due to the molecular information of these gene panels.

TPS6086 Background: Nivolumab is the standard of care for patients (pts) with R/M HNSCC in the platinum-refractory setting. Up to 20% of R/M HNSCC pts are ineligible for cisplatin-based CT due to poor performance status and/or comorbidities. ERBITAX (weekly cetuximab + paclitaxel) is a recommended regimen for this patient population according to the Spanish Society of Medical Oncology guidelines. Preclinical data suggests a role for paclitaxel as immuno-modulator, mainly by increasing tumor infiltrating CD8+ (Galluzzi L., et al 2015). NIVOTAX trial aims to evaluate efficacy and safety of nivolumab + paclitaxel vs ERBITAX as first-line treatment for R/M HNSCC pts with platinum-refractory disease or ineligible for platinum-based chemotherapy. Methods: NIVOTAX (NCT04282109) is a randomized, open-label, multicenter, phase II trial sponsored by the Spanish Group of Head and Neck Cancer Treatment (TTCC) including R/M HNSCC pts not amenable for curative-intent therapy, previously untreated for R/M disease and not candidates for cisplatin-based chemotherapy. Population is distributed in 3 Groups: 1= Platinum-refractory; 2=Platinum-sensitive but unable to receive cisplatin due to: Karnofsky performance status (KPS) 70% and/or major comorbidities (renal/heart failure, grade ≥2 hearing loss) and/or previous allergic reactions to platinum compounds; 3= Platinum-sensitive but cumulative cisplatin dose received ≥225 mg/m² for locally-advanced disease. Pt are stratified according to: KPS (70% vs 80-100%); PD-L1 by Combined Positive Score (CPS ≥1 vs < 1); and HPV positivity (HPV+ oropharynx vs HPV-/non-oropharyngeal). 141 Pt are being randomized 2:1 to NIVOTAX (nivolumab 240 mg q2 weeks + weekly paclitaxel at 80 mg/m2 up to 12 weeks followed by maintenance nivolumab 480 mg/ q4 weeks) or ERBITAX ( weekly 250 mg/m2 plus paclitaxel 80 mg/m2 up to 12 weeks followed by maintenance cetuximab 250 mg/m2 weekly). Both arms will be continued up to a maximum of 24 months. Primary end-point is to evaluate treatment efficacy in terms of 2-year overall survival (2-y OS). It is assumed that 2-y OS in the NIVOTAX arm will be at least 26% (10% gain when compared to the expected 16% 2-y OS rate in this pt population). Secondary objectives include progression free survival (PFS), overall response rate, disease control rate, duration of response, 6m PFS, 5y-OS and safety profile. Response endpoints will be assessed using RECIST 1.1 criteria. As of February 12, 2021, 64 pts have been randomized. Planned safety data review for the first 10 pts treated with NIVOTAX regimen did not show any unexpected AE. Clinical trial information: NCT04282109.

Background: Inhibitor of Apoptosis Proteins (IAPs) regulate apoptosis and modulate NFκB signaling, which in turn drives the expression of genes involved in immune and inflammatory responses. Debio 1143 is an orally available antagonist of IAPs with the potential to enhance tumor response, when combined with chemo/radiotherapy and/or immunotherapy, that is currently being tested in phase II clinical trials. Methods: We investigated the pharmacokinetics and pharmacodynamic effects of Debio 1143 monotherapy (200 mg/day D1-15 +/-2 p.o.) in paired tumor samples collected at diagnosis and at time of surgical resection in a window of opportunity trial in patients with potentially resectable squamous cell carcinoma of the head and neck (SCCHN) (EudraCT Number: 2014-004655-31). Pharmacokinetic disposition of Debio 1143 was evaluated in tumor samples by quantitative mass spectrometry imaging (QMSI), and in plasma by LC-MS/MS. Immunohistochemistry for cellular IAP1 (cIAP1), cleaved caspase-3 apoptosis marker, Ki-67 proliferation marker, CD3+, CD4+ and CD8+ tumor-infiltrating lymphocytes (TILs), PD-1 and PD-L1 were performed in pre- and post-treatment specimens. Exploratory transcriptomic analyses were conducted to assess the effects of Debio 1143 on gene expression. Results: Twelve patients were evaluated. Debio 1143 monotherapy was well tolerated. Tumor penetration was high, with Debio 1143 concentrations up to 55-fold those found in plasma at the time of the resection. Pharmacodynamic analysis of resected tumors showed a significant target engagement with degradation of cIAP1 (p < 0.05). There was no significant change in cleaved caspase-3 or proliferation measured by Ki67. Overall, the levels of CD8+ TILs, PD-1 and PD-L1 positive immune cells increased significantly (p < 0.05) compared to pre-treatment levels. Changes were observed in the expression of genes related to NFκB signaling. Conclusions: This study demonstrates that Debio 1143 distributes widely into SCCHN tumors, engages its target cIAP1, and induces downstream effects that may modulate immunity in the tumor microenvironment supporting future combination therapy with immune-checkpoint agents in cancer patients. Citation Format: Carlos Gomez-Roca, Caroline Even, Christophe Le Tourneau, Neus Basté Rotllan, Jean-Pierre Delord, Jerome Sarini, Sebastien Vergez, Stephane Teman, Caroline Hoffmann, Philippe Rochaix, Bruno Gavillet, Elisabeth Rouits, Franck Brichory, Dalit Rechavi-Robinson, Vincent Bize, Sebastien Del Rizzo, Daniela Purcea, Silvano Brienza, Claudio Zanna, Gregoire Vuagniaux, Sergio Szyldergemajn. Open-label, non-randomized, exploratory pre-operative window-of-opportunity trial to investigate the pharmacokinetics and pharmacodynamics of the smac mimetic Debio 1143 in patients with resectable squamous cell carcinoma of the head and neck [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5001.