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BACKGROUND: In a pilot study involving patients with cutaneous squamous-cell carcinoma, a high percentage of patients had a pathological complete response with the use of two doses of neoadjuvant cemiplimab before surgery. Data from a phase 2 study are needed to confirm these findings. METHODS: We conducted a phase 2, confirmatory, multicenter, nonrandomized study to evaluate cemiplimab as neoadjuvant therapy in patients with resectable stage II, III, or IV (M0) cutaneous squamous-cell carcinoma. Patients received cemiplimab, administered at a dose of 350 mg every 3 weeks for up to four doses, before undergoing surgery with curative intent. The primary end point was a pathological complete response (the absence of viable tumor cells in the surgical specimen) on independent review at a central laboratory, with a null hypothesis that a pathological complete response would be observed in 25% of patients. Key secondary end points included a pathological major response (the presence of viable tumor cells that constitute ≤10% of the surgical specimen) on independent review, a pathological complete response and a pathological major response on investigator assessment at a local laboratory, an objective response on imaging, and adverse events. RESULTS: A total of 79 patients were enrolled and received neoadjuvant cemiplimab. On independent review, a pathological complete response was observed in 40 patients (51%; 95% confidence interval [CI], 39 to 62) and a pathological major response in 10 patients (13%; 95% CI, 6 to 22). These results were consistent with the pathological responses determined on investigator assessment. An objective response on imaging was observed in 54 patients (68%; 95% CI, 57 to 78). Adverse events of any grade that occurred during the study period, regardless of whether they were attributed to the study treatment, were observed in 69 patients (87%). Grade 3 or higher adverse events that occurred during the study period were observed in 14 patients (18%). CONCLUSIONS: Neoadjuvant therapy with cemiplimab was associated with a pathological complete response in a high percentage of patients with resectable cutaneous squamous-cell carcinoma. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov number, NCT04154943.)

Chemotherapy; Quality of life; Symptoms Quimioterapia; Calidad de vida; Síntomas Quimioteràpia; Qualitat de vida; Símptomes Background In a phase III, randomised, active-controlled study (EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9; R2810-ONC-1676; NCT03257267) and cemiplimab significantly improved survival versus investigator's choice of chemotherapy among patients with recurrent cervical cancer who had progressed on platinum-based therapy. Here we report patient-reported outcomes in this pivotal study. Methods Patients were randomised 1:1 to open-label cemiplimab (350 mg intravenously every 3 weeks) or investigator's choice of chemotherapy in 6-week cycles. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 during cycles 1–16. Least-squares mean changes from baseline in global health status (GHS)/quality of life (QoL) and physical functioning (PF) were secondary end-points in the statistical hierarchy. Results Of 608 patients (304/arm), 77.8% patients had squamous cell carcinoma and 22.2% patients had adenocarcinoma. Questionnaire completion rates were ∼90% throughout. In the squamous cell carcinoma population, overall between-group differences statistically significantly favoured cemiplimab in GHS/QoL (8.49; 95% confidence interval [CI]: 3.77–13.21; P = 0.0003) and PF (8.35; 95% CI: 4.08–12.62; P < 0.0001). Treatment differences favoured cemiplimab in both histologic populations by cycle 2. Overall changes from baseline in most functioning and symptom scales favoured cemiplimab, with clinically meaningful treatment differences in role functioning, appetite loss and pain in both populations. The sensitivity analyses, responder analyses and time to definitive deterioration favoured cemiplimab in both populations. Conclusions Cemiplimab conferred favourable differences in GHS/QoL and PF compared with chemotherapy among patients with recurrent cervical cancer, with benefits in PF by cycle 2, and clinically meaningful differences favouring cemiplimab in role functioning, appetite loss, and pain. This work was supported by Regeneron Pharmaceuticals, Inc., and Sanofi.

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Purpose:This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors.Patients and Methods:Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m2) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1.Results:Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3–84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients.Conclusions:The safety profile of cemiplimab was comparable with other anti–PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.

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Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas.Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20–400 mg twice a day, days 1–7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort.Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2. Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response.Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702. Clin Cancer Res; 23(15); 4119–26. ©2017 AACR.

Background: Patients with recurrent cervical cancer have a poor prognosis. Cemiplimab, the fully human programmed cell death 1 (PD-1)-blocking antibody approved to treat lung and skin cancers, has been shown to have preliminary clinical activity in this population. Methods: In this phase 3 trial, we enrolled patients who had disease progression after first-line platinum-containing chemotherapy, regardless of their programmed cell death ligand 1 (PD-L1) status. Women were randomly assigned (1:1) to receive cemiplimab (350 mg every 3 weeks) or the investigator's choice of single-agent chemotherapy. The primary end point was overall survival. Progression-free survival and safety were also assessed. Results: A total of 608 women were enrolled (304 in each group). In the overall trial population, median overall survival was longer in the cemiplimab group than in the chemotherapy group (12.0 months vs. 8.5 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.84; two-sided P

Cemiplimab; Càncer de coll uterí metastàtic; Càncer de coll uterí recurrent Cemiplimab; Cáncer de cuello uterino metastásico; Cáncer de cuello uterino recurrente Cemiplimab; Metastatic cervical cancer; Recurrent cervical cancer Objectives To characterize the safety, tolerability, and anti-tumor activity of cemiplimab as monotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression. Methods In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levels were analyzed from The Cancer Genome Atlas (TCGA). Results Twenty patients enrolled in both cohorts in total; 10 had squamous histology. The most common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesions were not included in the response assessments. In separate archived specimens ( N = 155), PD-L1 protein expression in tumor and immune cells was negative (

Aims: To examine real-world treatment patterns for Hedgehog pathway inhibitors (HHIs) for the treatment of advanced basal cell carcinoma. Patients & methods: HHI initiators between January 2013 and June 2019 were identified from IBM MarketScan® claims data. Time to treatment discontinuation and reinitiation were estimated using Kaplan–Meier methods using a 60-day grace period. Results: Among 526 patients with basal cell carcinoma who initiated an HHI, median time to first discontinuation was 144 days, and risk of discontinuation by 12 months was 88.0%. Probability of reinitiation within 12 months was 19.7%, and median time to second discontinuation was 118 days. Conclusion: HHI discontinuation was common and reinitiation uncommon in clinical practice. Future research should evaluate persistence with recently approved therapies.

OBJECTIVES: Ribavirin inhibits eukaryotic translation initiation factor 4E (eIF4E), thereby decreasing cap-dependent translation. In this two-part study, we assessed the pharmacodynamic effects and therapeutic potential of ribavirin in human papillomavirus (HPV)–related malignancies. METHODS: In the pharmacodynamic study, ribavirin (400 mg BID for 14 days) was evaluated in 8 patients with HPV-positive localized oropharyngeal carcinoma with phosphorylated-eIF4E (p-eIF4E) ≥30%. In the therapeutic study, ribavirin (1400 mg BID in 28-day cycles, continuously dosed) was evaluated in 12 patients with recurrent and/or metastatic HPV-related cancer. Dose interruptions or reductions were allowed according to prespecified criteria. Toxicities were assessed in accordance with National Cancer Institute Common Terminology Criteria for Adverse Events version 4; response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1. Patients remained on study until disease progression or unacceptable toxicity. RESULTS: Six patients were evaluable in the pharmacodynamic study: 4 had decreased p-eIF4E after 14 days of ribavirin. In the therapeutic study, 12 patients were evaluable for toxicity, and 9 were evaluable for response. Among these, median follow-up was 3.5 months, and best overall response was stable disease in 5 patients and progression of disease in 4 patients. Median progression-free survival was 1.8 months. The most common treatment-related adverse events (grade >2) were anemia, dyspnea, and hyperbilirubinemia. All patients had anemia (grades 1–3), with 33% having at least 1 dose reduction. CONCLUSION: Oral ribavirin decreases p-eIF4E levels and is well-tolerated. However, a clear signal of efficacy in patients with recurrent and/or metastatic HPV-related cancers was not observed. (NCT02308241, NCT01268579)

TPS277 Background: There is a need to develop novel immunotherapeutic approaches to enhance responses to immune checkpoint blockade. REGN7075 is a human costimulatory bispecific antibody designed to bridge epidermal growth factor receptor (EGFR)-expressing tumor cells with CD28-positive T cells to support further T-cell activation by endogenous tumor antigens. Methods: This is an open-label, Phase 1/2, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN7075 (EGFRxCD28) alone and in combination with cemiplimab (anti-programmed cell death [PD]-1) in patients with advanced solid tumors (NCT04626635). This study includes a dose-escalation (Bayesian optimal interval design; Part 1) and a dose-expansion phase (Part 2). Patients must have a protocol-defined advanced solid tumor, have an Eastern Cooperative Oncology Group performance status of 0 or 1, and be naive to anti–PD-1/anti–PD-ligand(L)1 therapy in the dose-expansion phase. In Part 1, heavily pre-treated patients with advanced solid tumors receive a lead-in of REGN7075 monotherapy every week for 3 weeks followed by combination therapy with cemiplimab 350 mg every 3 weeks. Planned dose levels (DLs) of REGN7075 are 0.03, 0.1, 0.3, 1, 3, 10, 30, 100, 300, and 900mg. Once the recommended Phase 2 dose is determined in Part 1, five tumor-specific expansion cohorts will be opened in Part 2: colorectal cancer (microsatellite stable [MSS-CRC]), non-small cell lung cancer (NSCLC, PD-L1 ≥50%), triple-negative breast cancer, cutaneous squamous cell carcinoma, and head and neck squamous cell carcinoma (PD-L1 combined positive score ≥1). Patients with MSS-CRC with RAS or BRAF wild type mutations must have received anti-EGFR therapy or anti-vascular endothelial growth factor (VEGF therapy). Primary endpoints are safety and tolerability of REGN7075 alone or in combination with cemiplimab for Part 1, and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 for Part 2. For Part 2, a secondary objective is to assess the effect of REGN7075 on patient-reported outcomes as measured by several validated instruments including the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), and EORTC QLQ-CR29 (CRC patients only). Approximately 400 patients will be enrolled in this phase 1/2 study, including ~80 patients in Part 1 and ~320 patients in Part 2 (including ~70 in the CRC cohort). As of September 13, 2022, 30 patients were treated in the dose-escalation phase, up to the 300 mg DL for REGN7075 in combination with cemiplimab. This study is ongoing and currently open to enrollment. Clinical trial information: NCT04626635 .

Until recently, patients discontinuing first-line (1L) hedgehog inhibitors (HHIs) for basal cell carcinoma (BCC) had few subsequent treatment options. The objective of this study was to describe the treatment journey and prognosis of patients discontinuing 1L HHI for BCC.This was a retrospective cohort study of patients with BCC who discontinued 1L HHI treatment in The US Oncology Network between 1 January 2012 and 1 January 2019 (with follow-up until 1 May 2020). Two cohorts were identified: patients who initiated a second-line (2L) treatment (2L initiators), and patients with 1L progression or toxicity without pathology-confirmed complete response who did not initiate 2L treatment (2L non-initiators). Patient demographics, treatment characteristics, and outcomes are reported for each cohort.Among 115 patients with BCC who received 1L HHI treatment, 63.5% (n = 73/115) discontinued 1L HHIs. Of those, 50.7% (n = 37/73) discontinued because of documented toxicity or progression, without evidence of a complete response. We identified 4 patients who initiated 2L systemic treatment (median age 68.7 years, 100.0% female) and 15 patients who were eligible for the 2L non-initiator cohort (median age 80.2 years, 20.0% female). Median 1L HHI duration was 6.8 months (range 1.9-20.6 months) for the 2L non-initiator cohort and 8.6 months (range 6.8-42.2 months) for 2L initiators. At the end of follow-up, among 2L non-initiators (median follow-up duration 9.7 months), 40.0% were lost to follow-up, 33.3% had died, 20.0% continued observation, and 6.7% transitioned to an academic medical center or hospital; among 2L initiators (median follow-up duration 6.3 months), 50.0% were lost to follow-up, 25.0% had died, and 25.0% continued observation.Following 1L HHI discontinuation, lack of standardized care and suboptimal outcomes were observed, including limited receipt of 2L treatment. Further studies are necessary to evaluate the impact of newer BCC treatment options.

BackgroundThe prognosis for advanced and metastatic cutaneous squamous cell carcinoma (CSCC) remains poor for many patients with the disease despite approval of the anti-PD1 antibodies cemiplimab and pembrolizumab.1 2 RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity, which is further improved by combining anti-PD-1 therapy.3 Preliminary results from IGNYTE, a phase I/II clinical study of RP1 in combination with nivolumab showed a high rate of deep and durable responses in patients (pts) with CSCC.4 The objective of this trial is to evaluate the safety and efficacy of cemiplimab + RP1 versus cemiplimab alone in advanced CSCC.MethodsThis global, multicenter, randomized phase 2 study is enrolling pts with metastatic or unresectable, locally advanced CSCC who are not candidates for/refuse surgery and/or radiotherapy. Key eligibility criteria include no prior treatment with anti-PD1/PD-L1 antibodies or oncolytic viruses. The clinical trial will enroll approximately 180 pts from centers in the EU, Australia, Canada and USA. Pts will be randomized in a 2:1 ratio favoring the RP1 + cemiplimab arm. Pts will receive 350 mg of cemiplimab intravenously (IV) Q3W for up to 108 weeks. In the RP1 + cemiplimab arm, RP1 will be injected intratumorally at a starting RP1 dose of 1 × 10^6 plaque forming units (PFU)/mL alone, followed by up to 7 doses of RP1 at 1 × 10^7 PFU/mL Q3W together with cemiplimab. Pts in the combination arm may receive up to 8 additional RP1 doses. No crossover will be allowed. Pts will be stratified by disease status and prior systemic therapy. Tumor assessments will be performed every 9 weeks. Primary endpoints are overall response rate and complete response rate by blinded independent review. Secondary endpoints include safety, progression free survival, duration of response and overall survival. Exploratory endpoints include viral shedding and biodistribution, and immune biomarker analyses. This trial is currently enrolling pts.Trial RegistrationNCT04050436ReferencesMigden MR, Rischin D, Schmults CD, Guminski A, Hauschild A, Lewis KD, Chung CH, Hernandez-Aya L, Lim AM, Chang ALS, Rabinowits G, Thai AA, Dunn LA, Hughes BGM, Khushalani NI, Modi B, Schadendorf D, Gao B, Seebach F, Li S, Li J, Mathias M, Booth J, Mohan K, Stankevich E, Babiker HM, Brana I, Gil-Martin M, Homsi J, Johnson ML, Moreno V, Niu J, Owonikoko TK, Papadopoulos KP, Yancopoulos GD, Lowy I, Fury MG. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med 2018;379(4):341–351.Grob JJ, Gonzalez R, Basset-Seguin N, Vornicova O, Schachter J, Joshi A, Meyer N, Grange F, Piulats JM, Bauman JR, Zhang P, Gumuscu B, Swaby RF, Hughes BGM. Pembrolizumab monotherapy for recurrent or metastatic cutaneous squamous cell carcinoma: a single-arm phase II trial (KEYNOTE-629). J Clin Oncol 2020;38(25):2916–2925.Thomas S, Kuncheria L, Roulstone V, Kyula JN, Mansfield D, Bommareddy PK, Smith H, Kaufman HL, Harrington KJ, Coffin RS. Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1. J Immunother Cancer 2019;7(1):214.Middleton M, Aroldi F, Sacco J, Milhem M, Curti B, VanderWalde A, Baum S, Samson A, Pavlick A, Chesney J, Niu J, Rhodes T, Bowles T, Conry R, Olsson-Brown A, Earl Laux D, Kaufman H, Bommareddy P, Deterding A, Samakoglu S, Coffin R, Harrington K. 422 An open-label, multicenter, phase 1/2 clinical trial of RP1, an enhanced potency oncolytic HSV, combined with nivolumab: updated results from the skin cancer cohorts. J Immunother Cancer 2020; 8 (3).Ethics ApprovalThe study was approved by institutional review board or the local ethics committee at each site. Informed consent was obtained from patients before participating into the trial.

BackgroundT-cell redirecting bispecific antibodies (bsAbs) are therapeutics that recognize two distinct antigens: a tumor-associated antigen on tumor cells to promote recruitment of T-cells to the tumor, and a receptor on T-cells to potentiate anti-tumor activity. REGN7075 is a human immunoglobulin G4-based costimulatory bsAb designed to bridge epidermal growth factor receptor (EGFR) positive tumor cells with CD28 positive T-cells and to provide amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor, through the activation of CD28 co-stimulation. In genetically humanized immunocompetent mouse models, REGN7075 in combination with anti–PD-1 (antibody directed against programmed cell death-1 receptor) improved anti-tumor activity compared with either single agent alone.1MethodsThis is an open label, Phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN7075 (EGFRxCD28) alone and in combination with cemiplimab in patients with advanced solid tumors (NCT04626635). Patients must have a protocol-defined advanced solid tumor, be ≥18 years of age (≥20 years in Japan), have an Eastern Cooperative Oncology Group performance status of 0 or 1, and be naïve to anti–PD-1/anti–PD-ligand(L)1.This study includes dose escalation (a 4+3 design modified from 3+3; Part 1) and expansion phases (Part 2). In Part 1, patients will receive a lead-in of REGN7075 monotherapy for 3 weeks followed by combination therapy with cemiplimab 350 mg every 3 weeks. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or other stopping criterion is met. Once a recommended Phase 2 dose is determined in Part 1, four tumor-specific expansion cohorts will be opened: non-small cell lung cancer (PD-L1 ≥50%), triple-negative breast cancer, colorectal cancer (microsatellite stable), and cutaneous squamous cell carcinoma. Primary endpoints are safety and tolerability of REGN7075 alone or in combination with cemiplimab for Part 1, and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 for Part 2. This study is currently open to enrollment.Trial RegistrationClinicalTrials.gov identifier NCT04626635.ReferencesWaite JC, Wang B, Haber L, et al. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy. Sci Transl Med 2020;12:2325.Ethics ApprovalThis study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The study protocol and all amendments were approved by the institutional review board/ethics committee at each participating study site.ConsentAll patients provided written informed consent.

Introduction/Background* There is no standard of care regimen in the second-line setting for women with recurrent/metastatic (R/M) cervical carcinoma. Cemiplimab was recently shown to significantly improve overall survival (OS) compared with investigator’s choice (IC) chemotherapy in patients with R/M cervical cancer after first-line platinum-based chemotherapy (NCT03257267; ESMO-VP-2021). We present a pre-planned exploratory subgroup analysis comparing cemiplimab to individual IC chemotherapy options. Methodology EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 is an open-label, randomised (1:1), multi-centre, Phase 3 clinical trial of anti-programmed cell death (PD)-1 cemiplimab vs IC single agent chemotherapy in R/M cervical cancer that has progressed after first-line platinum-based treatment. The selection of single-agent chemotherapy by the investigator (gemcitabine, pemetrexed, vinorelbine, topotecan or irinotecan) was not protocol-defined, but the regimen had to be chosen prior to randomisation. Adult females (age ≥18 years) were enrolled regardless of PD-ligand 1 expression and received cemiplimab 350 mg intravenously every 3 weeks or IC chemotherapy for up to 96 weeks; and were stratified by histology (squamous cell carcinoma/adenocarcinoma or adenosquamous), geographic region (North America/Asia/rest of world), prior bevacizumab, and ECOG performance status (0/1). Primary endpoint was OS. Additional endpoints included progression-free survival (PFS), objective response rate (ORR), duration of response, quality of life and safety. Data cutoff was 4 January 2021. Result(s)* A total of 608 patients were randomised: 304 to cemiplimab and 304 to IC chemotherapy (gemcitabine, n=121; premetrexed, n=111; vinorelbine, n=32; topotecan, n=21; irinotecan, n=19) across geographic regions and histologies. Median duration of study follow-up (range) was 4.8 months (0.0–25.9) for the overall population. At second interim analysis, the trial was stopped early for efficacy. OS, PFS and ORR (table 1) demonstrated improvements with cemiplimab vs each IC chemotherapy treatment similar to those observed with cemiplimab vs pooled IC chemotherapy. Conclusion* Improvements in OS, PFS and ORR with cemiplimab trended consistently with the results for the overall population regardless of IC chemotherapy drug.

Purpose Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration–approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. Methods and Materials This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design. Results Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans. Conclusions The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted.

Purpose: This first-in-human study assessed the safety, tolerability, dose-limiting toxicities (DLT), antitumor activity, and pharmacokinetics of cemiplimab, a monoclonal anti-programmed cell death-1 (PD-1), as monotherapy and in combination with hypofractionated radiotherapy (hfRT) and/or cyclophosphamide (CPA) in patients with advanced solid tumors. Patients and Methods: Patients were enrolled in 1 of 10 dose escalation cohorts and received cemiplimab 1, 3, or 10 mg/kg every 2 weeks intravenously for up to 48 weeks. Depending on the cohort, patients received hfRT and/or low-dose (200 mg/m2) CPA. Safety was evaluated. Antitumor activity was assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Results: Sixty patients were enrolled. The median duration of follow-up was 19.3 weeks (range, 2.3–84.3). There were no DLTs. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (45.0%), nausea (36.7%), and vomiting (25.0%). The most common immune-related adverse events (irAEs) of any grade were arthralgia (10.0%), hypothyroidism (8.3%), and maculopapular rash (8.3%). Cemiplimab pharmacokinetic parameters increased in a close to dose-proportional manner and were similar regardless of combination therapy regimen. Two patients (one with cutaneous squamous cell carcinoma and one with cervical cancer) experienced a complete response; 7 had a partial response. Observed duration of response was ≥12 months in 6 patients. Conclusions: The safety profile of cemiplimab was comparable with other anti–PD-1 agents. Addition of hfRT and/or CPA did not appear to increase grade ≥3 irAEs, suggesting that cemiplimab can be safely administered with hfRT and/or CPA. Cemiplimab exhibited encouraging antitumor activity with 2 complete responses and 7 partial responses observed; responses were also durable.

Summary Background Cemiplimab has shown substantial antitumour activity in patients with metastatic cutaneous squamous cell carcinoma. Patients with locally advanced cutaneous squamous cell carcinoma have poor prognosis with conventional systemic therapy. We present a primary analysis of the safety and antitumour activity of cemiplimab in patients with locally advanced cutaneous squamous cell carcinoma. Methods This pivotal open-label, phase 2, single-arm trial was done across 25 outpatient clinics, primarily at academic medical centres, in Australia, Germany, and the USA. Eligible patients (aged ≥18 years with histologically confirmed locally advanced cutaneous squamous cell carcinoma and an Eastern Cooperative Oncology Group performance status of 0–1) received cemiplimab 3 mg/kg intravenously over 30 min every 2 weeks for up to 96 weeks. Tumour measurements were done every 8 weeks. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response, according to independent central review as per Response Evaluation Criteria in Solid Tumors version 1.1 for radiological scans and WHO criteria for medical photography. Data cutoff was Oct 10, 2018, when the fully enrolled cohort reached the prespecified timepoint for the primary analysis. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. This study is registered with ClinicalTrials.gov , number NCT02760498 . Findings Between June 14, 2016, and April 25, 2018, 78 patients were enrolled and treated with cemiplimab. The median duration of study follow-up was 9·3 months (IQR 5·1–15·7) at the time of data cutoff. An objective response was observed in 34 (44%; 95% CI 32–55) of 78 patients. The best overall response was ten (13%) patients with a complete response and 24 (31%) with a partial response. Grade 3–4 treatment-emergent adverse events occurred in 34 (44%) of 78 patients; the most common were hypertension in six (8%) patients and pneumonia in four (5%). Serious treatment-emergent adverse events occurred in 23 (29%) of 78 patients. One treatment-related death was reported that occurred after onset of aspiration pneumonia. Interpretation Cemiplimab showed antitumour activity and an acceptable safety profile in patients with locally advanced cutaneous squamous cell carcinoma for whom there was no widely accepted standard of care. Funding Regeneron Pharmaceuticals and Sanofi.

BackgroundTo provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL).MethodsPatients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks).ResultsMedian duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (pConclusionsThis is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement.Trial registration numberClinicalTrials.gov Registry (NCT02760498), https://clinicaltrialsgov/ct2/show/NCT02760498.

Lessons Learned Background Refractory and metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) generally does not respond to PD-1 inhibitor monotherapy. Cemiplimab is a human anti–PD-1 monoclonal antibody. An expansion cohort enrolled patients with R/M HNSCC in a phase I study combining cemiplimab plus radiation therapy (RT), cyclophosphamide, and granulocyte macrophage colony-stimulating factor (GM-CSF). Methods Patients with R/M HNSCC refractory to at least first-line therapy and for whom palliative RT is clinically indicated received cemiplimab plus RT, cyclophosphamide, and GM-CSF. The co-primary objectives were the safety, tolerability, and efficacy of cemiplimab plus RT, cyclophosphamide, and GM-CSF in 15 patients with R/M HNSCC. Results Fifteen patients were enrolled. Patients discontinued treatment due to progression of disease. The most common treatment-emergent adverse events (TEAEs) of any grade were fatigue (40.0%), constipation (26.7%), and asthenia, dyspnea, maculo-papular rash, and pneumonia (each 20%). The only grade ≥3 TEAE that occurred in two patients was pneumonia (13.3%). By investigator assessment, there was one partial response (6.7%); disease control rate was 40.0% (95% confidence interval [CI], 16.3–67.7; five patients with stable disease); seven patients had progressive disease, and two were not evaluable. Median progression-free survival by investigator assessment was 1.8 months (95% CI, 1.7–4.7). Conclusion The regimen demonstrated tolerability but not efficacy above that which can be achieved with anti–PD-1 inhibitor monotherapy for R/M HNSCC.

Objectives Blockade of programmed cell death-1 (PD-1) and its ligand (PD-L1) has transformed the treatment of NSCLC. In a first-in-human, Phase 1, dose escalation and cohort expansion study, cemiplimab, a monoclonal antibody directed against PD-1, was evaluated for the treatment of patients with advanced solid tumors (NCT02383212). Here, we report results in patients with advanced NSCLC from the dose expansion cohort. Materials and methods Immune-checkpoint inhibitor naive patients with advanced NSCLC (stage III/IV), irrespective of PD-L1 status, who had progressed after, or were refractory to first- or later-line therapy were enrolled and received cemiplimab 200 mg every 2 weeks intravenously for up to 48 weeks. Primary study objectives were to assess safety and tolerability, and to evaluate clinical activity of cemiplimab. Results Twenty patients with NSCLC were enrolled. Median age was 64.0 years (range: 50–82); 65.0 % were male; 80.0 % had an ECOG performance status of 1; 60.0 % had a histology of adenocarcinoma. Median number of prior lines of systemic therapy was 2 (range: 1–4). Median duration of follow-up was 7.0 months (range: 1.0–18.2). All patients experienced ≥1 treatment-emergent adverse event (TEAE) of any grade. Most common TEAEs were arthralgia, asthenia, cough, and dyspnea (each 4/20; 20.0 %). Grade ≥3 TEAEs occurred in 60.0 % (12/20) of patients. Of patients with measurable disease per independent central review (ICR), five had partial response (PR), four had stable disease (SD) and 10 had progressive disease. Objective response rate (ORR; complete response + PR) was 25.0 % (95 % CI: 8.7–49.1 %). Duration of response exceeded 8 months in four of the five responding patients at the time of data cut-off (April 30, 2019). The disease control rate per ICR (ORR + SD) was 50.0 % (95 % CI: 27.2–72.8 %). Conclusion Cemiplimab showed an acceptable safety profile and demonstrated antitumor activity in pretreated patients with NSCLC.

Summary Background Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. Methods We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov , NCT03132636 , and is no longer recruiting new participants. Findings Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8–18). An objective response per independent central review was observed in 26 (31%; 95% CI 21–42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3–4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths. Interpretation Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. Funding Regeneron Pharmaceuticals and Sanofi.

Background HHIs, vismodegib and sonidegib, are approved for treatment of patients with mBCC or locally advanced BCC who are not candidates for surgery or radiation. There is no approved option for patients who progress on or are intolerant to HHIs. Cemiplimab is an anti-programmed cell death-1 monoclonal antibody approved for treatment of patients with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidates for curative surgery or curative radiation. Here we present the prespecified interim analysis of the mBCC cohort from the pivotal Phase 2, non-randomized, multi-center study of cemiplimab in patients with advanced BCC who discontinued HHI therapy due to disease progression, intolerance, or no better than stable disease after 9 months (NCT03132636). Methods Patients with mBCC (nodal and/or distant) received cemiplimab 350 mg intravenously every 3 weeks; interim analysis included patients with the opportunity to be followed for approximately 57 weeks. The primary endpoint was objective response rate (ORR) per independent central review (ICR). Secondary objectives included assessment of safety and tolerability, estimation of duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results In this interim efficacy analysis of 28 patients, 82.1% were males and median age was 65.5 years (range 38−90). Six patients had a partial response, per ICR, for an ORR of 21.4% (95% CI, 8.3, 41.0). ORR per investigator assessment was 28.6% (95% CI, 13.2, 48.7). Among responders, observed DOR was 9−23 months. Median time to response per ICR was 3.2 months (range, 2.1−10.5). Median Kaplan–Meier (KM) estimation of PFS was 8.3 months. Median DOR had not been reached and median KM estimation of OS was 25.7 months. All six responses had observed durations of at least 8 months. The disease control rate was 67.9% (95% CI, 47.6, 84.1).The most common treatment emergent adverse events (TEAEs) regardless of attribution were fatigue (50.0%), diarrhea (35.7%), pruritus (25.0%), and constipation (25.0%). Hypertension (n=2) was the only Grade ≥3 TEAE regardless of attribution occurring in ≥2 patients. TEAEs leading to death occurred in one (3.6%) patient who died from staphylococcal pneumonia, considered unrelated to study treatment. Conclusions This interim analysis demonstrates that cemiplimab is the first agent to provide clinically meaningful anti-tumor activity, including durable responses, in patients with mBCC after progression or intolerance on HHI therapy. Acknowledgements Editorial acknowledgment: Medical writing support was provided by Cindi Hoover, PhD of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc. and Sanofi. Ethics Approval The study protocols and all amendments were approved by the institutional review board at each participating study site. The study was conducted in accordance with the principles of the Declaration of Helsinki and with Good Clinical Practice guidelines as defined by the International Conference on Harmonization. All patients provided written informed consent before enrollment.

Introduction This study outlined cemiplimab intravenous (IV) dosing strategy to move from body weight (BW)-based 3 mg/kg every-2-week (Q2W) dosing in first-in-human study (study 1423; NCT02383212) to fixed 350 mg every-3-week (Q3W) dosing, utilizing population pharmacokinetics (PopPK) modeling and simulations, and supported by a limited dataset from a phase 2 study (study 1540; NCT02760498). Methods Cemiplimab concentration data from a total of 505 patients were pooled from study 1423 in advanced malignancies and study 1540 in advanced cutaneous squamous cell carcinoma (CSCC). All patients received weight-based cemiplimab dose (1, 3, 10 mg/kg Q2W or 3 mg/kg Q3W) except 4% who received 200 mg Q2W. A linear two-compartment PopPK model incorporating covariates that improved goodness-of-fit statistics was developed to compare cemiplimab exposure at 350 mg Q3W versus 3 mg/kg Q2W. Upon availability, observed cemiplimab concentration at 350 mg Q3W in study 1540 was then compared with the simulated values. Results Post hoc estimates of cemiplimab exposure and variability (505 patients; weight range 30.9–156 kg; median 76.1 kg) at steady state were found to be similar at 350 mg Q3W and 3 mg/kg Q2W. Effect of BW on cemiplimab exposure was described by exposure versus BW plots and at extreme BW. Overlay of individual observed cemiplimab concentrations in 51 patients with metastatic CSCC on simulated concentration–time profiles in 2000 patients at 350 mg Q3W confirmed cemiplimab exposure similarity and demonstrated the robustness of dose optimization based on PopPK modeling and simulations. Conclusions Cemiplimab 350 mg Q3W is being further investigated in multiple indications. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01638-5.

Aim: To estimate the comparative efficacy of cemiplimab, a programmed cell death protein 1 inhibitor, versus EGFR inhibitors, pembrolizumab and platinum-based chemotherapy in terms of overall survival (OS) and progression-free survival. Patients & methods: We performed an indirect treatment comparison of cemiplimab and other available systemic therapies for patients with advanced cutaneous squamous cell carcinoma. Results: Cemiplimab was associated with benefits in OS (hazard ratios range: 0.07–0.52) and progression-free survival (hazard ratios range: 0.30–0.67) versus EGFR inhibitors and pembrolizumab (data from KEYNOTE-629). Cemiplimab was more efficacious versus platinum-based chemotherapy in terms of OS. Conclusion: Cemiplimab may offer improvements in survival for advanced cutaneous squamous cell carcinoma patients compared with existing systemic therapies.

An understanding of the mechanisms underlying acquired resistance to cetuximab is urgently needed to improve cetuximab efficacy in patients with head and neck squamous cell carcinoma (HNSCC). Here, we present a clinical observation that MET pathway activation constitutes the mechanism of acquired resistance to cetuximab in a patient with HNSCC. Specifically, RNA sequencing and mass spectrometry analysis of cetuximab-sensitive (CetuxSen ) and cetuximab-resistant (CetuxRes ) tumors indicated MET amplification and overexpression in the CetuxRes tumor compared to the CetuxSen lesion. Stimulation of MET in HNSCC cell lines was sufficient to reactivate the MAPK pathway and to confer resistance to cetuximab in vitro and in vivo. In addition to the direct role of MET in reactivation of the MAPK pathway, MET stimulation abrogates the well-known cetuximab-induced compensatory feedback loop of HER2/HER3 expression. Mechanistically, we showed that the overexpression of HER2 and HER3 following cetuximab treatment is mediated by the ETS homologous transcription factor (EHF), and is suppressed by MET/MAPK pathway activation. Collectively, our findings indicate that evaluation of MET and HER2/HER3 in response to cetuximab in HNSCC patients can provide the rationale of successive line of treatment.

Background: Cemiplimab is the first treatment approved in the US (as cemiplimab-rwlc) for patients with metastatic basal cell carcinoma (mBCC) or locally advanced disease (laBCC) after hedgehog inhibitor (HHI) treatment or for whom an HHI is not appropriate. Cemiplimab provided substantial clinical benefit and an acceptable safety profile in patients with laBCC who discontinued HHI therapy due to progressive disease (PD), intolerance, or no better than stable disease (SD) after 9 months (NCT03132636). Here, we present the primary analysis of the mBCC cohort. Methods: Patients with mBCC (nodal or distant) post-HHI treatment received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until PD. The primary endpoint was objective response rate (ORR) by independent central review (ICR). Key secondary endpoints included safety and tolerability, ORR per investigator (INV) assessment, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and complete response (CR) rate (data cutoff date: May 20, 2021). Results: Fifty-four patients were enrolled (70.4% male; median age 63.5 years [range, 38−90]; Eastern Cooperative Oncology Group performance status 0 [66.7%] and 1 [33.3%]). Median duration of follow-up was 8.4 months (range 1.5-36.2). ORR per ICR was 24.1% (95% confidence interval [CI], 13.5-37.6); with 1 CR and 12 partial responses (PRs). ORR per INV was 25.9% (95% CI, 15.0-39.7), with 2 CRs and 12 PRs. Among responders, median time to response per ICR was 4.0 months (range, 2.0−10.5). Estimated median DOR per ICR was 16.7 months (95% CI, 9.8-not evaluable). Disease control rate was 63.0% (95% CI, 48.7-75.7) per ICR and 70.4% (95% CI, 56.4-82.0) per INV. Median OS was not reached. Median PFS per ICR was 8.3 months (95% CI, 4.2-15.9). The most common treatment-related adverse events were fatigue (37.0%), diarrhea (14.8%), pruritus (13.0%), hyperthyroidism (9.3%), and arthralgia (9.3%) as well as hypothyroidism, asthenia, constipation, and maculo-papular rash (7.4% each). There were no treatment-related deaths. Conclusions: Cemiplimab provided clinically meaningful antitumor activity, including durable responses, and an acceptable safety profile in patients with mBCC who had progressed on or were intolerant to HHI therapy. Citation Format: Karl Lewis, Ketty Peris, Aleksander Sekulic, Alexander J. Stratigos, Lara Dunn, Zeynep Eroglu, Anne Lynn S. Chang, Michael R. Migden, Suk-Young Yoo, Kosalai Mohan, Ebony Coates, Emmanuel Okoye, Timothy Bowler, Jean-François Baurain, Oliver Bechter, Axel Hauschild, Marcus O. Butler, Leonel Hernandez-Aya, Lisa Licitra, Rogerio I. Neves, Emily S. Ruiz, Frank Seebach, David M. Weinreich, George D. Yancopoulos, Israel Lowy, Priscila Goncalves, Matthew G. Fury. Primary analysis of phase 2 results for cemiplimab in patients with metastatic basal cell carcinoma who progressed on or were intolerant to hedgehog inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT165.

TPS9592 Background: CSCC is the second most common skin cancer with an estimated incidence of 1 million cases per year in the US. While the surgical cure rate for CSCC is > 95%, some pts have high risk of recurrence as assessed by immune status, primary disease stage, extent of nodal involvement, presence of extracapsular extension (ECE), and prior treatment. Postoperative RT is recommended for these pts but relapse with locoregional recurrence or distant metastases may still occur. C-POST is evaluating the efficacy of cemiplimab as adjuvant therapy for pts with high-risk CSCC. Here, we provide summary of the most recent study protocol amendment. Methods: C-POST is a randomized, placebo-controlled, double-blind, multicenter Phase 3 study to evaluate cemiplimab as adjuvant treatment for pts with high-risk CSCC, based on surgical and clinicopathologic findings, who completed surgery and postoperative RT (minimum total dose 50Gy, within 10 weeks before randomization) (NCT03969004). Pts with at least one of the following high-risk features are eligible: (1) nodal disease with (a) ECE and at least one node ≥20 mm or (b) at least three lymph nodes positive on surgical pathology report, regardless of ECE; (2) in-transit metastases; (3) T4 lesion; (4) perineural invasion; and (5) recurrent CSCC with at least one other risk factor. Pts with CSCC involvement in at least three lymph nodes (feature 1b) were added to the eligibility criteria, as this group was found to be at similar risk of CSCC recurrence as the initially planned study population. Protocol amendment now allows patients with chronic lymphocytic leukemia (CLL) who are not on active treatment to be enrolled. The study has two parts. In Part 1 (blinded), pts are randomly assigned 1:1 to receive cemiplimab 350 mg or placebo intravenously every 3 weeks for 12 weeks, followed by cemiplimab 700 mg or placebo every 6 weeks for 36 weeks. In optional Part 2 (unblinded), pts in the placebo arm who experience disease recurrence and pts in the cemiplimab arm who experience disease recurrence ≥3 months after completion of 48-week treatment in Part 1 are eligible to receive open-label cemiplimab for up to 96 weeks. The trial is expected to enrol 412 pts from about 100 sites in North and South America, Europe, and Asia-Pacific regions. Key primary objective is to compare disease-free survival; secondary objectives include evaluating overall survival, freedom from locoregional relapse, and distant relapse with adjuvant cemiplimab versus placebo in patients with high-risk CSCC. This study is once again open for enrolment following interruptions owing to the COVID-19 pandemic. Clinical trial information: NCT03969004.

TPS9593 Background: RP1 is an oncolytic virus (HSV-1) that expresses a fusogenic glycoprotein (GALV-GP R-) and granulocyte macrophage colony stimulating factor (GM-CSF). In preclinical studies, RP1 induced immunogenic tumor cell death and provided potent systemic anti-tumor activity, which is further improved by combining anti-PD-1 therapy. The prognosis for advanced and metastatic cutaneous squamous cell carcinoma (CSCC) remains poor for many patients despite the adoption of cemiplimab and pembrolizumab as a standard treatment. Preliminary results from IGNYTE, a phase I/II clinical study of RP1 in combination with nivolumab showed a high rate of deep and durable responses in patients (pts) with CSCC. This study is evaluating the efficacy and safety of cemiplimab ± RP1 versus cemiplimab alone in advanced CSCC. Methods: This global, multicenter, randomized phase 2 study is enrolling pts with metastatic or unresectable, locally advanced CSCC who are not candidates for/refuse surgery and/or radiation therapy. Key eligibility criteria include no prior treatment with anti-PD1/PD-L1 antibodies or oncolytic viruses. The clinical trial is enrolling approximately 180 pts from centers in the EU, Australia, Canada, and USA. Pts are randomized in a 2:1 ratio to receive combination therapy or monotherapy respectively. Pts receive 350 mg of cemiplimab intravenously (IV) Q3W for up to 108 weeks. In the RP1 + cemiplimab arm, RP1 is injected intratumorally at a starting RP1 dose of 1 × 106 plaque-forming units (PFU)/mL alone, followed by up to 7 doses of RP1 at 1 × 107 PFU/mL Q3W together with the same dose of cemiplimab. Pts in the combination arm may receive up to 8 additional RP1 doses if protocol specific criteria are met. No crossover is allowed. Pts are stratified by disease status (nodal or distant metastatic or locally advanced CSCC) and prior systemic therapy. Tumor assessments are performed every 9 weeks. The dual independent primary endpoints are overall response rate and complete response rate, both by a blinded independent review. Secondary endpoints include safety, progression-free survival, duration of response, and overall survival. Exploratory endpoints include quality of life, and immune biomarker analyses. This trial is currently enrolling pts. Clinical trial information: NCT04050436.

ispartof: ANNALS OF ONCOLOGY vol:32 issue:7 pages:940-941 status: published

Background Activating events along the PI3K/mTOR pathway are common in head and neck squamous cell carcinomas (HNSCC), and preclinical studies suggest additive or synergistic effects when combining mTORC1 inhibitors with carboplatin and paclitaxel chemotherapy. Patients and methods In this single-institution phase II study, the combination of temsirolimus 25 mg, carboplatin AUC 1.5, and paclitaxel 80 mg/m2 administered on days 1 and 8 of a 21-day cycle was evaluated in 36 patients with recurrent and/or metastatic (R/M) HNSCC. The primary end point was objective response rate after two cycles of treatment. Secondary end points include the safety and tolerability profile and overall survival. Correlative studies with exome mutational analysis were performed in pre-treatment biopsy samples from 21 patients. Results Fifteen (41.7%) patients had an objective response, which were all partial responses, and 19 (52.3%) patients had stable disease as best response. The two patients who were designated as ‘non-responders’ were removed from study prior to two cycles of treatment, but are included in the efficacy and safety analyses. The median duration on study was 5.3 months and the median progression-free survival and overall survival were 5.9 months (95% confidence interval, 4.8–7.1) and 12.8 months (95% confidence interval, 9.8–15.8), respectively. The most common grade 3 and 4 adverse events were hematologic toxicities. Three (3.8%) patients developed neutropenic fever on study. Three of four patients with PIK3CA mutations experienced tumor regressions, and responses were also seen in patients with other genetic alterations in the PI3K/mTOR pathway. Conclusion The combination of temsirolimus with low-dose weekly carboplatin and paclitaxel appears to have meaningful clinical efficacy in the treatment of R/M HNSCC. This regimen has a relatively high response rate compared to other treatments evaluated in R/M HNSCC, and potential associations with genetic alterations in the PI3K/mTOR pathway should be further explored.

Purpose: The PARP inhibitor veliparib enhances the cytotoxicity of alkylating agents. This phase I study evaluated veliparib with the bifunctional alkylator bendamustine (VB) in patients with relapsed/refractory lymphoma, multiple myeloma, and solid malignancies, with a cohort expansion of VB with rituximab (VBR) in patients with B-cell lymphomas. Experimental Design: This dose-escalation study evaluated safety, pharmacokinetics, and preliminary efficacy of veliparib (20–400 mg twice a day, days 1–7 of 28-day cycle) and bendamustine (70 and 90 mg/m2 intravenously, days 1 and 2). A cohort expansion was conducted, which combined veliparib and bendamustine at the maximum tolerated dose (MTD) with rituximab (375 mg/m2, day 1) in patients with B-cell lymphomas. Thirty-four patients were treated in seven dose-escalation cohorts and seven patients in the dose-expansion cohort. Results: The MTD was veliparib 300 mg twice daily plus bendamustine 90 mg/m2. Dose-limiting toxicities (DLT) were anemia, nausea, hypertension, and hyperhidrosis. Grade ≥3 toxicities included lymphopenia (87.8%), anemia (19.5%), neutropenia (12.2%), thrombocytopenia (9.8%), leukopenia (9.8%), nausea (7.3%), and hypophosphatemia (7.3%). Apparent veliparib clearance was slightly lower than previously reported. Of 14 patients with lymphoma evaluable for response, five of seven (71%) on VB and six of seven (86%) on VBR achieved objective response. One patient with multiple myeloma achieved partial response. Conclusions: VB and VBR were generally well-tolerated. VBR had preliminary clinical activity in patients with B-cell lymphoma, which warrants further investigation in a phase II trial. This trial was registered at www.clinicaltrials.gov as NCT01326702. Clin Cancer Res; 23(15); 4119–26. ©2017 AACR.

Background Patients with recurrent and/or metastatic, radioactive iodine-refractory thyroid carcinoma have limited treatment options. Sorafenib, an oral kinase inhibitor, is approved by the US Food and Drug Administration for the treatment of radioactive iodine-refractory thyroid carcinoma, although it demonstrated low response rates (12.2%) as a single agent in the first-line setting. The objective of the current study was to determine whether adding the mammalian target of rapamycin inhibitor temsirolimus to sorafenib could improve on these results. Methods In this single-institution, phase 2 study, 36 patients with metastatic, radioactive iodine-refractory thyroid carcinoma of follicular origin received treatment with the combination of oral sorafenib (200 mg twice daily) and intravenous temsirolimus (25 mg weekly). The receipt of prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary endpoint was the radiographic response rate. Results The best response was a partial response in 8 patients (22%), stable disease in 21 (58%), and progressive disease in 1 (3%). Six patients were not evaluable for a response. Patients who had received any prior systemic treatment had a response rate of 10% compared with 38% of those who had not received prior systemic treatment. One of 2 patients with anaplastic thyroid cancer had an objective response. The progression-free survival rate at 1 year was 30.5%. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis. Conclusions Sorafenib and temsirolimus appear to be an active combination in patients with radioactive iodine-refractory thyroid carcinoma, especially in patients who received no prior treatment compared with historic data from single-agent sorafenib. Activity is also observed in patients who previously received sorafenib. This regimen warrants further investigation. Cancer 2017;123:4114-4121. © 2017 American Cancer Society.

e18742 Background: HHIs are the only approved 1L systemic Tx for aBCC. Many pts develop resistance or are intolerant to HHIs and may require second-line (2L) Tx. Little is known about patient outcomes following HHI discontinuation. In this study, we describe characteristics and outcomes among pts with aBCC who discontinued 1L HHIs due to progression or toxicity. Methods: In this retrospective cohort study, we identified adult pts diagnosed with aBCC who discontinued 1L HHI monotherapy between January 2012 and November 2019 in The US Oncology Network (Network), a community-based network of > 450 oncology clinics. Pts with ≥2 Network visits and no Tx for other primary malignancy 3 years prior to index date were included. Structured and unstructured data in the electronic health records were used to extract information on pt characteristics and outcomes. Pts were grouped based on initiation of 2L systemic Tx post-HHI discontinuation into 2L initiators and 2L non-initiators. 2L non-initiators were followed for ≥90 days post-HHIs discontinuation, and those undergoing surgery or radiation during this period (i.e. potential neoadjuvant HHI use) were excluded. Index date was date of 2L Tx initiation for 2L initiators and 90 days post 1L HHI discontinuation for 2L non-initiators. Pts were followed from index date until death, Tx initiation for another primary cancer, loss to follow-up, or end of study (February 1, 2020), whichever occurred first. Pt disposition and outcomes were described separately for each group. Results: We identified 73 aBCC pts who discontinued 1L HHI monotherapy during the specified period. Of those, 19 (26%) pts (4 [21%] 2L initiators and 15 [79%] 2L non-initiators) were included in the study: 12 (63%) were male and 3 (21%) were metastatic at diagnosis, with a mean age of 73 years. Median (range) follow-up time from index date was 10 (3‒42) months for 2L non-initiators and 6 (1‒61) months for 2L initiators. Fourteen (74%) pts discontinued HHI due to toxicity (all 2L non-initiators) and 5 (26%) due to progression (4 2L initiators and 1 2L non-initiator). Median time to discontinuation of 1L HHI was 7 (2‒9) months in 2L non-initiators and 9 (7‒42) months in 2L initiators. 2L initiators received subsequent Tx 2‒130 days following discontinuation of 1L HHI. Time to discontinuation of 2L Tx ranged 4–11 months. Six deaths (32%) were observed during study period (5 2L non-initiators and 1 2L initiator). Conclusions: The short duration of 1L HHI Tx in our small cohort of aBCC pts who did not respond to and/or tolerate HHI is consistent with previous findings. During the study period, limited therapeutic options existed post-HHI, highlighting the unmet need for more effective Tx strategies in a 2L aBCC setting.

e18740 Background: HHIs are the only approved 1L systemic Tx for aBCC and Tx options following HHI Tx failure are limited. The objective of this study was to assess frequency, characteristics, and subsequent Tx patterns of pts with aBCC discontinuing 1L HHIs due to toxicity or disease progression. Methods: We conducted a retrospective cohort study using electronic health records of pts treated in The US Oncology Network (Network), a community-based network of > 450 oncology clinics. We identified adults (18+ years) with aBCC, not treated for another primary malignancy in the past 3 years, with ≥2 Network visits who discontinued 1L HHI monotherapy between January 2012 and November 2019 due to documented toxicity or progression without evidence of complete response (CR) who subsequently initiated second-line (2L) systemic Tx (2L initiators) or not (2L non-initiators). To exclude pts potentially using neoadjuvant HHIs, we required 2L non-initiators to be followed for ≥90 days after HHI discontinuation and excluded pts who underwent surgery or radiation during this period. Index date was Tx initiation for 2L initiators and 90 days after HHI discontinuation for 2L non-initiators. We describe cohort attrition and characteristics of 2L initiators and 2L non-initiators as well as Txs initiated among 2L initiators. Results: We identified 138 aBCC pts treated with HHIs regardless of line of therapy with fully accessible charts: 115/138 (83.3%) received HHIs as 1L systemic therapy for aBCC; 73/115 (63.5%) discontinued 1L HHIs; 37/73 (50.7%) discontinued due to documented toxicity or progression without evidence of CR. 4/37 pts (10.8%) initiated 2L systemic Tx (1 carboplatin & paclitaxel; 1 cemiplimab; 1 nivolumab; 1 pembrolizumab) within a median of 75 days (range: 2‒130) from HHI discontinuation. 2L initiators were 68.7 years of median age (range: 48.4‒71.1); 100% female; 75% White; 75% immunocompetent; 100% treated with 1L vismodegib for a median of 8.6 months (range: 6.8‒42.2); 100% discontinued 1L HHIs due to documented disease progression. We identified 15 2L non-initiators; median age 80.2 years (range: 49.6‒90+); 20% female; 100% White; 86.7% immunocompetent; 100% treated with 1L vismodegib for a median of 6.8 months (range: 1.9‒20.6); 93.3% discontinued 1L HHIs due to documented toxicity and 6.7% due to progression. Conclusions: In this small cohort of aBCC pts discontinuing 1L HHIs, ̃50% discontinued due to toxicity or disease progression. There was no clear standard of care among pts who experienced HHI Tx failure, with only a minority initiating subsequent 2L Tx. Effective Tx strategies for pts who do not respond to or cannot tolerate HHIs are needed.