- Paolo A. Ascierto (Napoli, Italy)
- Salvador Martin Algarra (Pamplona, Spain)
- Ana M. Arance (Barcelon, Spain)
- Piotr Rutkowski (Warsaw, Poland)
LBA70 - Talimogene laherparepvec (T-VEC) in combination (combo) with ipilimumab (ipi) versus ipi alone for advanced melanoma: 3-year landmark analysis of a randomized, open-label, phase II trial (ID 1090)
- Jason A. Chesney (Louisville, United States of America)
Abstract
Background
This is the first and only randomized trial testing the addition of an oncolytic virus to an immune checkpoint inhibitor in advanced melanoma. Previously, the study met its primary endpoint: the combo of T-VEC plus ipi resulted in a significantly higher objective response rate (ORR) vs. ipi alone (39% vs. 18%; odds ratio, 2.9; 95% Cl, 1.5–5.5; P = 0.002) (Chesney et al. J Clin Oncol. 2017). Here, we present results from the 3-year landmark analysis.
Methods
Pts with unresectable, stages IIIB to IV melanoma were randomized 1:1 to receive the combo or ipi alone. T-VEC was injected intratumorally on day 1 of wk 1 at 106 plaque-forming units (PFU)/mL followed by subsequent doses at 108 PFU/mL on day 1 of wk 4, and every 2 wks thereafter. Intravenous ipi (3 mg/kg) was given every 3 wks starting on day 1 of wk 6 for up to 4 doses. Response was assessed by investigators per immune-related response criteria every 12 wks until disease progression. The primary endpoint was ORR; key secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. This analysis occurred 36 months (mos) after the last pt was randomized.
Results
198 pts were randomized (98 to combo; 100 to ipi). As of 25 Feb 2019, the median follow-up time was 40.0 mos in the combo arm and 34.3 mos in the ipi arm. ORR was significantly higher with the combo vs. ipi alone (36.7% vs. 16.0%; odds ratio, 3.0; 95% CI, 1.6 to 6.0; P = 0.002). Median PFS was 13.5 mos with combo and 4.5 mos with ipi (hazard ratio, 0.78; 95% Cl, 0.55–1.11; P = 0.159). Median OS was not reached in either arm (HR, 0.85; 95% CI, 0.55–1.32; P = 0.480). 45 pts (45.9%) in the combo arm and 64 pts (64%) in the ipi arm received subsequent anticancer therapy, with the median time from randomization to the first subsequent therapy being 27.7 mos and 8.3 mos, respectively. No new safety signals were detected.
Conclusions
At the 3-year follow-up, T-VEC plus ipi combo continued to provide durable and statistically superior ORR compared with ipi alone. PFS was numerically longer with the combo than ipi. Survival is likely confounded by subsequent anticancer therapies (NCT01740297).
Clinical trial identification
NCT01740297, release date December 4, 2012.
Editorial acknowledgement
Medical writing assistance was provided by Yang Li (Amgen Inc).
Legal entity responsible for the study
Amgen.
Funding
Amgen.
Disclosure
J.A. Chesney: Advisory / Consultancy, Travel / Accommodation / Expenses: Replimune; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Merck; Research grant / Funding (institution): BMS; Licensing / Royalties, Patents, Royalties, and Other Intellectual Property: University of Louisville. I. Puzanov: Advisory / Consultancy: 4SC; Advisory / Consultancy: Amgen. F. Collichio: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Merck. P. Singh: Advisory / Consultancy: AstraZeneca. M. Milhem: Advisory / Consultancy: Blueprint Medicines; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Amgen; Advisory / Consultancy: Trieza; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Biontech. O. Hamid: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Genentech; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Sanofi/Regeneron; Research grant / Funding (institution): Arcus; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): CytomX; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Iovance; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): NextCure; Research grant / Funding (institution): Parker; Research grant / Funding (institution), Additional research funding for institution: Polynoma. : Pfizer. M.I. Ross: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Research grant / Funding (institution), Travel / Accommodation / Expenses: Provectus; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Castle Biosciences. P. Friedlander: Advisory / Consultancy: Regeneron; Advisory / Consultancy: Puma Biosciences; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Aspyrian Therapeutics; Shareholder / Stockholder / Stock options: Incyte; Shareholder / Stockholder / Stock options: Clovis; Shareholder / Stockholder / Stock options: Merrimack Phamaceuticals; Shareholder / Stockholder / Stock options: Allergan. C. Garbe: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Neracare; Honoraria (self), Advisory / Consultancy: Philogen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Sanofi. T. Logan: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Acceleron; Research grant / Funding (institution): Abbott; Research grant / Funding (institution): Abraxis; Research grant / Funding (institution): Argos; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Aveo; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Immatics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Synta; Research grant / Funding (institution): Threshold; Research grant / Funding (institution): Millenium; Honoraria (self), Research grant / Funding (institution), Additional research funding to institution disclosure: Tracon, Cerulean, EMD Serono, Macrogenic, Peloton, Iovance, MedImmune, Dynavax. : Prometheus. A. Hauschild: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): BMS; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD/Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pierre Fabre; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Provectus; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy, Research grant / Funding (institution): Philogen; Advisory / Consultancy, Research grant / Funding (institution): Regeneron; Advisory / Consultancy: OncoSec. C. Lebbe: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self): Pierre-Fabre; Honoraria (self): Pfizer; Honoraria (self): Incyte; Officer / Board of Directors: Aventis. M. Yi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. A. Sharma: Shareholder / Stockholder / Stock options, Full / Part-time employment: Amgen. J.M. Mehnert: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: EMD Serono; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy: Amgen; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Polynoma; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Immunocore; Research grant / Funding (institution): Macrogenics; Research grant / Funding (institution): Incyte. All other authors have declared no conflicts of interest.
1312PD - Safety and efficacy of TRIplet combination of nivolumab (N) with dabrafenib (D) and trametinib (T) [TRIDeNT] in patients (pts) with BRAF-mutated metastatic melanoma (MM): A single center phase II study (ID 5704)
- Elizabeth M. Burton (Houston, United States of America)
Abstract
Background
Although targeted therapies (TT) and immunotherapies (IMT) have improved survival for pts with BRAF V600 mutated stage IV MM, many pts progress and will ultimately die from this disease. Preclinical data has shown that BRAF inhibition (BRAFi) in BRAF-mutated tumors is associated with increased T cell infiltration, supporting the rationale for a clinical combinatorial approach with IMT. Although there are multicentered trials ongoing evaluating this combinatorial approach for pts with untreated MM, there are no approved therapies for pts after TT and IMT failure. Notably, patients with untreated brain metastases (BM) are often excluded from such trials. We hypothesized that N in combination with DT is safe and will demonstrate clinical activity in BRAF-mutated pts refractory to PD1 therapy and in pts with BM.
Methods
We report a single arm phase II study (NCT02910700) of NDT in pts with BRAF-mutated, unresectable stage III or stage IV MM. Prior IMT is allowed, but pts who have received BRAF/MEKi are ineligible. Pts with untreated BM and asymptomatic or mildly symptomatic/requiring stable or decreasing steroids (up to PO dexamethasone of 8 mg or equivalent) are also allowed. Pts received 3mg/kg Q2wks of N (later amended to 480 mg q4wks), 150mg BID of D and 2mg QD of T, all starting on Day 1. The primary objective of this study is to determine safety and efficacy (ORR by RECIST 1.1) of the NDT combination. This study is continuously monitored for safety and futility. Tissue and blood-based samples to assess for correlative studies are also collected.
Results
Following a 6 pts safety run-in which no DLTs were observed, 24 patients in total have received NDT – 18 of which were PD1 refractory. 6 pts have discontinued due to toxicities. 7 of the 18 PD1 refractory pts had untreated BM. Of the 19 total evaluable pts, 15 achieved PR and 2 CR (ORR 89%). 12 PD1 refractory were evaluable for response; 2 achieved CR and 10 PR (ORR 67%).
Conclusions
NDT is well-tolerated and shows promising clinical activity in pts with IMT refractory disease and with BM. Further investigation into the correlatives and mechanisms of action is warranted.
Clinical trial identification
NCT02910700.
Legal entity responsible for the study
The University of Texas, MD Anderson Cancer Center.
Funding
Bristol-Myers Squibb.
Disclosure
R.N. Amaria: Research grant / Funding (institution): Merck. J. Wargo: Honoraria (self): BMS; Honoraria (self): Illumina; Advisory / Consultancy: GSK; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca. M.A. Davies: Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Sanofi Aventis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Merck; Advisory / Consultancy: Vaccinex. H.A. Tawbi: Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Celegene. All other authors have declared no conflicts of interest.
Invited Discussant LBA70 and 1312PD (ID 6880)
- Paolo A. Ascierto (Napoli, Italy)
Q&A led by Discussant (ID 6888)
LBA71 - Phase II multicenter open label study of pembrolizumab and entinostat in adult patients with metastatic uveal melanoma (PEMDAC study) (ID 1989)
- Henrik Jespersen (Göteborg, Sweden)
Abstract
Background
While recent years have seen a revolution in the treatment of metastatic cutaneous melanoma, no treatment has yet been able to demonstrate any prolonged survival in patients with metastatic uveal melanoma. Reports of treatment with immune checkpoint inhibitors in monotherapy have been disappointing. There is preclinical evidence that the effect of immunotherapy may be augmented by epigenetic therapy through mechanisms including enhanced expression of HLA class I and cancer antigens, and suppression of myeloid suppressor cells.
Methods
We performed a multicenter, open label phase II study assessing the efficacy of concomitant use of the PD-1 inhibitor pembrolizumab and the HDAC inhibitor entinostat in 29 adult patients with metastatic uveal melanoma. Eligible patients had histologically confirmed metastatic uveal melanoma, ECOG performance status 0–1, and measurable disease as per RECIST 1.1. Patients received pembrolizumab 200 mg intravenously every third week in combination with entinostat 5 mg orally once weekly. Primary endpoint was objective response rate (ORR). Secondary endpoints include clinical benefit rate (CBR; CR, PR or SD) at 18 weeks, overall survival (OS), and safety assessed by adverse events (AE).
Results
At the data cut off of June 21, 2019, 29 patients had been enrolled and received at least one dose of treatment with a median follow up of 7.7 months. Ninety per cent had liver metastases and 59% had received previous treatment for metastatic disease. A partial response (PR) was observed in 3 patients resulting in an ORR of 10%. Nine patients (31%) had a best overall response of stable disease (SD). Clinical benefit at week 18 was observed in 7 out of 29 patients (24%). Median OS was 11.5 months. Twenty-eight patients (97%) experienced treatment related AEs, and grade 3-4 AEs were reported in 18 patients (62%). There were no treatment related deaths.
Conclusions
The PEMDAC study has demonstrated that combined HDAC- and PD-1-inhibition can result in clinical efficacy in metastatic uveal melanoma with manageable toxicities. The obtained data warrant further investigation to address clinical and immunological characteristics of patients achieving clinical benefit.
Clinical trial identification
NCT02697630 (Registered 3 March 2016). EudraCT: 2016-002114-50.
Legal entity responsible for the study
Sahlgrenska University Hospital, Västra Götaland Region.
Funding
Syndax Pharmaceuticals and Merck & Co. Inc.
Disclosure
R. Olofsson Bagge: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). G. Ullenhag: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). I. Ljuslinder: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). M. Levin: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). U. Stierner: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). L. Ny: Advisory / Consultancy: Merck & Co. Inc. (MSD Sweden). All other authors have declared no conflicts of interest.
LBA72 - Pembrolizumab for recurrent/metastatic cutaneous squamous cell carcinoma (cSCC): Efficacy and safety results from the phase II KEYNOTE-629 study (ID 3622)
- Jean Jacques Grob (Marseille, France)
Abstract
Background
The global, single-arm, phase II KEYNOTE-629 trial (NCT03284424) studied the safety and efficacy of pembrolizumab in patients with recurrent/metastatic (R/M) cSCC.
Methods
Patients with R/M cSCC received pembrolizumab 200 mg Q3W for up to 35 infusions (Grob JJ et al. J Clin Oncol. 2019;37(suppl; abstr TPS9598)). The primary end point was ORR by blinded independent central review per RECIST v1.1. Secondary end points were DOR, DCR, PFS, OS, and safety. DOR, PFS, and OS were estimated using the Kaplan-Meier method. Results of an interim analysis are presented.
Results
Of 105 patients, 76.2% were male, median age was 72 years, 86.7% had previously received ≥1 line of systemic therapy, and 74.3% had previously undergone radiation. At data cutoff (April 8, 2019), median duration of follow-up was 9.5 months (range, 0.4-16.3 months). ORR was 34.3% (95% CI, 25.3%-44.2%); 4 patients (3.8%) achieved CR (95% CI, 1.0%-9.5%), and 32 patients (30.5%) achieved PR (95% CI, 21.9%-40.2%). Median DOR was not reached (range, 2.7-13.1+ months). Of the 36 responders, 31 patients and 7 patients had a minimum follow-up of 6 months and 12 months, respectively, after achieving response; 25 (79.5%) and 1 (65.6%) were estimated to have ongoing responses at > 6 months and >12 months, respectively. DCR (CR + PR + stable disease ≥12 weeks) was 52.4% (95% CI, 42.4%-62.2%). Median PFS was 6.9 months (95% CI, 3.1-8.5 months); 12-month PFS rate was 32.4%. Median OS was not reached (95% CI, 10.7 months-not reached); 12-month OS rate of 60.3%. Treatment-related adverse events (TRAEs) occurred in 70 patients (66.7%), and 6 patients (5.7%) had grade 3-5 TRAEs; 1 patient died of treatment-related cranial nerve neuropathy. The most common TRAEs were pruritus (14.3%), asthenia (13.3%), and fatigue (12.4%).
Conclusions
Pembrolizumab demonstrated a clinically meaningful ORR (34.3%), durable responses, and remarkable PFS and OS in patients with R/M cSCC, most of whom were heavily pretreated. Treatment was well tolerated, and the safety profile was generally consistent with that of other pembrolizumab monotherapy studies; no new safety signals were identified. These data support pembrolizumab for the treatment of R/M cSCC.
Clinical trial identification
NCT03284424, October 26, 2017.
Editorial acknowledgement
Medical writing and/or editorial assistance was provided by Holly Cappelli, PhD, and Dana Francis, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA).
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Disclosure
J.J. Grob: Honoraria (self): Roche, Novartis, BMS, MSD, Pierre Fabre, Amgen, Sunpharma, Sanofi, Merck, Pfizer; Advisory / Consultancy: Roche, Novartis, BMS, MSD, Pierre Fabre, Amgen, Sunpharma, Sanofi, Merck, Pfizer; Travel / Accommodation / Expenses: Novartis, BMS, MSD, Pierre Fabre. N. Basset-Seguin: Research grant / Funding (institution), Financial contract with St Louis Hospital for the clinical trial: MSD. O. Vornicova: Honoraria (self), Travel / Accommodation / Expenses: BMS; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Travel / Accommodation / Expenses: Roche. J. Schachter: Honoraria (self): BMS; Honoraria (self): Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: MSD. N. Meyer: Advisory / Consultancy, Research grant / Funding (institution), Personal fees: MSD; Advisory / Consultancy, Research grant / Funding (institution), Personal fees: BMS; Advisory / Consultancy, Personal fees: Roche; Advisory / Consultancy, Personal fees: Novartis; Advisory / Consultancy: Incyte; Non-remunerated activity/ies, Personal fees: Sun pharma; Advisory / Consultancy, Personal fees: Pierre Fabre. F. Grange: Advisory / Consultancy: MSD. J.M. Piulats: Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Merck Serono; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Janssen. J. Bauman: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bayer. P.(. Zhang: Full / Part-time employment: Merck & Co., Inc.. B. Gumuscu: Full / Part-time employment: MSD. R.F. Swaby: Full / Part-time employment: Merck & Co., Inc.. B.G.M. Hughes: Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Boehringer. All other authors have declared no conflicts of interest.
LBA73 - SELPAC: A 3 arm randomised phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel (PT) in metastatic uveal melanoma (UM) (ID 3904)
- Paul Nathan (Northwood, Middlesex, United Kingdom)
Abstract
Background
The MAPK pathway is constitutively activated in uveal melanoma (UM), a disease for which there remains no standard of care for metastatic disease. In a randomised phase II clinical trial, selumetinib (AZD6244, ARRY-142886), a MEKi, showed superiority vs dacarbazine (DTIC). A phase III study of the combination of selumetinib (SEL) + DTIC however failed to show superiority over DTIC alone. Pre-clinical data support synergistic cytotoxic activity for MEKi + taxane combinations in a number of cancer cell line models and suggest that interrupting selumetinib before taxane exposure may be beneficial.
Methods
Following ethical approval, 77 patients with metastatic UM who had not received previous chemotherapy were randomised to either A: SEL 75mg bd po B: SEL 75mg bd po + PT 80mg/m2 weeks 1, 2 and 3 (q28) or C: SEL 75mg bd po interrupted for 2 days before exposure to PT 80mg/m2 weeks 1, 2, 3 (q28) at 13 UK and 1 German sites. Primary endpoint was PFS; OS, ORR and toxicity were secondary endpoints. After an amendment, arms B & C were combined and compared to arm A for PFS, OS and ORR using intention to treat analyses. Reflecting the pooled comparison, the sample size was re-adjusted to detect hazard ratio: 0.55, 80% power at 1-sided 5% significance level. Sensitivity analysis was performed to explore whether there were detectable differences in outcome between patients receiving continuous or interrupted SEL in combination with PT (arms B & C).
Results
Primary analysis was triggered after 68 events. The median PFS in the combination arms B & C was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (95% CI: 2.0 - 3.9) in the SEL alone arm A (hazard ratio 0.61 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in arms B & C and A respectively. Median OS in arms B & C was 9 months and was not significantly different from arm A at 10 months (hazard ratio 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469). SAEs and grade 3+ toxicities were similar between treatment arms.
Conclusions
SelPac met its primary endpoint, demonstrating a statistically significant improvement in PFS for SEL + PT without a significant increase in toxicity. No trend for a prolongation of OS was observed.
Clinical trial identification
ISRCTN 29621851.
Legal entity responsible for the study
University of Liverpool & Liverpool Cancer Trials Unit.
Funding
Cancer Research UK and AstraZeneca.
Disclosure
P. Nathan: Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: AstraZeneca; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: BMS; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Merck; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: MSD; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Immunocore; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Pfizer; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Ipsen; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: 4SC; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Consultancy / advisory board: Roche; Research grant / Funding (self), Audit: Pfizer; Leadership role, Non-remunerated activity/ies, Chair: NCRI Bladder and Renal CSG; Leadership role, Non-remunerated activity/ies, Steering Committee and Uveal Melanoma Lead: EORTC Melanoma Group; Leadership role, Non-remunerated activity/ies, IRCI UK Uveal Melanoma Lead: IRCI UK . P.G. Corrie: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker fees and Advisory Boards: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker fees and Advisory Boards: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker fees and Advisory Boards: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker fees and Advisory Boards: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Advisory Board: Incyte; Honoraria (self), Advisory / Consultancy, Consultancy : LifeArc; Honoraria (self), Advisory / Consultancy, ISDMC membership: Celgene; Shareholder / Stockholder / Stock options, Stock ownership: Genesiscare; Research grant / Funding (institution), Commercial-sponsored clinical trials: BMS; Research grant / Funding (institution), Commercial-sponsored clinical trials: MSD; Research grant / Funding (institution), Commercial-sponsored clinical trials: Celgene; Research grant / Funding (institution), Commercial-sponsored clinical trials: Array Pharmaceuticals; Research grant / Funding (institution), Commercial-sponsored clinical trials: Immunocore; Research grant / Funding (institution), Commercial-sponsored clinical trials: Novartis; Research grant / Funding (institution), Grant for investigator led trials: Celgene; Non-remunerated activity/ies, UK Chief Investigator for clinical trials sponsored by Halozyme: Halozyme; Non-remunerated activity/ies, UK Chief Investigator for clinical trials sponsored by Novartis: Novartis; Non-remunerated activity/ies, UK Chief Investigator for clinical trials sponsored by BMS: BMS; Leadership role, Non-remunerated activity/ies, Chair : NCRI pancreatic cancer workstream. S. Danson: Honoraria (self), Speaker Bureau / Expert testimony, Speaker bureau, lecturer: Amgen; Honoraria (self), Travel / Accommodation / Expenses, Conference attendance and travel: MSD; Honoraria (self), Travel / Accommodation / Expenses, Conference attendance and travel: BMS; Honoraria (self), Advisory / Consultancy, Consultancy: GSK; Honoraria (self), Advisory / Consultancy, Consultancy: Incanthera; Honoraria (self), Travel / Accommodation / Expenses, Conference attendance and travel: AbbVie; Honoraria (self), Advisory / Consultancy, Advisory board: MSD; Honoraria (self), Advisory / Consultancy, Advisory board: BMS; Honoraria (self), Honararium: Aquarius; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: BMS; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: MSD; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Boehringer; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Virttu; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Amgen; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Novartis; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Sierra; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Bayer; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Lilly; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: AstraZeneca; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Astex; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: Immunocore; Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: NeRRe therapeutics; Leadership role, NIHR National specialty head for cancer; early phase trials (renumerated for 4 hours per week) : NIHR ; Leadership role, Sheffield ECMC Lead - funding from CRUK and Department of Health: Sheffield Experimental Cancer Medicine Centre (ECMC); Research grant / Funding (institution), Multiple clinical trials run by the University of Sheffield: GSK. J. Evans: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker, Advisory Board: BMS; Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker, Advisory Board: Eisai; Honoraria (institution), Speaker Bureau / Expert testimony, Speaker: Bayer; Honoraria (institution), Speaker Bureau / Expert testimony, Speaker: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker, Advisory Board: Celgene; Honoraria (institution), Speaker Bureau / Expert testimony, Speaker: MSD; Honoraria (institution), Advisory / Consultancy, Advisory Board: Nucana; Honoraria (institution), Advisory / Consultancy, Advisory Board: Modulate Therapeutics; Honoraria (institution), Advisory / Consultancy, Chair ISDMC: Genmab; Honoraria (institution), Advisory / Consultancy, Member TSC: BMS; Honoraria (institution), Advisory / Consultancy, Leadership role, Membership of advisory board (honorarium payments to employing institution): Karus Therapeutics; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: AstraZeneca; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Basilea; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: BMS; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Bayer; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Celgene; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: MSD; Honoraria (institution), Leadership role, Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Mina Therapeutics; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Roche; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Medovia; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Pfizer; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Sierra; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Verastem; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Lilly; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Eisai; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Nucana; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: GSK; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Novartis; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Immunocore; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Bicycle therapeutics; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Halozyme; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Berg; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Johnson and Johnson; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Cytomx; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Beigene; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Vertex; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Plexxikon; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Biolinerx; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Boehringer; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Athenex; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Lion / Iovance; Research grant / Funding (institution), Institutional financial interests - all payable to institution for commercial clinical trials: Adaptimmune; Leadership role, Non-remunerated activity/ies, Clinical expert review panel, Clinical research committee, ECMC - industry alliance joint SC: Cancer Research UK; Leadership role, Non-remunerated activity/ies, NCRI Upper GI Clinical Group, member of occular and pancreas subgroup: NCRI; Leadership role, Non-remunerated activity/ies, Chair - catalyst committee: Breast Cancer Now; Leadership role, Non-remunerated activity/ies, Member of the grants panel : Pancreatic Cancer Research Fund; Leadership role, Non-remunerated activity/ies, EORTC GI group member: EORTC; Honoraria (institution), Leadership role, Clinical subjects editor, honorarium payable to institution : British Journal of Cancer; Leadership role, Non-remunerated activity/ies, Chair, ISDMC: Wales Clinical Trials Unit; Leadership role, Non-remunerated activity/ies, Abstract reviewer committee: ILCA; Non-remunerated activity/ies, Member: British Association for Cancer Research; Non-remunerated activity/ies, Member : European Association for Cancer Research; Non-remunerated activity/ies, Member: Association of Cancer Physicians ; Non-remunerated activity/ies, Member: ESMO; Non-remunerated activity/ies, Member: ASCO; Non-remunerated activity/ies, Member: AACR; Travel / Accommodation / Expenses, Support to attend conferences : BMS; Travel / Accommodation / Expenses, Support to attend conferences: MSD; Travel / Accommodation / Expenses, Support to attend conferences : Eisai; Travel / Accommodation / Expenses, Support to attend conferences: Bayer; Travel / Accommodation / Expenses, Support to attend conferences : Roche; Travel / Accommodation / Expenses, Support to attend conferences : Celgene; Advisory / Consultancy, Chair - review panel of clinical trial centres programme: Institut National Du Cancer . S. Ochsenreither: Honoraria (self): BMS; Honoraria (self): MSD; Honoraria (self): Merck; Honoraria (self): Ipsen; Honoraria (self): Janssen; Honoraria (self): CureVac; Honoraria (self): Glenmark; Honoraria (self): Incyte. J.M.G. Larkin: Honoraria (self), Advisory / Consultancy, Consultancy: Achilles; Honoraria (self), Advisory / Consultancy, Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy, Consultancy: Boston Biomedical; Honoraria (self), Advisory / Consultancy, Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Consultancy : Eisai; Honoraria (self), Advisory / Consultancy, Consultancy: EUSA Pharma; Honoraria (self), Advisory / Consultancy, Consultancy: GSK; Honoraria (self), Advisory / Consultancy, Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy, Consultancy: Imugene; Honoraria (self), Advisory / Consultancy, Consultancy: Incyte; Honoraria (self), Advisory / Consultancy, Consultancy: iOnctura; Honoraria (self), Advisory / Consultancy, Consultancy: Kymab; Honoraria (self), Advisory / Consultancy, Consultancy: Merck Serono; Honoraria (self), Advisory / Consultancy, Consultancy: MSD; Honoraria (self), Advisory / Consultancy, Consultancy: Nektar; Honoraria (self), Advisory / Consultancy, Consultancy: Novartis; Honoraria (self), Advisory / Consultancy, Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy, Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Consultancy: Roche/Genentech; Advisory / Consultancy, Consultancy: Secarna; Research grant / Funding (institution), Currently 3 studies estimated total for these studies: £290K: Novartis; Research grant / Funding (institution), Currently 13 studies estimated total for these studies up to £1.7M: BMS; Research grant / Funding (institution), Currently 4 studies estimated total for these studies up to present: £178: Roche; Research grant / Funding (institution), Currently 4 studies estimated total for these studies up to present: £470K: Pfizer; Research grant / Funding (institution), Currently 1 study estimated total for these studies up to present: £275K: Covance; Advisory / Consultancy, Currently 1 study estimated total for these study up to present: £30K: Immunocore; Advisory / Consultancy, Currently 1 study estimated total for these study up to present: £20K: Pharmacyclics; Research grant / Funding (institution), Currently 1 study estimated total for these study up to present: £40K: Aveo; Research grant / Funding (institution), Currently 1 study estimated total for these study up to present: £20K: Nektar Therapeutics; Research grant / Funding (institution), Currently 4 studies estimated total for these studies up to present: £200K: Merck, Sharp & Dohme Limited (MSD); Research grant / Funding (institution), Currently 1 study estimated total for these study up to present: £100K: Achilles Therapeutics. I. Karydis: Honoraria (self), Advisory / Consultancy, Consultancy, public speaking : Delcath Inc; Honoraria (self), Advisory / Consultancy, Advisory board: Merck Serono ; Honoraria (self), Advisory / Consultancy, Public speaking : Pierre Fabre Ltd. N.M. Steven: Honoraria (institution), Speaker Bureau / Expert testimony, Fee for speaking paid to employees: Merck Serono; Leadership role, Non-remunerated activity/ies, Chair melanoma subgroup NCRI skin cancer CSG. member of same CSG: NCRI. R. Plummer: Honoraria (self), Advisory / Consultancy: Pierre Faber; Honoraria (self), Advisory / Consultancy: Genmab; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Octimet; Honoraria (self), Advisory / Consultancy: Clovis Oncology; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Karus Therapeutics; Honoraria (self), Advisory / Consultancy: Biosceptre; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy, Honoraria for attending advisory boards: Sanofi Aventis; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: AstraZeneca; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: Novartis; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: Bayer; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: Tesaro ; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: BMS; Honoraria (self), Speaker Bureau / Expert testimony, Honoraria for giving educational talks: Expert Medical Events ; Licensing / Royalties, Discretionary payment from Newcastle University (royalty payments received Clovis Oncology): Newcastle University; Research grant / Funding (self), Part funding of CASE PhD studentship: AstraZeneca; Research grant / Funding (institution), Clinical trial costs from multiple trial sponsors to cover costs of clinical investigators: Sponsor’s; Non-remunerated activity/ies, Principal Investigator on multiple trials with multiple sponsors (>30 over last 2 years): Sponsor’s. P. Patel: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Speaker & Ad hoc Advisory Board: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Ad hoc Advisory Board: Novartis; Honoraria (self), Advisory / Consultancy, Ad hoc Advisory Board: Eisai; Honoraria (self), Advisory / Consultancy, Ad hoc Advisory Board: Merck; Honoraria (self), Speaker Bureau / Expert testimony, Speaker: Pfizer; Honoraria (self), Advisory / Consultancy, Ad hoc Advisory Board: Ipsen; Research grant / Funding (institution), Research funding: Scancell; Non-remunerated activity/ies, PI for clinical trial sponsored by Scancell: Scancell; Leadership role, Non-remunerated activity/ies, Head of Division of Cancer & Stem Cells, University of Nottingham: Cancer & Stem Cells, University of Nottingham; Leadership role, Non-remunerated activity/ies, Chairman of NCRI, Skin Cancer Study Group: NCRI, Skin Cancer Study Group. H.M. Shaw: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory/consulting/speakers bureau: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory/consulting/speakers bureau: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory/consulting/speakers bureau: BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory/consulting/speakers bureau: Sanofi-Genzyme; Research grant / Funding (institution), Clinical trial funding: Novartis; Research grant / Funding (institution), Clinical trial funding: Sanofi-Genzyme; Research grant / Funding (institution), Clinical trial funding: Genmab; Research grant / Funding (institution), Clinical trial funding: Roche; Research grant / Funding (institution), Joint working project - project manager funding: BMS; Research grant / Funding (institution), Joint working project - NMP funding: Novartis; Research grant / Funding (institution), Data manager funding: Immunocore; Non-remunerated activity/ies, Principal Investigator: Novartis; Non-remunerated activity/ies, Principal Investigator: Merck; Non-remunerated activity/ies, Principal Investigator: Genmab; Non-remunerated activity/ies, Principal Investigator: Roche; Non-remunerated activity/ies, National Coordinating Investigator: Idera; Non-remunerated activity/ies, National Coordinating Investigator: Iovance; Non-remunerated activity/ies, National Coordinating Investigator : MacroGenics; Non-remunerated activity/ies, Project board - BMS/Mount Vernon - Immuno Pt Pathway: Bristol-Myers Squibb; Non-remunerated activity/ies, Project lead - Novartis/Mount Vernon - Non-Medical Prescriber Clinic: Novartis. S. Leyvraz: Honoraria (self), Advisory / Consultancy, Consultancy: Bayer. C. Rawcliffe: Research grant / Funding (institution), Externally sponsored scientific research grant: AstraZeneca . J.J. Sacco: Honoraria (self), Advisory / Consultancy, Speaker/ presenter/ interview for video: BMS; Honoraria (self), Advisory / Consultancy, Advisory board: MSD; Honoraria (self), Advisory / Consultancy, Advisory board: Delcath; Honoraria (self), Advisory / Consultancy, Advisory board: Amgen; Honoraria (self), Advisory / Consultancy, Speaker : Pierre Fabre; Honoraria (self), Advisory / Consultancy, Advisory board/ consultancy: Immunocore; Research grant / Funding (institution), Trial funding (as co-CI): AstraZeneca; Research grant / Funding (institution), Trial funding (as CI): BMS; Research grant / Funding (institution), Trial funding (local PI): Immunocore; Research grant / Funding (institution), Trial funding (local PI): Replimune; Research grant / Funding (institution), Trial funding (local PI): Amgen ; Research grant / Funding (institution), Trial funding (local PI): MSD; Research grant / Funding (institution), Trial funding (local PI): Delcath; Leadership role, Non-remunerated activity/ies, Member of the H&N clinical studies group: H&N clinical studies group; Travel / Accommodation / Expenses, travel and conference attendance-: BMS; Travel / Accommodation / Expenses, Travel and conference attendance-: MSD. All other authors have declared no conflicts of interest.
LBA74 - Phase II study of neoadjuvant cemiplimab prior to surgery in patients with stage III/IV (M0) cutaneous squamous cell carcinoma of the head and neck (CSCC-HN) (ID 7194)
- Neil Gross (Houston, United States of America)
Abstract
Background
Cutaneous squamous cell carcinoma (CSCC) harbors a high tumor mutation burden (TMB) due to ultraviolet light-mediated DNA damage, and are highly immune-responsive. Cemiplimab, a monoclonal antibody directed against programmed death 1 (PD-1), is approved by the FDA and EMA as treatment for advanced CSCC patients who are not candidates for curative surgery. Here we explore the efficacy of neoadjuvant cemiplimab in CSCC- head and neck (HN) patients for whom surgery and radiation was planned.
Methods
Patients with stage III/IV (M0) (AJCC 8th Ed) CSCC-HN were treated with 2 doses of cemiplimab 350 mg intravenously every 3 weeks prior to surgery. The primary endpoint was overall response rate (ORR) per RECIST v1.1. Secondary endpoints included pathologic response rate, safety and tolerability, and analysis of candidate biomarkers from pre- and post-treatment blood and tumor specimens.
Results
Twenty patients (18M, 2F) enrolled with median age 69 years (range: 42-88) and stage III (n = 8) or IV (n = 12) disease. Seven (35%) patients experienced grade 1 or 2 adverse events (AEs); 6 (30%) grade 1 rash/pruritis, 1 (5%) grade 2 myalgia, and 1 (5%) grade 2 fatigue. There were no grade ≥ 3 AEs and no surgical delays. ORR by RECIST was 30% (6 partial response, 12 stable disease, 2 progressive disease). Pathologic complete response (pCR) was observed in 11 (55%) patients and major pathology response (MPR, ≤ 10% viable tumor) in an additional 3 (15%) patients. TMB and PD-L1 expression analyses in pre-treatment samples are in process. Eleven (55%) patients did not receive planned radiotherapy after surgery based on the pathologic responses. No recurrences have been observed with a median follow up of 3.8 months (range: 1.5-11.2).
Conclusions
Neoadjuvant cemiplimab was well-tolerated and induced a pCR or MPR in 70% of stage III/IV (M0) CSCC patients. A multicenter phase II study is planned to confirm these results and to describe the ability of neoadjuvant cemiplimab to allow less extensive treatment.
Clinical trial identification
NCT03565783.
Legal entity responsible for the study
The University of Texas MD Anderson Cancer Center.
Funding
Regeneron.
Disclosure
N. Gross: Advisory / Consultancy, Research grant / Funding (self): Regeneron; Advisory / Consultancy: PDS Biotechnology; Advisory / Consultancy: Intuitive Surgical. B.S. Glisson: Research grant / Funding (institution): Pfizer; Research grant / Funding (self): ISA Pharmaceuticals. All other authors have declared no conflicts of interest.
Invited Discussant LBA71, LBA72, LBA73 and LBA74 (ID 6881)
- Ana M. Arance (Barcelon, Spain)
Q&A led by Discussant (ID 6885)
LBA75 - 18-months relapse-free survival (RFS) and biomarker analyses of OpACIN-neo: A study to identify the optimal dosing schedule of neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) in stage III melanoma (ID 1739)
- Elisa A. Rozeman (Amsterdam, Netherlands)
Abstract
Background
Primary analysis of the OpACIN-neo study testing 3 dosing schedules of neoadj IPI+NIVO identified 2 cycles IPI 1 mg/kg + NIVO 3 mg/kg (IPI1+NIVO3; arm B) as most favourable, with 20% grade 3-4 irAEs and a pathologic response rate (pRR) of 77%. After a median FU of 8.3 mo none of the pts with a pathologic response versus 9/21 (43%) of the non-responders had relapsed. Here we present updated RFS and biomarker analyses.
Methods
OpACIN-neo is a multicentre, randomized phase II trial in resectable stage III melanoma pts with ≥1 measurable lymph node metastasis (RECIST 1.1). 86 pts were randomized to arm A: 2x IPI3+NIVO1 Q3W (n = 30); B: 2x IPI1+NIVO3 Q3W (n = 30); or C: 2x IPI3 Q3W followed by 2x NIVO3 Q2W (n = 26). Lymph node dissection was planned at wk 6. Primary endpoints were toxicity, radiologic RR and pRR; RFS and biomarker analyses were secondary endpoints. Mutational profiles, gene expression signatures (GES) and immune protein expression were examined in baseline biopsies by whole exome seq, RNA seq and digital spatial profiling (DSP) analysis. Pre- and post-treatment plasma samples were profiled for 92 proteins.
Results
After a median FU of 17.7 mo, the median RFS was not reached in any of the arms. Estimated 18-mo RFS was 85% for all pts (95% CI 78%-93%), 90% for arm A (95% CI, 80%-100%), 82% for arm B (95% CI, 70%-98%) and 83% for arm C (95% CI, 70%-100%). Relapses were observed in 1/64 (2%) pathological responders versus 13/21 (62%) of the non-responders. High tumour mutational burden (TMB) and high interferon-y (IFN-y) signature were associated with pathologic response and favourable RFS. Cytokine and PD-1 levels in plasma increased post-treatment irrespective of response. Additional GES and DSP analysis will be presented.
Conclusions
The 18-mo FU confirms that durable RFS can be achieved with 2 cycles of neoadj IPI+NIVO without any additional adjuvant therapy. Pathologic response remains the strongest marker for RFS. TMB and IFN-y signature might serve as baseline markers identifying pts benefiting from neoadj IPI+NIVO. Neoadj 2 cycles IPI1+NIVO3 should be tested in a randomized phase III study versus adjuvant therapy.
Clinical trial identification
NCT02977052.
Legal entity responsible for the study
Netherlands Cancer Institute.
Funding
BMS.
Disclosure
E.A. Rozeman: Travel / Accommodation / Expenses: NanoString; Travel / Accommodation / Expenses: MSD. A.M. Menzies: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pierre Fabre. O. Krijgsman: Research grant / Funding (institution): BMS. T.M. Van: Travel / Accommodation / Expenses: NanoString. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: MSD-Merck; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. R.A. Scolyer: Advisory / Consultancy: MSD; Advisory / Consultancy: Neracare; Advisory / Consultancy: Novartis. J. Hansson: Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis. G.V. Long: Advisory / Consultancy: Aduro; Advisory / Consultancy: Amgen; Advisory / Consultancy: BMS; Advisory / Consultancy: Mass Array; Advisory / Consultancy: MSD; Advisory / Consultancy: Novartis; Advisory / Consultancy: Oncosec; Advisory / Consultancy: Pierre-Fabre; Advisory / Consultancy: Roche. C.U. Blank: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GSK; Advisory / Consultancy: GenMap; Advisory / Consultancy: Pierre Fabre; Research grant / Funding (institution): NanoString. All other authors have declared no conflicts of interest.
1313PD - 3-year relapse-free survival (RFS), overall survival (OS) and long-term toxicity of (neo)adjuvant ipilimumab (IPI) + nivolumab (NIVO) in macroscopic stage III melanoma (OpACIN trial) (ID 4298)
- Christian U. Blank (Amsterdam, Netherlands)
Abstract
Background
Outcome of high-risk stage III melanoma patients (pts) was poor with a 5-year OS rate of < 50%. Adjuvant (adj) IPI improved 5-year RFS and OS and adjuvant anti-PD-1 improved RFS further. Preclinical data suggested that neoadjuvant (neoadj) treatment might be more favorable due to broader immune activation. The investigator-initiated OpACIN trial compared neoadj with adj IPI + NIVO. Neoadj IPI + NIVO induced a pathologic (path) response in a high percentage of pts (7/9 evaluable pts, 78%). None of the reponders relapsed during the first 2 years, but long-term outcome is pending. Here we present the 3-year landmark safety and survival data.
Methods
Between Augustus 2015 and October 2016, 20 stage IIIB/IIIC melanoma pts with palpable nodal disease were included in the phase Ib feasibility OpACIN trial. Pts were randomized to receive IPI 3 mg/kg + NIVO 1 mg/kg, either adj 4 courses or split 2 courses neoadj and 2 adj. Path response, as reviewed by a blinded pathologist, was defined as < 50% viable tumor cells. Landmark 3-year RFS and OS were estimated using Kaplan Meier method. All efficacy endpoints are descriptive since the study was not powered to compare both arms.
Results
After a median FU of 36.7 months (minimum 28.3 months FU of pts alive) none of the 7 pts with a path response in the neoadj arm have relapsed. Both non-responding pts in the neoadj have relapsed versus 4 pts in the adj arm. One pt has died in the neoadj arm and 3 in the adj arm. The estimated 3-year RFS rate was 80% for the neoadj arm and 60% for the adj arm. The 3-year OS rates were 90% and 67%, respectively. Of the 18 (90%) pts that had developed 1 or more grade 3-4 adverse events all have recovered to ≤ grade 1, except for grade 2 endocrine toxicities needing hormonal supplementation therapy that are ongoing in 8 (50%) of 16 pts alive.
Conclusions
OpACIN was the first trial investigating neoadj IPI + NIVO in pts with macroscopic stage III melanoma, thus having the longest FU. At 3 years FU, no new safety events occurred and none of the pts with a path response have relapsed, suggesting that path response could be considered as surrogate marker for RFS and OS in neoadjuvant checkpoint inhibitor trials.
Clinical trial identification
NCT02437279.
Legal entity responsible for the study
Netherlands Cancer Institute.
Funding
BMS.
Disclosure
C.U. Blank: Advisory / Consultancy: MSD; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy: Roche; Advisory / Consultancy: GSK; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: GenMab; Advisory / Consultancy: Lilly; Research grant / Funding (institution): NanoString; Advisory / Consultancy: Pierre Fabre. J.V. van Thienen: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis. J.B.A.G. Haanen: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: AZ/MedImmune; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Bayer; Advisory / Consultancy: Immunocore; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Neon Therapeutics; Advisory / Consultancy: Celsius Therapautics; Advisory / Consultancy: Gadet; Advisory / Consultancy: GSK. A.C.J. van Akkooi: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: MSD Merck; Advisory / Consultancy: Merck-Pfizer; Advisory / Consultancy: 4SC. T.N. Schumacher: Advisory / Consultancy: Adaptive Biotechnologies; Advisory / Consultancy, Shareholder / Stockholder / Stock options: AIMM Therapeutics; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Allogene Therapeutics; Advisory / Consultancy: Amgen; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Merus; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Neon Therapeutics; Advisory / Consultancy: Scenic Biotech; Research grant / Funding (institution): MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck KGaA; Shareholder / Stockholder / Stock options: Neogene Therapeutics; Shareholder / Stockholder / Stock options, Venture partner: Third Rock Venture. E.A. Rozeman: Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: NanoString. All other authors have declared no conflicts of interest.
Invited Discussant LBA75 and 1313PD (ID 6883)
- Piotr Rutkowski (Warsaw, Poland)
Q&A led by Discussant (ID 6886)
1314PD - Cell phenotypes associated with response and toxicity defined by high resolution flow cytometry in melanoma patients receiving checkpoint inhibition (ID 4560)
- Jeffrey S. Weber (New York City, United States of America)
Abstract
Background
Peripheral blood T cell and myeloid-derived suppressor cells (MDSC), as well as myeloid and macrophage subsets, have been associated with a poor clinical outcome in a variety of cancers. We analyzed circulating cells from patients (pts) that received either nivolumab (NIVO) then ipilimumab (IPI) (cohort A, 16 pts) or IPI then NIVO (cohort B, 17 pts) in a randomized clinical trial to determine if peripheral blood phenotypes were associated either at baseline or on treatment with outcome.
Methods
Frozen peripheral blood mononuclear cells (PBMC) from the ChekMate 064 study were assessed at baseline and on treatment at week 13 for circulating cell subsets by 28-color, high-dimensional flow cytometry with CytoBrute, a rapid computational platform that performs high-parameter Boolean analysis. Correlations with response and survival as well as toxicity were evaluated using the machine learning algorithm ElasticNet.
Results
In cohort B pts the frequency of resting Ki67-, long-lived memory CD45+/CD45RO+/CD127+ T cells was reduced (p = 0.005), and dividing Ki-67+ CD4+/CD45RO+/CD95+ T cells susceptible to apoptosis were increased after IPI (p = 0.007), but were associated at baseline with a poor outcome with cohort A (p = 0.0002). Subsets of myeloid cells that were CD66b+/CD33+/41-BB+/CD86+ at baseline were associated with survival in cohort B (p = 0.0006). A macrophage subset that was PD-L2+/CD163+/41-BBL+/CD40+ was associated with survival for cohort A (p = 0.0001). Additional phenotypes were associated with grade 1 compared with grades 2-4 toxicity that differentiated side effects from either IPI or NIVO, and other phenotypes distinguished normals and pts (AUC=0.96).
Conclusions
A circulating CD4+/CD45RO+/CD95+ proliferating memory T cell phenotype signature is augmented after IPI and is associated at baseline with poor survival with NIVO in CheckMate 064. We discriminated pts and healthy controls with great specificity and sensitivity at baseline, and demonstrated new phenotypes associated with immune-related toxicity. Peripheral blood immune monitoring may be of value in selecting melanoma pts to be treated with immunotherapy.
Clinical trial identification
NCT01783938.
Legal entity responsible for the study
BMS.
Funding
Perlmutter Cancer Center.
Disclosure
J.S. Weber: Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Genentech; Honoraria (self), Advisory / Consultancy: Incyte; Honoraria (self), Advisory / Consultancy: EMD Serono; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Hoffmann-La Roche. S. Hodi: Honoraria (self), Advisory / Consultancy: BMS. M. Wind-Rotolo: Full / Part-time employment: BMS. D. Woods: Shareholder / Stockholder / Stock options: BMS. All other authors have declared no conflicts of interest.
1315PD - Unsorted single-cell RNA sequencing profiles of metastatic melanoma patients reveal the heterogeneity of melanoma-associated fibroblasts (ID 4008)
- Krisztian Homicsko (Lausanne, Vaud, Switzerland)
Abstract
Background
Single cell transcriptomic analyses of the tumor microenvironment provides unprecedented opportunities to guide precision immune therapy of melanoma patients. Previous single-cell RNA sequencing studies in metastatic melanoma patients have shown that the TME composition can be deciphered with a FACS-based single cell assay. Here, we applied droplet-based single-cell RNA sequencing for the decomposition of the tumor microenvironment of metastatic melanoma patients before PD1-based immune therapies and, when possible, during or after PD1 therapy.
Methods
Fresh biopsies and surgical excisions from melanoma patients destined for standard-of-care immune therapy were collected and processed within 2 hours. To capture the global cell composition, cells were not FACS sorted. We performed single-cell RNA sequencing using the 10x Chromium platform. We used both 3’ and 5’ RNA sequencing. Libraries were sequenced at the Campus Biotech platform in Geneva. Standard analytical pipelines were applied (Cell Ranger 3.0, Seurat 2.0).
Results
Our current dataset comprises a total of 26 tumors from 18 patients with a total number of 66’923 cells. The mean number of cells analyzed per patient was 2573 (Range: 160-12’676). Immune TME cell types could be readily identified, but with a significant patient-to-patient heterogeneity. Importantly, melanoma-associated fibroblasts (MAFs) were observed in most tumors (23/26), with an abundance of > 1% in 19 out of 26 tumors. The MAF population, which in total comprised 4722 cells (median 2.1%/tumor, range: 0-59.8%) was heterogeneous and was composed of at least two different sub-clusters. The MAF subtypes were correlated with outcomes from PD1 therapy, with an immune evasion gene signature, and with bulk TCGA melanoma data, as will be presented.
Conclusions
Unsorted single-cell RNA sequencing of fresh human melanoma samples demonstrably provides an insightful snapshot of heterotypic cell compositions. In contrast to previous FACS-based scRNAseq assays, both immune and non-immune components of the tumor microenvironment are efficiently captured. MAFs form a sizeable and heterogenous component of melanoma tumors, heretofore underappreciated in melanoma.
Legal entity responsible for the study
CHUV.
Funding
SystemsX.
Disclosure
All authors have declared no conflicts of interest.
1316PD - Plasma proteomics in patients with metastatic cutaneous melanoma treated with immune checkpoint inhibitors (ID 4800)
- Hanna Eriksson (Stockholm, Sweden)
Abstract
Background
The introduction of immune checkpoint inhibitors (ICIs) or therapies targeting the MAPK-pathway (MAPKis) has significantly improved clinical outcomes in metastatic melanoma patients. Till, a large proportion of the patients become resistant to therapy and there is a need for treatment predictive biomarkers. The aim of this study was to analyze the treatment predictive biomarkers based on the plasma proteome of patients with metastatic melanoma treated with ICIs.
Methods
We analyzed serial plasma samples from 48 patients with metastatic melanoma collected; 24 patients were treated with ICIs and with MAPKis as a control group. A non-biased, high-resolution isoelectric focusing of peptides-liquid chromatography-mass spectrometry (HiRIEFLC-MS/MS)-based method, and with proximity ligation assays (PEA) targeting 92 immuno-oncology-related proteins were used. We analyzed the change in protein levels during treatment with a paired t-test, and their association with progression free survival (PFS) with Cox proportional hazards models.
Results
HiRIEFLC-MS/MS detected 1,835 proteins. We detected statistically-significant log2-fold-changes in 109 protein levels out of 1,160 proteins tested (not corrected for multiple testing). PDCD-1 had the highest log2-fold change (FC = 1.27) after treatment (p = 0.02). After stratifying for treatment type, PDCD-1 levels increased in patients treated with ICIs (FC = 2.13, p = 0.0008), but not in MAPKis-treated patients. PEA analyses confirmed this observation. The PEA panel showed association between 44 proteins and shorter PFS (pcoefficient <0.05, pLRT<0.05, qLRT<0.05), among them: LGALS1, CSF1, VEGFA, CASP8, CCL2, TNFSF14, ANGPT2, IL10, IL6, and ADGRG1. Of these, increase in plasma levels during treatment of LGALS1, CCL2 and ADGRG1 were associated with longer PFS. HiRIEF LC-MS/MS detected 69 proteins associated with PFS (pcoefficient< 0.05, pLRT< 0.05, qLRT < 0.05).
Conclusions
By using HiRIEFLC-MS/MS, we could detect putative treatment predictive proteins in plasma from patients with metastatic melanoma treated with ICIs. Our findings require further validation.
Legal entity responsible for the study
The authors.
Funding
The Swedish Cancer Society, The Radiumhemmet research funds, the Swedish Medical Society of Research, The Swedish Medical Society, Waldenström fund.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 1314PD, 1315PD and 1316PD (ID 6884)
- Salvador Martin Algarra (Pamplona, Spain)