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- Teresa M. Amaral (Tübingen, Germany)
- Enrique Espinosa (Madrid, Spain)
LBA48 - Pathologic response and exploratory analyses of neoadjuvant-adjuvant versus adjuvant pembrolizumab (PEM) for resectable stage IIIb-IV melanoma from SWOG S1801
- Sapna Patel (Houston, United States of America)
Abstract
Background
Primary efficacy results from SWOG S1801 showed an improved event-free survival (EFS) in patients who received neoadjuvant-adjuvant (NAT) PEM compared to adjuvant (AT) PEM. In pooled analyses and smaller neoadjuvant studies, pathologic response has been suggested as an important surrogate marker of clinical outcome.
Methods
S1801 was a randomized phase II trial for clinically detectable, resectable AJCC 8th edition stage IIIB-IV melanoma. Participants were randomized 1:1 to AT PEM (surgery then 18 doses of PEM q3w) or NAT PEM (3 doses pre-operative PEM, surgery, 15 doses PEM q3w). Sites submitted surgical specimens for central review. For determination of pathologic response to NAT, these specimens were assessed for percentage of necrosis and viable tumor by a single pathologist blind to the clinical results.
Results
As of August 31, 2023, 281 participants had surgery (138 NAT, 143 AT). Of those randomized to NAT, 109 specimens were reviewed for pathologic response, 89 were lymph node specimens. Pathologic response and recurrence-free survival (RFS) outcomes for these lymph node specimens are shown in the table. 130 of 138 NAT participants who underwent surgery had RECIST response data; 15 (12%) achieved complete response (CR), 50 (38%) partial response (PR) for an overall response rate of 50%; 50 (38%) experienced stable disease (SD), and 15 (12%) progression of disease (PD). 1RFS measured from date of surgery
NAT N=89 pathologic complete response (pCR) 36 (40%) pathologic near complete response (pnCR) 10 (11%) pathologic partial response (pPR) 26 (29%) pathologic non-response (pNR) 17 (19%) N=89 pCR (n=36) 97% (92-100) pnCR (n=10) 80% (59-100) pPR (n=26) 73% (58-92) pNR (n=17) 48% (28-82) N=130 CR (n=15) 93% (82-100) PR (n=50) 89% (81-99) SD (n=50) 64% (52-80) PD (n=15) 67% (47-95)
Conclusions
The use of NAT with single-agent PEM in resectable stage IIIB-IV melanoma results in a 51% major pathologic response rate (pCR + pnCR) with 40% pathologic complete responses. 2-year RFS rates are highest in those achieving pathologic or radiographic response.
Clinical trial identification
NCT03698019.
Legal entity responsible for the study
SWOG.
Funding
SWOG, Merck Sharp & Dohme.
Disclosure
S. Patel: Financial Interests, Personal, Advisory Board: TriSalus, Cardinal Health, Castle Biosciences, Novartis, BMS, Pfizer, Immatics; Financial Interests, Personal, Other, Consultant for educational materials: Advance Knowledge in Healthcare; Financial Interests, Personal, Advisory Board, Advisory Board and Corporate Day speaker (unbranded): Delcath; Financial Interests, Personal, Other, Independent Data Monitoring Committee: Immunocore; Financial Interests, Personal, Other, Consultant: Guidepoint Global; Financial Interests, Institutional, Trial Chair: Provectus Biopharmaceuticals, Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Lyvgen, InxMed, Foghorn Therapeutics, Ideaya, Novartis, Seagen, Syntrix Bio; Financial Interests, Institutional, Steering Committee Member: TriSalus Life Sciences; Non-Financial Interests, Member: ASCO, AACR, International Society of Ocular Oncology, Society for Melanoma Research; Non-Financial Interests, Leadership Role: SWOG. C.D. Lao: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Institutional, Local PI, Research funding: BMS, Novartis, Genentech, Oncosec. A. Hegde: Financial Interests, Institutional, Local PI: BeiGene, Jounce Therapeutics, Cytomx Therapeutics, Calithera Biosciences Inc, AstraZeneca Pharmaceuticals LP, Arcus Biosciences Inc, Takeda Pharmaceuticals Company Ltd, AbbVie Inc. E. Buchbinder: Financial Interests, Personal, Advisory Board: Instilbio, Nektar, Novartis, BMS, Iovance, Merck, Sanofi, Xilio; Financial Interests, Institutional, Coordinating PI: Genentech, Partners therapeutics; Other, Spouse employment: AstraZeneca, Takeda. V.K. Sondak: Financial Interests, Personal, Advisory Board: Merck, Bristol Myers Squibb, Iovance, OncoSec, Regeneron, Ultimovacs; Financial Interests, Personal, Other, Independent Data Safety Monitoring Committee: Alkermes, Novartis; Financial Interests, Personal, Other, Independent medical monitor for clinical trial: Genesis Drug Discovery & Development; Financial Interests, Institutional, Research Grant, Research grant to institution: Turnstone Biologics; Financial Interests, Institutional, Coordinating PI, Per patient funding to institution to support clinical trial: Skyline DX; Financial Interests, Institutional, Local PI, Research grant to institution: Neogene Therapeutics. A. Ribas: Financial Interests, Personal, Advisory Board, Honoraria for consulting: Amgen, Astra-Zeneca, Merck, Novartis, Jazz; Financial Interests, Personal, Advisory Board, Member of the Scientific Advisory Board: Apricity, Appia, Arcus, Compugen, Immpact, Lutris, MapKure, Merus, PACT Pharma, Synthekine, Tango; Financial Interests, Personal, Member of Board of Directors, Member of the Board of Directors: Arcus, Lutris, PACT Pharma; Financial Interests, Personal, Stocks/Shares, Stock ownership: 4C Biomed, Apricity, Appia, Arcus, Compugen, Highlight, ImaginAb, Immpact, Immunesensor, Inspirna, Isoplexis, Lutris, MapKure, Merus, Pluto, Synthekine, PACT Pharma, Tango, Advaxis, CytomX, RAPT, Kite-Gilead; Financial Interests, Personal, Advisory Board: Arsenal Bio; Financial Interests, Institutional, Funding: Agilent, Bristol-Myers Squibb; Non-Financial Interests, Advisory Role, Member of the scientific advisory board: Highlight, Immunesensor, Inspirna, Pluto. V. Prieto: Financial Interests, Personal, Other, Consultant: Orlucent, Merck, Castle Biosciencies, Novartis. All other authors have declared no conflicts of interest.
LBA49 - mRNA-4157 (V940) individualized neoantigen therapy + pembrolizumab vs pembrolizumab in high-risk resected melanoma: Clinical efficacy and correlates of response
- Jeffrey S. Weber (New York City, United States of America)
Abstract
Background
In patients (pts) with resected high-risk stage IIIB–IV melanoma, mRNA-4157 + pembrolizumab (pembro) extended recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) vs pembro alone (phase 2 KEYNOTE-942; NCT03897881). Minimal residual disease (MRD; by plasma circulating tumor DNA [ctDNA]) at treatment onset was associated with shorter RFS. We examined ctDNA longitudinal dynamics and associated clinical outcomes and report impact of ctDNA status on BRAF subgroup.
Methods
Pts were assigned to mRNA-4157 + pembro or pembro alone. RaDaR® (Inivata) was used to measure plasma ctDNA during treatment and at follow-up. The table defines longitudinal ctDNA molecular responders (MRs) and non-responders (MNRs). BRAF status was derived from whole exome sequencing of baseline tumor tissue. Kaplan–Meier method was used to estimate RFS and DMFS. Cox proportional hazards regression was used to estimate HRs.
Results
142/157 pts were evaluable for longitudinal ctDNA analyses (100/107 mRNA-4157 + pembro; 42/50 pembro alone). Across treatment arms, pts with available ctDNA and recurrence events were limited (n=30). 57% (8/14) of MRs and 94% (15/16) of MNRs had recurrence. Local recurrence was more common in MRs; MNRs had more distant events. This trend was supported by stronger separation in DMFS vs RFS between MRs and MNRs. There was a trend for enhanced efficacy of mRNA-4157 + pembro across BRAF V600E/K WT (n=96) (HR [95% CI]: 0.808 [0.366–1.784]) and MUT (n=61) subpopulations (0.332 [0.130–0.850]); however, considering ctDNA status by focusing on ctDNA-negative subpopulation increased similarity of efficacy across BRAF WT (n=68) and MUT (n=42) subgroups (0.334 [0.121–0.923] vs 0.069 [0.009–0.563]).
ctDNA subgroup Patient criteria Molecular responders Patients with MRD at baseline that resolved during treatment (ctDNA positive at treatment initiation became ctDNA negative) OR Patients with no MRD at baseline that became ctDNA positive on treatment (MRec), and then ctDNA negative again Molecular non-responders Patients with MRD at baseline that did not resolve during treatment (ctDNA positive at treatment initiation and stayed positive) OR Patients with no MRD at baseline who showed molecular progression (MRec, ctDNA negative at treatment initiation became ctDNA positive and stayed positive)
Conclusions
These results suggest a potential relationship between ctDNA dynamics and treatment outcomes in pts with high-risk resectable melanoma and support further exploration in upcoming planned studies.
Clinical trial identification
NCT03897881.
Editorial acknowledgement
Medical writing and editorial assistance were provided by Caudex, a division of IPG Health Medical Communications, New York, NY, USA in accordance with Good Publication Practice 2022 guidelines, funded by Moderna Inc., and under the direction of the authors.
Legal entity responsible for the study
Moderna TX.
Funding
Moderna Tx.
Disclosure
J.S. Weber: Financial Interests, Personal, Advisory Board, Ad Boards: BMS; Financial Interests, Personal, Advisory Board: Merck, GSK, Incyte, Genentech, Pfizer, Biond, OncoC4, AstraZeneca, Regeneron, ImCheck, Novartis; Financial Interests, Personal, Stocks/Shares: Biond, Evaxion, Instil Bio, OncoC4; Financial Interests, Personal, Royalties: Moffitt Cancer Center; Financial Interests, Institutional, Local PI: BMS, Regeneron; Financial Interests, Institutional, Coordinating PI: Merck, Novartis; Non-Financial Interests, Principal Investigator: Moderna, BMS; Non-Financial Interests, Member: ASCO. A. Khattak: Financial Interests, Personal, Funding: BMS. M. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, Oncosec, Merck, Sanofi, Ideaya, Pierre-Fabre, Eisai, Nektar, Regeneron. R.J. Sullivan: Financial Interests, Personal, Advisory Board: Merck, Novartis, Bristol Myers Squibb, Eisai, Iovance, Oncosec, Pfizer, Replimmune, Marengo; Financial Interests, Personal, Royalties: Up-to-date; Financial Interests, Institutional, Research Grant: Merck; Financial Interests, Institutional, Local PI: GSK, Sanofi, Moderna, BiomedValley DIscoveries, Astex, Compugen, Beigene, Novartis, Rubius, Alkermes, Synthekine; Financial Interests, Institutional, Coordinating PI: Pfizer, Roche-Genentech, Simcha Therapeutics, OnKure, Marengo. J.J. Luke: Financial Interests, Personal, Advisory Board: Amgen, Evaxion, Bayer, Eisai, EMD Serono, Janssen, Castle, BMS, Arch Oncology. M. Taylor: Financial Interests, Personal, Advisory Board: BMS, Eisai, Novartis, Merck, Bayer, Sanofi/Genzyme, Regeneron, Loxo, Blueprint, Exelixis. G. Ansstas: Financial Interests, Personal, Advisory Board: BMS, Merck. K. Kim: Financial Interests, Personal and Institutional, Advisory Board: Genetech, BMS, Merck. M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, Eisai, IQVIA, Merck, Moderna; Financial Interests, Personal, Other, Consulting: iTeos; Financial Interests, Institutional, Research Grant: Acentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GSK, IDEAYA Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therpeutics, TMUNITY Therapeutics, TopAlliance Biosciences, Aadi Biosciences, Alpine Immune Sciences, Arcs Biosciences, Bayer, Arvinas, ASCO, Astellas, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono, Erasca, Foghorn Therapeutics, Kechow Pharma, G1 Therapeutics, Gilead Sciences, ImmVira Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid Biosciences, Scholar Rock, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Xilio. M. Faries: Financial Interests, Institutional, Research Grant: Merck, BMS, Pfizer, Amgen. C..L. Cowey: Financial Interests, Institutional, Research Funding: Merck, BMS, Novartis. A. Pecora: Financial Interests, Institutional, Research Funding: Merck, BMS, bayer, eisai, emd serono. V.G. Atkinson: Financial Interests, Personal, Advisory Board: BMS, MSD, Nektar, Novartis, Pierre fabre, QBiotics; Financial Interests, Personal, Invited Speaker: BMS, MSD, Novartis, Pierre Fabre, Limbic; Financial Interests, Personal, Other, Travel Support: BMS. G. Gibney: Financial Interests, Personal, Advisory Board, Limited Consultant Role: Bristol Myers-Squibb, Merck, Lyell, Eisai, Regeneron, Genentech, Sapience Therapeutics; Financial Interests, Personal, Other, Consultant: Novartis; Financial Interests, Personal, Advisory Board, Consultant for data monitoring committee.: Huyabio; Financial Interests, Personal, Advisory Board, Limited role on data monitor committee.: Exicure; Financial Interests, Institutional, Coordinating PI, Support for investigator initiated trial.: Exelixis, Lucerno Dynamics; Financial Interests, Institutional, Local PI, Support for clinical trial: Jounce. E. Buchbinder: Financial Interests, Personal, Advisory Board: Instilbio, Nektar, Novartis, BMS, Iovance, Merck, Sanofi, Xilio; Financial Interests, Institutional, Coordinating PI: Genentech, Partners therapeutics; Other, Spouse employment: AstraZeneca, Takeda. R. Meehan: Financial Interests, Personal, Full or part-time Employment: Moderna TX. G.V. Long: Financial Interests, Personal and Institutional, Research Grant: BMS; Financial Interests, Personal and Institutional, Research Funding: Merck, Pfizer, Amgen, EMD serono. All other authors have declared no conflicts of interest.
1081O - ctDNA reduction and clinical efficacy of the darovasertib + crizotinib (daro + crizo) combination in metastatic uveal melanoma (MUM)
- Meredith Mckean (Nashville, United States of America)
Abstract
Background
MUM has limited effective therapies. Driver mutations in
Methods
Eligibility included RECIST 1.1 measurable disease, ECOG 0-1 and adequate organ function. Dose escalation used a 3 + 3 design with 3 escalation cohorts, followed by expansion at 300 mg BID Daro + 200 mg BID Crizo. Safety, efficacy, and circulating tumor (ct) DNA were assessed.
Results
At 08Mar2023 data cut-off, of 68 MUM pts treated at the expansion dose (safety population (SP)) as of September 2022, 63 were evaluable for response (per-protocol efficacy population (PPEP)). The PPEP had a large tumor burden: 66% with largest metastatic lesion > 3cm, 64% with hepatic + extrahepatic disease, & 60% with elevated LDH. HLA-A2*02:01 status (n=51 tested): 63% neg., 37% pos. In the SP, the most common drug-related adverse events (AEs) (>30%) were diarrhea, nausea, edema, fatigue, hypotension & rash. AEs were largely Grade 1-2. Related Serious AEs were seen in 6 (9%) pts and AEs leading to discontinuation in 4 (6%) pts. In the PPEP, 30% had a confirmed partial response (cPR) with 92% of patients having tumor shrinkage. First-line (1L) pts (n=20) had a cPR of 45% with 95% of patients having tumor shrinkage. Median PFS (mPFS) in both PPEP and 1L pts was ∼7 months. In pts with hepatic only disease (n=20 pts, 1L and pretreated), an ORR of 35% and mPFS was 11 months. Clinical efficacy was seen in both HLA-A2 pos. and neg. pts. There were deep & sustained ctDNA molecular responses in the majority of pts.
Conclusions
Initial evaluation of Daro + Crizo in both 1L & pretreated pts with MUM showed a manageable safety profile and clinical efficacy that appears superior to current standards of care. ctDNA was reduced in almost all pts. These data support the registrational phase II/III study for potential accelerated approval in 1L HLA-A2 neg. MUM, where there are no FDA approved therapies.
Clinical trial identification
NCT03947385.
Legal entity responsible for the study
The authors.
Funding
IDEAYA Biosciences.
Disclosure
M. Mckean: Financial Interests, Institutional, Other, Consulting: Pfizer, Castle Biosciences, Eisai, IQVIA, Merck, Moderna; Financial Interests, Personal, Other, Consulting: iTeos; Financial Interests, Institutional, Research Grant: Ascentage Pharma Group, Bicycle Therapeutics, Dragonfly Therapeutics, Epizyme, Exelixis, Genentech, GSK, IDEAYA Biosciences, Ikena Oncology, Infinity Pharmaceuticals, Jacobio Pharmaceuticals, Moderna, NBE Therapeutics, Novartis, Oncorus, Plexxicon, Prelude Therapeutics, Regeneron, Sapience Therapeutics, Seattle Genetics, Tizona Therapeutics, Tmunity Therapeutics, TopAlliance Biosciences, Aadi Biosciences, Alpine Immune Sciences, Arcs Biosciences, Bayer, Arvinas, ASCO, Astellas, BioMed Valley Discoveries, BioNTech, C4 Therapeutics, EMD Serono, Erasca, Foghorn Therapeutics, G1 Therapeutics, Gilead Sciences, ImmVira Pharma, Kechow Pharma, Kezar Life Sciences, Kinnate BioPharma, MedImmune, Mereo BioPharma, Metabomed, Nektar, OncoC4, PACT Pharma, Pfizer, Poseida, Pyramid Biosciences, Scholar Rock, Synthrox, Takeda Pharmaceuticals, Teneobio, Tempest Therapeutics, Xilio. B. Chmielowski: Financial Interests, Personal, Other, DMC: Nektar; Financial Interests, Personal, Advisory Board: Novartis, Delcath Systems, Instil Bio, Replimune; Financial Interests, Institutional, Local PI, Clinical trial support: Bristol Myers Squibb, Macrogenics, Karyopharm Therapeutics, Infinity Pharmaceuticals, Advenchen Biotherapeutics, Xencor, Compugen, Iovance, PACT Pharma, RAPT Therapeutics, Immunocore, Ascentage, Atreca, Replimune, IDEAYA Biosciences, Instil Bio; Financial Interests, Institutional, Local PI, clinical trial support: Adagene, TriSalus Life Sciences, Kinnate Biopharma, PTC Therapeutics, Xilio Therapeutics, Kezar Life Sciences. M.O. Butler: Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb, Merck, Novartis, Sanofi, Pfizer; Financial Interests, Personal, Advisory Board: Merck, Bristol Myers Squibb, Novartis, Adaptimmune, Instil Bio, Iovance, Sun Pharma, GSK, Sanofi, LaRoche Possey, Pfizer, Medison, IDEAYA, Regeneron; Financial Interests, Personal, Research Grant: Merck, Takara Bio, Novartis. R. Carvajal: Financial Interests, Personal, Advisory Board: Alkermes, Bristol Myers Squibb, Castle Biosciences, Delcath, Eisai, Hengrui, IDEAYA, Immunocore, InxMed, Iovance, Merck, Novartis, OncoSec, Pierre Fabre, Puretech Health, Regeneron, Sanofi, TriSalus. J. Rodon: Financial Interests, Personal, Advisory Board: Ellipses Pharma, iOnctura SA; Financial Interests, Personal, Other, Consultancy: Aadi Bioscience, Clarion Healthcare, Debiopharm, Monte Rosa Therapeutics, Cullgen, Pfizer, Merus N.V., Macrogenics, Oncology One, Envision Pharma, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero de Empleo y Seguridad, Chinese University of Hong Kong, Boxer Capital LLC, Tang Advisors LLC, Incyte; Financial Interests, Institutional, Other, Clinical Research: Novartis, Spectrum Pharmaceuticals, Symphogen, BioAtla, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millennium, GSK; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, Aadi Bioscience, Nuvation, Fore Biotherapeutics, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, IDEAYA, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, Bayer; Other, Travel: European Society for Medical Oncology; Other: VHIO/Ministero de Empleo y Seguridad Social. M. Carlino: Financial Interests, Personal, Advisory Board, Consultant Advisor: MSD, BMS, Novartis, Amgen, OncoSec, Merck, Sanofi, IDEAYA, Pierre Fabre, Eisai, Nektar, Regeneron. K.B. Kim: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Aveo, Regeneron, Sanofi; Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb; Financial Interests, Personal, Stocks/Shares: Arvinas; Financial Interests, Institutional, Funding, Moderna has provided funding to the institution for conducting a clinical trial of Moderna's drug: Moderna. T. Wise-draper: Financial Interests, Personal, Other, Consultant: Shattuck Labs, Need Inc.; Financial Interests, Personal, Advisory Board: Exicure, Rakuten Medical, Merck & Co.; Financial Interests, Personal, Invited Speaker: Physician Education Resource; Financial Interests, Personal, Other, Consultant for Molecular Tumor Board: Caris Life Sciences; Financial Interests, Personal, Ownership Interest: High Enroll; Financial Interests, Personal, Research Grant: BMS, Merck & Co., Tesaro/GSK, AstraZeneca, Janssen; Financial Interests, Personal and Institutional, Local PI: BMS, EMD Serono, Replimune, AstraZeneca, Alkermes, Exicure, Shattuck Labs, Boston Medical, Debio Pharm, Eli Lilly, Epizyme, Iovance, Agenus, SQZ Biotech, Triumvera, Adlai Nortye, Yingli, Vyriad, IDEAYA, MINK, Sinogen. S. Khan: Financial Interests, Personal, Advisory Board: Castle Biosciences, Replimune Inc. A.K.S. Salama: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Iovance, Regeneron, Replimune, Novartis, Pfizer; Financial Interests, Institutional, Local PI: Bristol Myers Squibb, Ascentage, IDEAYA, Immunocore, Merck, Regeneron, Replimune, Seagen; Financial Interests, Institutional, Trial Chair: Olatec. J. Moser: Financial Interests, Personal, Advisory Board: BMS, Amunix, Thirona Bio, Adagene, IQVIA, Incyte, Boxer Capital, Oberland Capital; Financial Interests, Personal, Other, Consultant: Imaging Endpoints; Financial Interests, Personal, Invited Speaker: Immunocore, Caris Life Sciences; Financial Interests, Personal, Other, Molecular Tumor Board Member: Caris Life Sciences; Financial Interests, Institutional, Coordinating PI: Novocure; Financial Interests, Institutional, Local PI: Genentech, Alpine Immune Sciences, Amgen, Trishula Therapeutics, FujiFilm, ImmunSensor, Simcha Therapeutics, Repertoire Immune Sciences, Nektar Therapeutics, Synthorx Inc., Istari Oncology, IDEAYA Biosciences, Rubius Therapeutics, University of Arizona, Senwha Biosciences, Storm Therapeutics, Werewolf Therapeutics, Fate Therapeutics, Y-mab Therapeutics, Agenus; Financial Interests, Personal, Local PI: Bioeclipse Therapeutics. M. Maurer: Financial Interests, Personal, Other, Independent Medical Consultant for ongoing Healthy Volunteer study: The Global Health Drug Discovery Institute (GHDDI); Financial Interests, Personal, Full or part-time Employment, Full time employee of IDEAYA Biosciences; Financial Interests, Personal, Stocks/Shares, Own stock in BMS (BMY): BMS; Financial Interests, Personal, Stocks/Shares, Own stock and stock options in IDEAYA Biosciences (IDYA); Non-Financial Interests, Member, Regular member: ASCO. M. Abed: Financial Interests, Personal, Full or part-time Employment: IDEAYA Biosciences, Zentalis. B. Mitchell: Financial Interests, Personal, Full or part-time Employment, Employee of IDEAYA. Biosciences; Financial Interests, Personal, Stocks/Shares, Employee Stock Options: IDEAYA Biosciences. D. Beaupre: Financial Interests, Personal, Full or part-time Employment, Employee: IDEAYA; Financial Interests, Personal, Stocks/Shares, Stock: IDEAYA; Non-Financial Interests, Leadership Role, CMO of organization: IDEAYA; Non-Financial Interests, Institutional, Proprietary Information, Access to company confidential information: IDEAYA. M. Orloff: Financial Interests, Personal, Advisory Board: Tirsalus, Delcath, Replimune, IDEAYA Biosciences; Financial Interests, Personal, Speaker’s Bureau: Immunocore. All other authors have declared no conflicts of interest.
Invited Discussant LBA48, LBA49 and 1081O
- Teresa M. Amaral (Tübingen, Germany)
Q&A
- All Speakers (Lugano, Switzerland)
1082O - Concurrent intrathecal (IT) and intravenous (IV) nivolumab (N) for melanoma (MM) patients (pts) with leptomeningeal disease (LMD)
- Isabella C. Glitza (Houston, United States of America)
Abstract
Background
Pts with LMD have dismal prognosis and few clinical trial options. We previously reported safety and efficacy of the dose escalation (DE) phase of an open label, single arm, single center phase I/IB trial (NCT03025256) for MM pts with LMD. Concurrent IT/IV N was well tolerated, no new or unexpected CNS toxicities. 50mg IT N was the recommended dose (RD) for expansion accrual. Here we report the updated safety and efficacy results for the escalation and expansion cohorts.
Methods
Study design methods were previously reported (Glitza,
Results
Fifty pts total were treated (48 pts with MM, 2 pts with NSCLC), including 31 pts with IT N 50 mg. Median age at LMD diagnosis was 49 (19-74); 27 pts are male. All pts had radiographic evidence of LMD; 26 pts had positive CSF cytology at baseline. Median follow-up and OS is shown in the table. Safety profile remained consistent with prior reports: 9 pts (18%) experienced gr 3 AEs, none had gr 4 or 5. Nausea (46%), rash (40%), vomiting (34%), diarrhea (20%), and dizziness (20%) were the most common AEs. Thirty pts (60%) experienced AEs after IT N administration, including 2 gr 3 (vasogenic edema, elevated ALT); remainder were gr 1/2.
Med follow up wks (range) Median OS Wks (95% CI) OS 13 wks OS 26 wks OS 52 wks All 27.3 (2, 251) 30 (19, 64) 68% 54% 35% <50 mg 25 (5, 251) 25 (15, 143) 68% 47% 26% 50 mg 30 (2, 140) 41 (13, 65) 68% 58% 43%
Conclusions
This updated analysis confirms the safety of IT (50mg)/IV N. There were no significant differences in OS between the tx groups and no unexpected toxicities were observed at RD. These results support further evaluation of IT immunotherapy strategies for pts with LMD. Insights gained from translational studies on CSF samples will aid in the development of future IT immunotherapy strategies for these patients.
Clinical trial identification
NCT03025256.
Legal entity responsible for the study
The authors.
Funding
Bristol Myers Squibb.
Disclosure
I.C. Glitza: Financial Interests, Institutional, Speaker, Consultant, Advisor: Bristol Meyers Squibb, Array, Novartis, Sintetica; Financial Interests, Institutional, Principal Investigator: Bristol Meyers Squibb, Merck, Pfizer. S. Ferguson: Financial Interests, Institutional, Research Funding: Codiak. H.A. Tawbi: Financial Interests, Institutional, Speaker, Consultant, Advisor: Bristol Meyers Squibb, Genentech, Novartis, Merck, Boxer Capital, Karyopharm, Iovance, Eisai Jazz, Medicenna; Financial Interests, Institutional, Principal Investigator: Bristol Meyers Squibb, Novartis, Merck, Genentech, GSK, EMD Serono, Eisai, Dragonfly Therapeutics, RAPT Therapeutics. M. Davies: Financial Interests, Institutional, Speaker, Consultant, Advisor: Roche/Genentech, Array, Pfizer, Novartis, Bristol Meyers Squibb, GSK, Sanofi-Aventis, Vaccinex, Apexigen, Eisai, ABM Therapeutics; Financial Interests, Institutional, Principal Investigator: Roche/Genentech, GSK, Sanofi-Aventis, Merck, Myriad, Oncothyreon. All other authors have declared no conflicts of interest.
1085O - Atezolizumab, bevacizumab, and cobimetinib (TACo) in patients (pts) with PD1 refractory melanoma brain metastases (MBM)
- Elizabeth Burton (Houston, United States of America)
Abstract
Background
Combination immune checkpoint blockade (ICB) achieves frequent durable responses in pts with untreated MBM. However, systemic treatments (tx) after ICB failure are limited, especially in BRAF wild-type pts. We investigated the novel TACo regimen in ICB- refractory MBM based on biological insights that (1) VEGF can drive ICB resistance, and (2) MEK inhibition can increase MHC I expression and T cell infiltration to potentially synergize with ICB. We hypothesized this regimen would be safe and demonstrate efficacy in pts with MBM.
Methods
In this single-center phase II study evaluating TACo in pts with MBM (NCT03175432), primary objectives included safety and efficacy (intracranial response rate (ICRR) by modified RECIST 1.1). Secondary objectives included IC clinical benefit rate (ICCBR), progression free (PFS) and overall survival (OS), and duration on tx (DoT). Prior PD1 tx and ≥1 non irradiated lesion (5-30mm) were required. BRAF mutated pts were allowed after BRAF/MEK tx (3-month washout). Pts on ≤4m/day PO of dexamethasone or equivalent were allowed. Tx schedule: atezolizumab 840mg IV every 2 weeks (wks), bevacizumab 5mg/kg every 2 wks, cobimetinib 60mg PO daily for 3 wks followed by 1 wk off. MRIs were obtained prior to cycles 1-3, and 5.
Results
Of the 20 pts treated, 70% were male, median age 59.5 yrs (34-78), and 2 pts were BRAFV600E mutated. 11 pts had ≥ 1 prior tx for MBM. Median follow up was 8.2 mos (0.4-39.2). Median DoT was 8 wks (0.6-63.8). 18 pts experienced tx related adverse events (AEs), most commonly rash (70%), diarrhea (D) (55%), hypertension (HTN) (25%), proteinuria (25%). 35% pts had gr 3/4 AEs: HTN (15%), D (10%) were most common. 2 pts stopped tx due to toxicity. 18 pts were evaluable for IC response: ICRR was 39% (1 CR, 6 PR) and ICCBR was 56% (+SD). Median PFS was 2.7 mos (95% CI 0.9,7.3) and median OS was 9.3 (95% CI 3.8,20.9). 7 (35%) pts continued on tx post progression for ≥ 3 wks (3-55 wks).
Conclusions
In this heavily pretreated MBM pt population with no available standard systemic therapy options, TACo regimen was tolerable, demonstrated IC clinical benefit, and provided clinical benefit beyond progression, warranting further evaluation.
Clinical trial identification
NCT03175432.
Legal entity responsible for the study
MD Anderson Cancer Center - PI Hussein Tawbi.
Funding
Genentech.
Disclosure
V. Honaker: Financial Interests, Institutional, Full or part-time Employment, Research nurse: MD Anderson Cancer Center; Financial Interests, Personal, Stocks/Shares: Pfizer. I.C. Glitza: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Array, Novartis, Sintetica; Financial Interests, Institutional, Research Funding: BMS, Merck, Pfizer. R. Amaria: Financial Interests, Personal, Advisory Board: Iovance Biotherapeutics, Novartis, Erasca; Financial Interests, Institutional, Coordinating PI: Merck, Bristol Myers Squibb, Novartis; Financial Interests, Institutional, Local PI: Iovance, Roche; Financial Interests, Institutional, Trial Chair: Obsidian. S. Patel: Financial Interests, Personal, Advisory Board: TriSalus, Cardinal Health, Castle Biosciences, Novartis, BMS, Pfizer, Immatics; Financial Interests, Personal, Other, Consultant for educational materials: Advance Knowledge in Healthcare; Financial Interests, Personal, Advisory Board, Advisory Board and Corporate Day speaker (unbranded): Delcath; Financial Interests, Personal, Other, Independent Data Monitoring Committee: Immunocore; Financial Interests, Personal, Other, Consultant: Guidepoint Global; Financial Interests, Institutional, Trial Chair: Provectus Biopharmaceuticals, Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Lyvgen, InxMed, Foghorn Therapeutics, IDEAYA, Novartis, Seagen, Syntrix Bio; Financial Interests, Institutional, Steering Committee Member: TriSalus Life Sciences; Non-Financial Interests, Member: ASCO, AACR, International Society of Ocular Oncology, Society for Melanoma Research; Non-Financial Interests, Leadership Role: SWOG. A. Diab: Financial Interests, Institutional, Research Funding: BMS. M. Wong: Financial Interests, Personal, Speaker, Consultant, Advisor: Merck, Pfizer, BMS, Regeneron, EMD Serono, ExiCure, Castle Biosciences. J. Mcquade: Financial Interests, Personal, Speaker, Consultant, Advisor: BMS, Merck, Roche. C. Chung: Financial Interests, Personal, Officer, Vice-Chair: Quantitative Imaging Biomarker Alliance RSNA; Financial Interests, Institutional, Coordinating PI, Research funding: Siemens Healthineers; Financial Interests, Institutional, Coordinating PI, Research and Co-development Funding: RaySearch Laboratories; Non-Financial Interests, Leadership Role, Co-Chair of ICRU committee report: International Commission on Radiation Units and Measures (ICRU). J.S. Wefel: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Institutional, Other, Neurocognitive outcomes consultant: GT Medical Technologies, Novocure; Non-Financial Interests, Advisory Role: American Brain Tumor Association; Non-Financial Interests, Leadership Role: International Cognition and Cancer Task Force. M. Davies: Financial Interests, Personal, Advisory Board: Roche, Pfizer, Novartis, BMS, Sanofi-Aventis, GSK, Vaccinex, Apexigen, Eisai, Iovance, Merck, ABM Therapeutics; Financial Interests, Institutional, Coordinating PI: Pfizer; Financial Interests, Institutional, Research Grant: ABM Therapeutics, Lead Pharma, Genentech, GSK, Sanofi-Aventis, Merck, Oncothyreon; Financial Interests, Research Grant: Myriad. H.A. Tawbi: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Merck, Novartis, Genentech, Eisai, Karyopharm, Iovance, Pfizer, Jazz Pharmaceuticals; Financial Interests, Institutional, Trial Chair: Bristol Myers Squibb; Financial Interests, Institutional, Local PI: Merck, RAPT Pharmaceuticals; Financial Interests, Institutional, Steering Committee Member: Novartis, Genentech; Financial Interests, Institutional, Funding: GSK, Eisai. All other authors have declared no conflicts of interest.
Invited Discussant 1082O and 1085O
- Reinhard Dummer (Zurich, Switzerland)
Q&A
- All Speakers (Lugano, Switzerland)