Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma

Abstract

Purpose: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma.

Methods: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers.

Results: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response.

Conclusion: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.

Trial registration: ClinicalTrials.gov NCT02983045.

Conflict of interest statement

Adi DiabHonoraria: Array BioPharmaConsulting or Advisory Role: Nektar, CureVac, Celgene, IderaResearch Funding: Nektar, Idera, Celgene, Pfizer, Merck, ApexigenTravel, Accommodations, Expenses: Nektar Scott S. TykodiConsulting or Advisory Role: Merck, Intellisphere LLC, Natera, Bristol Myers Squibb, ExelixisResearch Funding: Genentech, Bristol Myers Squibb, Merck Sharp & Dohme, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, Clinigen GroupPatents, Royalties, Other Intellectual Property: Patent pending Gregory A. DanielsHonoraria: Sanofi/RegeneronConsulting or Advisory Role: Sanofi/RegeneronSpeakers' Bureau: Regeneron, Array BioPharma, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Amgen, Viralytics, Nektar, Merck Michele MaioStock and Other Ownership Interests: Theravance, Epigen TherapeuticsHonoraria: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma, Sanofi, LillyConsulting or Advisory Role: Bristol Myers Squibb, Roche, AstraZeneca, MSD, Merck, Pierre Fabre, AlfasigmaPatents, Royalties, Other Intellectual Property: DNA hypomethylating agents for cancer therapyTravel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma Brendan D. CurtiHonoraria: Clinigen Group, NektarConsulting or Advisory Role: MerckResearch Funding: Bristol Myers Squibb, Galectin Therapeutics, Clinigen GroupPatents, Royalties, Other Intellectual Property: Biomarkers for OX40 responseTravel, Accommodations, Expenses: Agonox Karl D. LewisHonoraria: Array BioPharma, Iovance BiotherapeuticsConsulting or Advisory Role: Array BioPharma, Merck, Roche, Regeneron, Sanofi, Iovance BiotherapeuticsResearch Funding: Roche/Genentech, Merck, Array BioPharma, Incyte, Nektar, Iovance Biotherapeutics, Bristol Myers Squibb, Kartos Therapeutics, OncoSec, Regeneron, Alkermes, Neon Therapeutics, Ultimovacs, Senhwa Biosciences, Replimune, AmgenTravel, Accommodations, Expenses: Merck, Roche/Genentech, Regeneron, Neon Therapeutics, AlkermesUncompensated Relationships: Roche/Genentech, Regeneron Sekwon JangConsulting or Advisory Role: Bristol Myers Squibb, EMD Serono, Novartis, Sanofi, Sun Biopharma, Genentech Ewa KalinkaHonoraria: Bristol Myers Squibb, MSD, AstraZeneca, Regeneron, Nektar, RocheConsulting or Advisory Role: Bristol Myers SquibbSpeakers' Bureau: Bristol Myers Squibb, RocheResearch Funding: Bristol Myers Squibb, Merck Sharp & Dohme, Nektar, AstraZeneca, RocheTravel, Accommodations, Expenses: Roche Igor PuzanovStock and Other Ownership Interests: CelldexConsulting or Advisory Role: Amgen, Iovance Biotherapeutics, Merck, Roche, Nouscom, Seneca Therapeutics Alexander I. SpiraStock and Other Ownership Interests: LillyHonoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, BayerConsulting or Advisory Role: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Merck, Bristol Myers SquibbResearch Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Oncology, Plexxikon, Amgen, Daiichi Sankyo, ADC Therapeutics, Janssen Oncology, Mirati Therapeutics, Rubius Therapeutics Daniel C. ChoConsulting or Advisory Role: Nektar, Pfizer, Werewolf TherapeuticsExpert Testimony: Genentech, Abbott/AbbVie Shanhong GuanEmployment: Nektar TherapeuticsStock and Other Ownership Interests: Nektar Therapeutics Erika PuenteEmployment: NektarStock and Other Ownership Interests: Nektar Tuan NguyenEmployment: Nektar, Theravance TherapeuticsStock and Other Ownership Interests: Nektar, Theravance Ute HochOther Relationship: Nektar Sue L. CurrieEmployment: NektarStock and Other Ownership Interests: Nektar Wei LinEmployment: Erasca Inc, NektarLeadership: Erasca IncStock and Other Ownership Interests: Nektar, Erasca IncTravel, Accommodations, Expenses: Nektar, Erasca Inc Mary A. TagliaferriEmployment: NektarLeadership: Nektar, ENZO BiochemStock and Other Ownership Interests: NektarPatents, Royalties, Other Intellectual Property: US 10576121Travel, Accommodations, Expenses: Nektar Jonathan ZalevskyEmployment: NektarLeadership: NektarStock and Other Ownership Interests: NektarTravel, Accommodations, Expenses: Nektar Mario SznolStock and Other Ownership Interests: Amphivena, Intensity Therapeutics, Adaptive Biotechnologies, Actym Therapeutics, Torque, Nextcure, EvolveImmune Therapeutics, Johnson & Johnson/Janssen, GlaxoSmithKlineConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca/MedImmune, Nektar, Lilly, Adaptimmune, Seattle Genetics, Pierre Fabre, Molecular Partners, AbbVie, Pieris Pharmaceuticals, Innate Pharma, Immunocore, Genocea Biosciences, Anaeropharma, Zelluna, Boston Pharmaceuticals, Alligator Bioscience, Servier, Dragonfly Therapeutics, Verastem, Boehringer Ingelheim, Agenus, Numab, BioNTech AG, Genentech/Roche, Gilead Sciences, Jazz Pharmaceuticals, Targovax, Sapience Therapeutics, Pfizer, Tessa Therapeutics, OncoSec, Trillium Therapeutics, StCube, Simcha, ITeos TherapeuticsOther Relationship: Haymarket Media, Physicians' Education Resource, DAVAOncology, CEC Oncology Michael E. HurwitzEmployment: Pfizer, Gamida Cell, ArvinasConsulting or Advisory Role: Nektar, Janssen, Crispr Therapeutics, Bristol Myers Squibb/Celgene, ExelixisResearch Funding: Apexigen, Astellas Pharma, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Corvus Pharmaceuticals, Lilly, Endocyte, Genentech, Genmab, Innocrin Pharma, Iovance Biotherapeutics, Merck, Nektar, Novartis, Pfizer, Progenics, Sanofi/Aventis, Seattle Genetics, Torque, Unum Therapeutics, Achilles TherapeuticsNo other potential conflicts of interest were reported.

Figures

FIG 1.

Clinical response to BEMPEG plus NIVO by blinded independent central review (response-evaluable population). (A) Waterfall plot of the maximum change in tumor size. (B) Percent change in target lesion size over time. Data cutoff: September 1, 2020. Response-evaluable population includes eligible patients with measurable disease (per RECIST v1.1) at baseline and at least one postbaseline assessment of tumor response. All objective responses are confirmed. BEMPEG, bempegaldesleukin; CR, complete response; NIVO, nivolumab; PD, progressive disease (because of non–target lesion progression or presence of new lesion); PD-L1, programmed death-ligand 1; PR, partial response (complete response for target lesion; non–target lesion still present); SD, stable disease.

FIG 2.

Kaplan-Meier estimates of (A) PFS by blinded independent central review and (B) OS in all patients (intent-to-treat population; N = 41). Data cutoff: September 1, 2020. NE, not estimable; OS, overall survival; PFS, progression-free survival.

FIG 3.

Single-cell cytokine analysis of biomarkers at baseline (C1D1) and on treatment (C1D8) and correlation with response by BICR. (A) Relationship between baseline tumor biomarkers and ORR.a,b (B) Relationship between CD8+ TIL, IFN-γ GEP, CD74, and HLA-E (high v low) in baseline tumor samples and PFS. (C) Change in polyfunctionality of CD8+ T cells on treatment by response. (D) Single-cell polyfunctional heatmap illustrating the single-cell cytokine combinations secreted by each sample. Each column corresponds to a specific cytokine or combination of cytokines, and the red squares represent the frequency at which the group was secreted by the corresponding sample. Cytokine groups are ordered by overall frequency across all the samples. (E) Change in single-cell PSI on treatment by response and cytokine representation (regulatory, chemoattractive, stimulatory, and effector). (F) Changes in the median values of blood biomarkers in paired samples on treatment versus baseline and relationship with the ORR.a,c (G) Relationship between CD8+ PSD and eosinophil FC and PFS. aFor each biomarker evaluated, the number of patients with an objective response (CR or PR; n), by BICR per RECIST v1.1, falling above and below the median biomarker measurement is presented. The denominator (N) is the number of patients evaluable for that biomarker. The difference in ORR for each biomarker on the basis of low (< median) or high (≥ median) is presented. bBiomarkers were evaluated in baseline tumor or blood samples: tumor PD-L1 expression by immunohistochemistry (PD-L1 IHC 28-8 PharmDx [Dako, an Agilent Technologies Inc company, Santa Clara, CA]), expressed as a percentage of tumor cell expression (negative, < 1% tumor cell expression; positive, ≥ 1% tumor cell expression); tumor CD8+ TIL by immunohistochemistry, cells/mm2; IFN-γ GEP, expression score; TMB, mutations per megabase; tumor CD74, HLA-A, HLA-B, and HLA-E expression score by immunohistochemistry; blood CD4+ PSI, CD8+ PSI, and NK cell PSI using single-cell cytokine analysis; blood lymphocytes, eosinophils, and neutrophils, all × 106/L; NEU/LYM ratio. cBiomarkers were evaluated in on-treatment blood biomarkers: CD4+, CD8+, and NK cell PSD (ie, difference in PSI between C1D1 and C1D8 measured using single-cell cytokine analysis); and the FC in levels of lymphocytes, eosinophils, neutrophils (all × 106/L), and NEU/LYM ratio between C1D1 and C1D8. BICR, blinded independent central review; C1D1, cycle 1 day 1 (baseline); C1D8, cycle 1 day 8 (on treatment); CR, complete response; EOS, eosinophils; FC, fold change; GEP, gene expression profile; HR, hazard ratio; IFN, interferon; IL-5, interleukin-5; MIP, macrophage inflammatory protein; NE, not estimable; NEU/LYM ratio, neutrophil to lymphocyte ratio; NK, natural killer; ORR, objective response rate; PD, progressive disease; PD-L1, programmed death-ligand 1; PFS, progression-free survival; polyfunctionality, cosecretion of two or more cytokines per cell; PR, partial response; PSD, polyfunctional strength difference; PSI, polyfunctional strength index (ie, percentage of polyfunctional cells in a sample, multiplied by the sum of secreted cytokine intensities of polyfunctional cells); SD, stable disease; TIL, tumor-infiltrating lymphocytes; TMB, tumor mutational burden; TNF, tumor necrosis factor.