Haanen, John B A G

Abstract Background The association of body composition with checkpoint inhibitor outcomes in melanoma is a matter of ongoing debate. In this study, we aim to investigate body mass index (BMI) alongside computed tomography (CT)-derived body composition metrics in the largest cohort to date. Methods Patients treated with first-line anti-PD1 ± anti-CTLA4 for advanced melanoma were retrospectively identified from 11 melanoma centers in The Netherlands. From baseline CT scans, 5 body composition metrics were extracted: subcutaneous adipose tissue index, visceral adipose tissue index, skeletal muscle index, density, and gauge. These metrics were correlated in univariable and multivariable Cox proportional hazards analysis with progression-free survival, overall survival, and melanoma-specific survival (PFS, OS, and MSS). Results A total of 1471 eligible patients were included. Median PFS and OS were 9.1 and 38.1 months, respectively. Worse PFS was observed in underweight patients (multivariable hazard ratio [HR] = 1.86, 95% CI = 1.14 to 3.06). Furthermore, prolonged OS was observed in patients with higher skeletal muscle density (multivariable HR = 0.88, 95% CI = 0.81 to 0.97) and gauge (multivariable HR = 0.61, 95% CI = 0.82 to 0.998), whereas higher visceral adipose tissue index was associated with worse OS (multivariable HR = 1.12, 95% CI = 1.04 to 1.22). No association with survival outcomes was found for overweight, obesity, or subcutaneous adipose tissue. Conclusion Our findings suggest that underweight BMI is associated with worse PFS, whereas higher skeletal muscle density and lower visceral adipose tissue index were associated with improved OS. These associations were independent of known prognostic factors, including sex, age, performance status, and extent of disease. No significant association between higher BMI and survival outcomes was observed.

Abstract Background In BRAF-mutated high-risk melanoma, targeted therapy (BRAF/MEK inhibitors) and checkpoint inhibitor (CPI) immunotherapy have durable benefits as first-line (1L) adjuvant therapy. Based on differing action mechanisms of BRAF/MEK inhibitors and CPI immunotherapies, there is interest in evaluating the activity of 2L adjuvant targeted therapy in decreasing the risk of subsequent recurrence after repeat resection following relapse on/after 1L adjuvant CPI. Patients and methods This was a retrospective review of BRAF V600-mutated resected stage III/IV melanoma patients in the United States, Australia, and The Netherlands who received 1L adjuvant CPI immunotherapy, relapsed locoregionally/distantly, were again resected to no evidence of disease, and received dabrafenib/trametinib (dab/tram) as 2L adjuvant therapy. The primary endpoint was relapse-free survival (RFS) from initiation of 2L adjuvant dab/tram (RFS-2), analyzed via Kaplan-Meier methods. Results Thirty-eight patients were included (median age 50 years, 63% male, 87% stage III, median follow-up 19 months from 2L dab/tram initiation). Median dab/tram duration was 10.1 months (range: 1 day–22.7 months), with half discontinuing due to progression or adverse events. Median (95% CI) RFS-2 was 18.9 (14.9–28.1) months, with 91%, 81%, and 58% remaining relapse-free at 6, 12, and 18 months, respectively. Most patients remained distant metastasis-free at 6, 12, and 18 months (97%, 85%, and 71%, respectively). Two patients were deceased at the last follow-up, with 97% alive at 18 months. Conclusions Over 80% of patients remained relapse- and metastasis-free at 12 months after 2L dab/tram initiation, with only 2 deaths observed. Dab/tram appears to have activity in the 2L adjuvant setting, although more follow-up is required.

AbstractPredicting who will benefit from treatment with immune checkpoint inhibition (ICI) in patients with advanced melanoma is challenging. We developed a multivariable prediction model for response to ICI, using routinely available clinical data including primary melanoma characteristics. We used a population‐based cohort of 3525 patients with advanced cutaneous melanoma treated with anti‐PD‐1‐based therapy. Our prediction model for predicting response within 6 months after ICI initiation was internally validated with bootstrap resampling. Performance evaluation included calibration, discrimination and internal–external cross‐validation. Included patients received anti‐PD‐1 monotherapy (n = 2366) or ipilimumab plus nivolumab (n = 1159) in any treatment line. The model included serum lactate dehydrogenase, World Health Organization performance score, type and line of ICI, disease stage and time to first distant recurrence—all at start of ICI—, and location and type of primary melanoma, the presence of satellites and/or in‐transit metastases at primary diagnosis and sex. The over‐optimism adjusted area under the receiver operating characteristic was 0.66 (95% CI: 0.64–0.66). The range of predicted response probabilities was 7%–81%. Based on these probabilities, patients were categorized into quartiles. Compared to the lowest response quartile, patients in the highest quartile had a significantly longer median progression‐free survival (20.0 vs 2.8 months; P < .001) and median overall survival (62.0 vs 8.0 months; P < .001). Our prediction model, based on routinely available clinical variables and primary melanoma characteristics, predicts response to ICI in patients with advanced melanoma and discriminates well between treated patients with a very good and very poor prognosis.

AbstractSince the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune‐surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first‐line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression‐free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti‐PD‐1‐based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI‐treated patients with a TFDR <2 years, median OS was 25.0 months, compared to 37.3 months for a TFDR >5 years (P = .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR <2 years compared to 11.1 months for >5 years, P = .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first‐line ICI or targeted therapy.

Abstract Purpose: To evaluate the association between neutrophil-to-lymphocyte ratio (NLR) and efficacy of avelumab plus axitinib or sunitinib. Experimental Design: Adult patients with untreated advanced renal cell carcinoma (RCC) with a clear-cell component, ≥1 measurable lesions, Eastern Cooperative Oncology Group performance status of 0 or 1, fresh or archival tumor specimen, and adequate renal, cardiac, and hepatic function were included. Retrospective analyses of the association between baseline NLR and progression-free survival (PFS) and overall survival (OS) in the avelumab plus axitinib or sunitinib arms were performed using the first interim analysis of the phase 3 JAVELIN Renal 101 trial (NCT02684006). Multivariate Cox regression analyses of PFS and OS were conducted. Translational data were assessed to elucidate the underlying biology associated with differences in NLR. Results: Patients with below-median NLR had longer observed PFS with avelumab plus axitinib [stratified HR, 0.85; 95% confidence interval (CI), 0.634–1.153] or sunitinib (HR, 0.56; 95% CI, 0.415–0.745). In the avelumab plus axitinib or sunitinib arms, respectively, median PFS was 13.8 and 11.2 months in patients with below-median NLR, and 13.3 and 5.6 months in patients with median-or-higher NLR. Below-median NLR was also associated with longer observed OS in the avelumab plus axitinib (HR, 0.51; 95% CI, 0.300–0.871) and sunitinib arms (HR, 0.30; 95% CI, 0.174–0.511). Tumor analyses showed an association between NLR and key biological characteristics, suggesting a role of NLR in underlying mechanisms influencing clinical outcome. Conclusions: Current data support NLR as a prognostic biomarker in patients with advanced RCC receiving avelumab plus axitinib or sunitinib.

Abstract Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy expressing a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1 and/or LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapies, including GSK3901961 and GSK3845097, incorporate further genetic modifications to enhance anticancer activity. GSK3901961 co-expresses the CD8α chain to stabilize TCR-human leukocyte A (HLA) class I interactions on CD4+ T cells, enhancing T-cell persistence and increasing helper functions such as Type 1 T-helper anti-tumor responses. GSK3845097 co-expresses a dominant negative transforming growth factor-β (TGF-β) type II receptor to reduce TGF-β pathway activation and maintain T-cell proliferation, cytokine production, and cytotoxicity in the tumor microenvironment. A first-time-in-human master protocol (NCT04526509) will evaluate the safety, tolerability, and recommended Phase 2 dose (RP2D) of these two therapies and possible subsequent ones. Substudy 1 will assess GSK3901961 in patients with advanced non-small cell lung cancer (NSCLC) or synovial sarcoma (SS). Substudy 2 will assess GSK3845097 in patients with advanced SS. Methods: Each substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage. Table 1 lists eligibility criteria. Primary endpoints are safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate, duration of response, and maximum expansion/persistence and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 and anti-GSK3845097 titers for the respective substudies. The substudies are open and recruiting. Funding: GSK (209012; NCT04526509) Initial screening criteriaInclusion criteriaExclusion criteriaSubstudies 1 and 2 (SS and NSCLC)≥18 years of agePrior malignancy that is not in complete remission or clinically significant systemic illnessMeasurable disease per RECIST v1.1 criteriaPrevious treatment with genetically modified NY-ESO-1-specific T cells, NY-ESO-1 vaccine, or NY-ESO-1 targeting antibodyExpression of HLA-A*02:01, A*02:05, or A*02:06Prior gene therapy using an integrating vectorExpression of NY-ESO-1/LAGE-1a in tumor archival or fresh biopsyPrevious allogeneic hematopoietic stem cell transplant within the last 5 years or solid organ transplantSubstudies 1 and 2 (SS only)Histologically confirmed advanced (metastatic or unresectable) SS diagnosisCentral nervous system metastasesPresence of t(X;18) translocation(Allowed for NSCLC participants on a case-by-case basis)Received, completed, or intolerant to treatment with anthracycline or anthracycline with ifosfamide for advanced (metastatic or unresectable) disease and has progressedSubstudy 1 (NSCLC only)Histologically or cytologically confirmed Stage IV NSCLCReceived or failed ≥3 lines of systemic therapyReceiving or previously received ≥1 prior line(s) of standard of care treatment including programmed death receptor-1/programmed death ligand-1 checkpoint blockade therapy, and received or be intolerant to doublet taxane and platinum chemotherapyPresence of actionable genetic aberration (activation epithelial growth factor receptor, anaplastic lymphoma kinase/c-ros oncogene 1) per NCCN guidelines Citation Format: Adam J. Schoenfeld, Mehmet Altan, Taofeek K. Owonikoko, Sandra D'Angelo, Brian H. Ladle, Jonathan Noujaim, Kai He, David Liebner, Adrian G. Sacher, John B.A.G. Haanen, Jeffrey Yachnin, Chao Huang, Brian A. Van Tine, Aisha Hasan, Thomas Faitg, Emily Butler, Aiman Shalabi, Steven Attia, Dejka M. Araujo. Master protocol to assess the safety and recommended Phase 2 dose of next generation NY-ESO-1-specific TCR T-cells in HLA-A*02 patients with synovial sarcoma and non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT219.

TPS11582 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell product using a genetically modified T-cell receptor to target cancer cells expressing the cancer testis antigen New-York esophageal squamous cell carcinoma 1 (NY-ESO-1). Lete-cel is currently being investigated alone and in combination in multiple tumor types [1,2]. NY-ESO-1 is expressed in 70‒80% of synovial sarcoma (SS) and 80‒90% of myxoid/round cell liposarcoma (MRCLS) tumors [3,4], suggesting these tumors may be prime lete-cel targets. This master protocol design (IGNYTE-ESO; NCT03967223) enables evaluation of multiple cell therapies in multiple tumor types and treatment stages in separate substudies, beginning with lete-cel in Substudies 1 and 2 for SS and MRCLS. Methods: Substudy 1 is a single-arm study assessing lete-cel in treatment-naïve patients (pts; ie, anthracycline therapy-naïve for metastatic disease) with advanced (metastatic/unresectable) NY-ESO-1+ SS or MRCLS as a first line of therapy (n=10 planned). Substudy 2 is a pivotal, single-arm study assessing lete-cel in pts with NY-ESO-1+ SS or MRCLS who progressed after anthracycline therapy (n=70 planned). Key eligibility criteria are age ≥10 y and NY-ESO-1 and HLA-A*02 positivity. Exclusion criteria include prior NY-ESO-1–specific/gene therapy, allogeneic stem cell transplant, and central nervous system metastases. Screened pts undergo leukapheresis for lete-cel manufacture, lymphodepletion, lete-cel infusion, and follow-up (FU). Long-term FU (15 y) may be done under a separate protocol. The Substudy 2 primary endpoint is overall response rate (ORR) per RECIST v1.1 assessed by central independent review. Substudy 1 is not testing any formal hypotheses; statistical analysis will be descriptive. Substudy 2 is comparing ORR with the historical control assuming at least 90% power with 0.025 one-sided type I error. Secondary endpoints include efficacy (time to/duration of response, disease control rate, progression-free survival), safety (adverse event [AE] frequency/severity, serious AEs, AEs of special interest), and pharmacokinetic (maximum transgene expansion [Cmax], time to Cmax, area under the time curve from zero to time t as data permit). Enrollment began in December 2019. References: 1. Reckamp KL, et al. Ann Oncol 2019;30(Suppl_5):v602–v660. 2. Rapoport A, et al. J Clin Oncol 2020 38:15_suppl, TPS8555. 3. D’Angelo SP, et al. Cancer Discov 2018;8(8):944–957. 4. D’Angelo SP, et al. J Clin Oncol 2018 36:15_suppl, 3005. Funding: GSK. Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Previously presented at BSG 2021 (P914542). Clinical trial information: NCT03967223.

TPS2661 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy using a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1/LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapies, such as GSK3901961 and GSK3845097, integrate added genetic modifications to enhance anticancer activity. GSK3901961 co-expresses the CD8α chain to stabilize TCR-human leukocyte A (HLA) class I interactions on CD4+ T cells, improving T-cell persistence and helper functions such as Type 1 T-helper antitumor responses. GSK3845097 co-expresses a dominant negative transforming growth factor-β (TGF-β) type II receptor to reduce TGF-β pathway activation and maintain T-cell proliferation, cytokine production, and cytotoxicity in the tumor microenvironment. A first-time-in-human master protocol (NCT04526509) will evaluate safety, tolerability, and recommended phase 2 dose (RP2D) of these and possible subsequent therapies. Substudy 1 will assess GSK3901961 in patients (pts) with advanced non-small cell lung cancer (NSCLC) or synovial sarcoma (SS). Substudy 2 will assess GSK3845097 in pts with advanced SS. Methods: Each substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage. Key inclusion criteria are age ≥18 y; measurable disease per RECIST v1.1; HLA-A*02:01, A*02:05, or A*02:06 positivity; NY-ESO-1/LAGE-1a tumor expression; advanced (metastatic/unresectable) SS with t(X;18) translocation and anthracycline-based therapy receipt/completion/intolerance (SS only); and Stage IV NSCLC, receipt of ≥1 prior line(s) of standard of care (SOC) therapy including programmed death receptor- or ligand-1 inhibitors, and SOC chemotherapy receipt/intolerance (Substudy 1 only). Key exclusion criteria are prior malignancy that is not in complete remission or clinically significant systemic illness; prior receipt of gene/NY-ESO-1–specific therapy or allogenic stem cell/solid organ transplant; central nervous system metastases (SS only); and actionable genetic aberration and receipt/failure of ≥3 systemic therapy lines (Substudy 1 only). Primary endpoints are safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate, duration of response, and maximum expansion/persistence and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 or -GSK3845097 titers as applicable. Analyses will be descriptive. The substudies are enrolling. Funding: GSK (209012; NCT04526509). Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health; funded by GSK. Previously presented at AACR 2021 (CT219). Clinical trial information: NCT04526509.

5061 Background: The phase 3 JAVELIN Renal 101 trial (NCT02684006) in treatment-naive patients with advanced renal cell carcinoma (aRCC) demonstrated significantly improved progression-free survival (PFS; hazard ratio [HR], 0.69; 95% CI, 0.56, 0.84; P < 0.001) and higher objective response rate (ORR; 51.4% vs 25.7%) with avelumab + axitinib vs sunitinib (Motzer RJ, et al. N Engl J Med. 2019;380:1103-15). NLR has emerged as a potential prognostic biomarker in aRCC; elevated NLR is associated with poorer prognosis. Here, we describe the association of NLR with the efficacy of avelumab + axitinib from JAVELIN Renal 101. Methods: We examined baseline NLR and its association with efficacy outcomes. PFS, best overall response (per blinded independent central review using RECIST 1.1), and overall survival (OS) data from the avelumab + axitinib arm from the first interim analysis of JAVELIN Renal 101 were analyzed (data cutoff, June 20, 2018). Multivariate Cox regression analyses of PFS and OS were also conducted. Results: In the avelumab + axitinib arm, patients with < median NLR (N = 217) had longer observed PFS (stratified HR, 0.85; 95% CI, 0.634, 1.153) and longer observed OS (stratified HR, 0.51; 95% CI, 0.300, 0.871) than patients with ≥ median NLR (N = 217). The ORR was 57.1% in patients with < median NLR vs 47.5% in patients with ≥ median NLR, with complete response in 5.5% vs 1.4%. Multivariate analysis showed that low NLR was associated with longer PFS and OS by treating baseline NLR as either a continuous variable or a binary variable (dichotomized by median). Conclusions: Low NLR was associated with better observed treatment outcomes in patients with aRCC who received avelumab + axitinib. Clinical trial information: NCT02684006 .