The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the 2023 ESMO Congress. Below is a recap of highlighted research presented from Friday, October 20 through Tuesday, October 24, 2023.
Exploring the clinical effectiveness of perioperative immune checkpoint inhibitors in combination with chemotherapy for advanced gastric and gastroesophageal junction cancer
LBA74. Pembrolizumab plus chemotherapy vs chemotherapy as neoadjuvant and adjuvant therapy in locally advanced gastric and gastroesophageal junction cancer: The phase III KEYNOTE-585 study
Kohei Shitara (National Cancer Center Hospital East, Kashiwa, Japan) presented results from KEYNOTE-585, a phase 3 study investigating the clinical benefits of perioperative chemotherapy combined with immunotherapy in patients with locally advanced, resectable gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. G/GEJ adenocarcinoma is associated with a high recurrence rate following surgical resection, and perioperative chemotherapy (chemo) has improved outcomes in patients with localized G/GEJ cancer. In the main cohort, 804 patients were randomized 1:1 to be treated with neoadjuvant pembrolizumab (pembro, n=402) or placebo (n=402) + chemo for three cycles, then after surgical resection, adjuvant pembro or placebo + chemo for 3 cycles, then adjuvant pembro or placebo for 11 cycles. In the main cohort, chemo was either cisplatin and capecitabine/XP or cisplatin and 5-FU/FP. The FLOT cohort (n=203; 100 patients in the pembro arm, 103 patients in placebo arm) followed the same protocol as the main cohort, but chemo was docetaxel, oxaliplatin, leucovorin, and 5-FU. Pathological complete response (pCR) was significantly improved in the pembro group compared to the placebo group for the main cohort (12.9% vs 2.0%, respectively) and numerically improved in the FLOT group (13.0% vs 2.4%, respectively). pCR benefits of pembro were observed in all patient subgroups, especially among patients with microsatellite instability-high (MSI-H) disease. Median EFS in the main cohort was 44.4 months for the pembro group and 25.3 months for the placebo group (HR 0.81), but this difference was not statistically significant. Results were consistent with most patient subgroups. Median overall survival in the main cohort was similar for both groups, with 60.7 months for the pembro group and 58.0 months for the placebo group (HR 0.90). Overall survival did favor pembro among patients with MSI-H disease (HR 0.38). In the FLOT cohort, no significant differences were seen between the two groups for median EFS (45.8% for pembro vs 25.7% for placebo) and for median OS (60.7% for pembro vs not reached for placebo). Across both cohorts, treatment-related adverse events of grade 3-4 occurred in 64% of patients receiving pembro and 63% of patients receiving chemo. Although perioperative pembro + chemo significantly improved pCR rates compared to placebo + chemo, no significant gains were observed for ES or OS. Although these results show some promise, more studies are needed to fully understand the benefits associated with perioperative immune checkpoint inhibitors for resectable G/GEJ.
Perioperative pembrolizumab is associated with significant survival benefits for early-stage non-small cell lung cancer
LBA56. Overall survival in the KEYNOTE-671 study of perioperative pembrolizumab for early-stage non-small-cell lung cancer (NSCLC)
Jonathan D. Spicer (McGill University Health Centre, Montreal, Canada) presented overall survival results of KEYNOTE-671, a phase 3 study of neoadjuvant pembrolizumab (pembro) combined with chemotherapy followed by resection and adjuvant pembro for early-stage non-small cell lung cancer. Although PD-(L)1 blockade-based regimens have become the standard of care for advanced and metastatic NSCLC without genetic aberrations, no immune checkpoint blockade-based regimens have shown statistically significant overall survival (OS) benefits for resectable early-stage NSCLC. The first interim analysis of KEYNOTE-671 indicate neoadjuvant pembro combined with chemotherapy followed by surgery and adjuvant pembro (pembro group) is associated with significant improvements in event free survival (EFS), major pathologic response (mPR), and pathological complete response (pCR) compared with neoadjuvant chemotherapy and surgery alone (placebo group). In this second interim analysis of overall survival, perioperative pembro was associated with significant improvements in OS compared with placebo. Median OS was not achieved in the pembro group and 52.4% in the placebo group (HR 0.72). OS benefits were generally consistent across all subgroups. EFS benefits were also observed, with median EFS 47.2% and 18.3% in the pembro and placebo groups, respectively (HR 0.59). The adverse events prfile was consistent with previous analyses, and no new safety signals and treatment-related deaths were reported. These results establish neoadjuvant pembro combined with chemotherapy followed by resection and adjuvant pembro as the new standard of care for resectable NSCLC, and this regimen has been recently approved by the FDA as follows.
On October 16, 2023, the Food and Drug Administration approved pembrolizumab (Keytruda, Merck) with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of single-agent pembrolizumab as post-surgical adjuvant treatment for resectable (tumors ≥4 cm or node positive) non-small cell lung cancer.
Neoadjuvant pembrolizumab and chemotherapy improve pathologic complete response rates among patients with ER+/HER2- breast cancer
LBA21. KEYNOTE-756: Phase III study of neoadjuvant pembrolizumab (pembro) or placebo (pbo) + chemotherapy (chemo), followed by adjuvant pembro or pbo + endocrine therapy (ET) for early-stage high-risk ER+/HER2– breast cancer
Fatima Cardoso (Champalimaud Clinical Center Lisbon, Portugal) presented the first interim analysis of KEYNOTE-756, a global phase 3 study of neoadjuvant pembrolizumab (pembro) or placebo + chemotherapy (chem) followed by adjuvant pembro or placebo + endocrine therapy (ET) in patients with early-stage high-risk ER+/HER2- breast cancer. The primary endpoints were pathological complete response (pCR) and event free survival (EFS). 1278 treatment naïve patients with grade 3 ER+/HER2- invasive ductal breast carcinoma were randomized to treatment with pembro + chemo (n=635) or placebo + chemo (n=643). At a median follow-up of 33.2 months, pembro + chemo significantly improved pCR (24.3%) compared to placebo (15.6%), and similar results were observed with different definitions of pCR. Clinical benefits associated with pembro + chemo were observed in all subgroups, and larger numeric benefit was observed in patients with ER-low disease. No new safety signals were observed; most adverse events (AEs) were related to chemotherapy. Neoadjuvant phase treatment-related AEs of grade 3 or higher were observed in 52.5% of patients in pembro + chemo arm and 46.4% of patients in the in placebo + chemo arm. The data indicate that the KEYNOTE-756 study has met one of its dual primary endpoints of pCR. Data for the other primary endpoint, EFS, are immature and continue to be evaluated.
Safety and efficacy of a DLL-targeting T cell engager for small cell lung cancer
LBA92. Tarlatamab for patients (pts) with previously treated small cell lung cancer (SCLC): Primary analysis of the phase II DeLLphi-301 study
Pilar Garrido Lopez (Universidad de Alcalá, Madrid, Spain) presented results from DeLLphi-301, a phase 2 study of tarlatamab, a bispecific delta-like ligand 3 (DLL3)-targeting T cell engager for patients with advanced small cell lung cancer (SCLC) previously treated with 2 or more lines of therapy. At a median follow-up of 10.6 months, the objective response rate (ORR) of a cohort of patients who received a 10 mg dose of the drug (n=100) was 40.0%. ORR was 31.8% among patients who received a 100 mg dose (n=88). Responses were observed regardless of tumor DLL3 expression levels. Median progression free survival was 4.9 months and 3.9 months for the 10 mg and 100 mg doses respectively. Median overall survival was 14.3 months for the 10 mg dose and not reached for the 100 mg dose, and median duration of response was not reached for either dose. 57.5% of responders experienced a response for 6 months or longer, and 55% responses were ongoing at data cutoff. The most common treatment emergent adverse event was cytokine release syndrome (CRS), observed in 51.1% of patients receiving the 10 mg dose and 60.9% of patients receiving the 100 mg dose. Most cases of CRS were grade 1 or 2, and cases were largely confined to first or second dose. Neurotoxicites occurred infrequently and were mostly associated with the 100 mg dose of tarlatamab. These promising clinical results and manageable toxicity profile support the use of tarlatamab for patients with previously treated SCLC. The DeLLphi-304 clinical will study efficacy and safety of tarlatamab in combination with standard of care chemotherapy for SCLC.
Initial dose exploration study of a STEAP1-targeting T cell engager for metastatic castration-resistant prostate cancer
1765O. Interim results from a phase I study of AMG 509 (xaluritamig), a STEAP1 x CD3 XmAb 2+1 immune therapy, in patients with metastatic castration-resistant prostate cancer (mCRPC)
William Kelly (Thomas Jefferson University, Philadelphia, United States of America) reported interim results from an initial dose exploration study of xaluritamig, a bispecific T cell engager, for metastatic castration-resistant prostate cancer (mCRPC) refractory to prior hormone therapy and 1-2 taxane regimens. Xaluritamig features two STEAP1 binding domains, exhibiting selectivity for tumor cells with high STEAP1 expression and reducing toxicities. The primary goal for this dose exploration study was safety. 97 patients received xaluritamig monotherapy intravenously weekly or every other week at different dose levels. Dosing schedules implemented step dosing and premedication to mitigate toxicities. The maximum tolerated dose was 1.5 mg administered intravenously weekly by 3-step dosing. Treatment emergent adverse events (TEAEs) and treatment related adverse events (TRAEs) were reported in 100% and 95.9% of patients, respectively. The most common AE was cytokine release syndrome (72.2%), and most cases were grade 1 or 2 and clinically manageable. TRAEs led to discontinuation of treatment in 17.5% of patients. PSA levels decreased by 50% or more in 49% of all patients (n=89) and in 59% of patients who received high doses of xaluritamig (0.3 - 1.0 mg; n=46). A PSA decrease of 90% or more was observed in 28% of all patients and 36% of patients who received high doses. Objective response rate as defined by RECIST was 24% in all patients and 41% among patients who received high doses. These preliminary results indicate that xaluritamig is tolerable and is associated with encouraging anti-tumor activity in patients with heavily pretreated mCRPC. Dose expansion and optimization is ongoing, and further studies of xaluritamig as monotherapy and in combination with other cancer treatments are in development.
Immune checkpoint inhibition combined with chemoradiotherapy for advanced cervical cancer is associated with significant clinical benefits
LBA38 - Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: A randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study
Domenica Lorusso (Catholic University of Rome, Rome, Italy) presented the first interim analysis of ENGOT-cx11/GOG-3047/KEYNOTE-A18, which investigated pembrolizumab (pembro) combined with concurrent chemoradiotherapy (CCRT) for locally advanced high-risk cervical cancer. Previous preclinical and clinical data suggest immunotherapy may enhance the benefit of chemoradiotherapy for treating advanced cervical cancer. 1060 patients with newly diagnosed untreated high-risk locally advanced cervical cancer randomized to receive 5 cycles of pembro (n=529) or placebo (n=531) combined with CCRT and brachytherapy, then 15 cycles of pembro or placebo. Primary endpoints were progression free survival (PFS) and overall survival (OS), and secondary endpoints were 24-month PFS, objective response rate, patient-reported outcomes, and safety. At a median follow-up of 17.9 months, pembro + CCRT significantly improved PFS compared to placebo + CCRT, with 24-month PFS of 67.8% and 57.3% respectively (HR 0.70). Median PFS was not reached in either group. Pembro + CCRT showed a favorable trend in OS compared to placebo + CCRT (24-month OS 87.2% vs 80.8%; HR 0.73), but the difference between the two groups was not statistically significant. Addition of pembro also increased objective response rate (79.3% vs 75.9%). Treatment related adverse events were manageable and similar to other studies of immunotherapy combined with CCCRT, and pembrolizumab had no negative effects on patient-reported outcomes. The significant and clinically meaningful PFS benefits, favorable trends in OS, and manageable safety profile support pembrolizumab plus chemoradiotherapy as a new standard of care for patients with previously untreated high-risk locally advanced cervical cancer.
First in-human study of a PD-1 x TIM-3 bispecific antibody for advanced non-small cell lung cancer
1313MO. Safety and preliminary efficacy of AZD7789, a bispecific antibody targeting PD-1 and TIM-3, in patients (pts) with stage IIIB–IV non-small-cell lung cancer (NSCLC) with previous anti-PD-(L)1 therapy
Benjamin Besse (Institut Gustave Roussy ,Villejuif, France) presented dose escalation results from the first in-human trial of sabestomig (AZD7789), a humanized bispecific antibody that blocks PD-1 and T cell immunoglobulin and mucin domain 3 (TIM-3). Sabestomig improves the anti-tumor T cell response through targeting of PD-1 and TIM-3 and targeting of TIM-3 increases myeloid cell-mediated phagocytosis and dendritic cell-mediated tumor antigen presentation. 45 patients with advanced non-small cell lung cancer (NSCLC) that was resistant to anti-PD-(L)1 therapy participated in the study, and 36 of these patients received a biologically active dose of 750 mg or higher. Sabestomig was well-tolerated, with no dose-limiting toxicities or deaths observed, and no treatment-related adverse events of grades 4 or 5. 4 of the 36 patients who received a biologically active dose had a confirmed partial response. Two responders did not respond to prior immunotherapy, three responders had received three or more prior lines of therapy, and one responder had PD-L1 levels less than 1%. Sabestomig drove expansion of existing and new peripheral T cells, consistent with TIM-3 mechanism of action. Sabestomig has a favorable safety profile and shows promising clinical activity. Expansion studies investigating sabestomig monotherapy for immunotherapy-resistant or -naïve NSCLC and for relapsed/refractory classical Hodgkin Lymphoma are currently recruiting patients.
Clinical benefits associated with immune checkpoint inhibitors combined with telomerase vaccine for second-line treatment of malignant mesothelioma
LBA99. First survival data from the NIPU trial: A randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second-line treatment in patients with malignant mesothelioma
Aaslaug Helland (Oslo Comprehensive Cancer Centre, Oslo, Norway) reported results from the NIPU trial, which investigated ipilimumab (ipi) and nivolumab (nivo) in combination with telomerase vaccine UV1 compared to ipi and nivo as second-line therapy for malignant pleural mesothelioma (MPM). Immune checkpoint inhibitors have improved survival rates among patients with MPM, but their prognosis is still poor. 118 patients with MPM were randomized 1:1 to receive ipi + nivo + UV1 vaccination (Arm A) or ipi + nivo. The primary endpoint of this study was progression free survival (PFS) by blinded, independent central review (BICR). At a median follow-up of 12.5 months, the study did not meet its primary endpoint of PFS by BICR, with a median PFS of 4.2 months for Arm A and 4.7 months for Arm B (HR 1.01). There was a significant difference in investigator determined PFS between Arms A and B, with median PFS of 4.3 months and 2.9 months, respectively (HR 0.6). Objective response rates were 31% in Arm A and 16% in Arm B. At a median follow-up of 17.3 months, overall survival was 15.4 months in arm A and 11.1 months in Arm B (HR 0.73). The total number of adverse events and the proportion of adverse events >= grade 3 were comparable between the two arms. Although the primary endpoint of PFS was not met, telomerase vaccine UV1 is associated with increased ORR and clinically meaningful gains in survival for second line treatment of MPM, supporting a larger clinical trial.
Tumor infiltrating lymphocyte cell therapy for advanced mucosal melanoma
1086MO. Lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients (pts) with advanced mucosal melanoma after progression on immune checkpoint inhibitors (ICI): Results from the phase II C-144-01 study
Evidio Domingo-Musibay (University of Minnesota, Minneapolis, United States of America) presented results from the C-144-01 study, investigating the efficacy and safety of lifleucel, one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy for patients with advanced mucosal melanoma that progressed after anti-PD-(L)1 therapy. Advanced mucosal melanoma is associated with worse outcomes after anti-PD-1 therapy compared to non-mucosal melanoma. 15 patients were enrolled in the study. One or more lesion was resected for lifleucel manufacturing, and 12 patients received lifleucel infusion and up to six doses of high-dose IL-2 after lymphodepleting chemotherapy. At a median follow-up of 35.7 months, overall response rate was 50%. Responses lasted longer than 6 months in all six responding patients, five patients experienced responses of 12 months or longer, and four of the six responding patients have durable and ongoing responses. Median duration of response was not reached. The safety profile of this study is consistent with known safety profiles of lymphodepletion and IL-2, and all patients experienced some type of hematologic abnormalities. The relationship of tumor mutation burden (TMB) and TIL persistence was also investigated. Although TMB is typically low for mucosal melanoma compared to cutaneous melanoma, TIL persistence in patients with mucosal melanoma was similar to TILS persistence in patients with cutaneous melanoma. Lifleucel-induced anti-tumor responses in this small study of mucosal melanoma were consistent with responses observed in prior studies of advanced melanoma, providing additional support for lifleucel as a one-time treatment for melanoma.
Exploratory analyses of TME features associated with response or resistance to atezolizumab
2232O. Atezolizumab (atezo) and tumour microenvironment in early triple-negative breast cancer (eTNBC): Exploratory biomarker analysis from IMpassion031
Carlos H. Barrios (Hospital São Lucas Porto Alegre, Brazil) reported results from exploratory biomarker analysis from IMpassion031, which showed that neoadjuvant chemotherapy (CT) + atezolizumab (atezo) significantly increased pathological complete response (pCR) and favored event free survival (EFS), disease free survival (DFS), and overall survival (OS) compared to CT + placebo in patients with early triple negative breast cancer (eTNBC). The goal of this substudy was to identify potential predictive tumor immune biomarkers associated with clinical benefit with atezolizumab. Patient samples were tested for tumor infiltration lymphocytes (TILs) and underwent RNA sequencing to derive molecular subtypes, biological pathways, cellular components, CD8 T cell immune phenotype. Biomarkers evaluated for association with pathological complete response (pCR), EFS, DFS, and OS. Atezo was associated with gains in pCR in tumors with basal-like immune activated (BLIA) and basal-like immune suppressed (BLIS) molecular subtypes and in tumors that expressed gene signatures for proliferation, gamma delta T cells, and pro-B cells. Atezo-associated gains in EFS were observed in tumors with BLIA molecular subtypes, immune inflamed tumors, and tumors enriched with CD4+ T memory cells and mast cells. OS gains were associated with both BLIA and BLIS molecular subtypes, immune deserts, and low levels of tumor infiltrating lymphocytes. The clinical benefits observed in tumors with low levels of stromal or intratumoral TILs suggest that introduction of immunotherapy may recover immune activation in these tumors. Atezo was not associated with clinical benefit in tumors that were highly proliferative, tumors with stromal biology, and in tumors enriched in hematopoietic stem cells, suggesting resistance to atezo. Changes in tumor subtypes were also observed upon exposure to either treatment (atezo + CT and placebo + CT), suggesting that chemotherapy with or without immunotherapy can induce molecular changes within the tumor microenvironment. Although these results provide promising hypothesis-generating insights into mechanisms of response or resistance to atezolizumab, these analyses were performed on small groups of patients and need to be validated with larger data sets.
Efficacy and safety of perioperative nivolumab for patients with resectable NSCLC
LBA1. CheckMate 77T: Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC
Tina Cascone (The University of Texas MD Anderson Cancer Center, Houston, United States of America) presented event free survival (EFS) interim analysis of CheckMate 77T, a phase 3 study evaluating neoadjuvant nivolumab + chemotherapy followed by surgery and adjuvant nivolumab (Nivo + chemo/Nivo) compared with neoadjuvant placebo + chemo followed by surgery and adjuvant placebo for resectable stage I – III non-small cell lung cancer (NSCLC). 461 patients participated in the study; 229 patients were assigned to the Nivo + chemo/Nivo arm, and 232 patients were assigned to the Placebo + chemo/Placebo arm. At a median follow-up of 25.4 months, neoadjuvant Nivo + chemo and adjuvant nivo significantly improved EFS compared to placebo + chemo, with median EFS not reached vs 18.4 months, respectively (HR 0.58). 18-month EFS for Nivo + chemo/Nivo was 70%, compared to 50% for Placebo + chemo/Placebo. Nivo also improved pathological complete response rates (25.3% vs 4.7%) and major pathological response rates (35.4% vs 12.1%). Benefits in EFS and pCR were observed in all subgroups. EFS benefits were specifically observed in patients with stage III disease and in patients with squamous histology. In exploratory analyses, Nivo + chemo/Nivo favored EFS in patients who achieved a pCR following neoadjuvant therapy and EFS in patients who received adjuvant therapy, regardless of pCR status (HR 0.45). Among patients who were not able to receive adjuvant therapy, Nivo + chemo/Nivo still provided clinical benefits over Placebo + chemo/Placebo. Safety signals and surgery rates were similar between the two arms. Neoadjuvant nivolumab combined with chemotherapy is the current standard of care for resectable NSCLC, and results from CheckMate 77T support the use of perioperative nivolumab as a new option for patients with resectable NSCLC.
Using artificial intelligence-based methods incorporating tumor volume and tumor heterogeneity to identify prognostic biomarkers among patients treated with immune checkpoint inhibitors
1022MO. Predicting overall survival of patients with melanoma and NSCLC treated with immunotherapy using AI combining total tumor volume and tumor heterogeneity on CT-Scans
Lama Dawi (Institut Gustave Roussy, Paris, France) reported results form a retrospective study using total tumor volume and AI tumor heterogeneity from baseline CT-scans to predict prognosis and identify patients who could benefit from immunotherapy. 19877 lesions were annotated from 607 patients. All patients had received anti-PD-(L)1 therapy, 280 for melanoma and 327 for non-small cell lung cancer (NSCLC). The total training set contained samples from 424 patients, the test set contained samples from 85 patients, and the total validation set contained samples from 183 patients. Total tumor volume (TTV) was found to be a better prognostic tool for overall survival in patients receiving PD-(L)1 inhibitors for melanoma and for NSCLC, with better predictive potential for melanoma. Radiomic heterogeneity was a better predictor for patients with NSCLC, while AI-based tumor heterogeneity scores were more predictive for patients with melanoma. The basis for this observation may be related to tumor size and is still under investigation. While the results from this study need further validation, data indicate that TTV may serve as a predictive biomarker for patient prognosis. Tumor heterogeneity measurements by radiomics or by AI applications are not completely correlated with TTV and show potential as prognostic tools.
Is there a role for immune checkpoint inhibitors in the treatment of metastatic hormone-sensitive prostate cancer?
1772MO. Pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): Randomized double-blind phase III KEYNOTE-991 study
Christian J. Gratzke (University Hospital Freiburg, Freiburg im Breisgau, Germany) presented results from KEYNOTE-991, a phase 3 study investigating pembro or placebo combined with antiandrogen medication enzalutamide (enza) and androgen deprivation therapy (ADT) in patients with next-generation hormonal agent (NHA)-naïve metastatic hormone-sensitive prostate cancer (mHSPC). Patients with mHSPC and two or more bone lesions or visceral disease were randomized 1:1 to receive pembro combined with enza and continuous ADT (pembro arm; n=626) or placebo combined with enza and continuous ADT (placebo arm; n=625). The dual primary endpoints were radiographic progression free survival (rPFS) and overall survival (OS). Secondary endpoints were time to initiation of first subsequent anticancer therapy (TFST) and time to first symptomatic skeletal-related event (TTSSRE). At a median follow-up of 21.1 months, there was no significant difference in rPFS or in OS between the two treatment arms (HR 1.20 and 1.16, respectively), and addition of pembro to enza and ADT provided no significant clinical benefit to any patient subgroup. Incidence of adverse events was higher in the pembro arm, and serious adverse events occurred in 40.3% of patients in the pembro arm, compared to 23.2% of patients in placebo arm. The study was stopped for futility at the interim analysis. These results suggest that the role and benefits of immune checkpoint inhibitors in prostate cancer are unclear, and more retrospective studies and clinical trials are needed to identify and characterize patients with mHSPC who are most likely to benefit from immune checkpoint inhibition.
Phase 1 study of a PD-1/CTLA-4 antibody for first-line treatment of advanced clear cell renal cell carcinoma
1883MO. MEDI5752 (volrustomig), a novel PD-1/CTLA-4 bispecific antibody, in the first-line (1L) treatment of 65 patients (pts) with advanced clear cell renal cell carcinoma (aRCC)
Martin H. Voss (Memorial Sloan Kettering Cancer Center, New York, United States of America) presented results from the first in-human trial of MEDI5752 (volrustomig), a monovalent PD-1/CTLA-4 bispecific antibody for advanced clear cell renal cell carcinoma (aRCC). MEDI5752 is designed to fully inhibit PD-1 while preferentially inhibiting CTLA-4 on activated PD-1 T cells, with the goal of maximizing the benefit of CTLA-4 inhibition while limiting toxicities. 32 patients received 750 mg volrustomig every 3 weeks (V750), and 33 patients received 500 mg volrustomig every 3 weeks (V500). All patients in the study were immunotherapy-naïve and vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) -naïve. The primary objective of this study was objective response rate. The median follow-up for M750 was 22.7 months, and 14.9 months for V500. ORR was similar for the two groups, with 48.4% for M750 and 45.5% for V500. V750 was associated with higher CR rate and disease control rate compared to M500 (CR rate 9.7% vs 6.1%, respectively; DCR 90.3% vs 69.7%, respectively). Patients in both treatment groups were able to achieve deep responses, with the median duration of response 17.0 months for M750 and 11.5 months for M500. Median PFS for V750 and V500 was 12.3 months vs 9.7 months, respectively. Incidence of grade 3-4 immune related adverse events (AEs) was higher in M750 (62.5%) compared to M500 (42.4%). Treatment related AEs led to treatment discontinuation in 46.9% of patients in the M750 cohort and 39.4% of patients in the M500 cohort. Both doses achieved peripheral CD4 activation, comparable to tremelimumab. An association between radiographic benefit and activation of CD4 T cell central memory was observed, with effects higher at M750. In this study, 750 mg and 500 mg volrustomig administered every three weeks exhibits preliminary promising efficacy for first-line treatment of aRCC. However, the high incidence of toxicities and treatment discontinuation rate raise concerns about the feasibility of combination regimens. A study of volrustomig in combination with lenvatinib for first-line treatment of aRCC is in progress.
Survival benefits of enfortumab vedotin and pembrolizumab surpass those of chemotherapy for first-line advanced metastatic bladder cancer
LBA6. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (Chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC)
Thomas B. Powles (University of London Barts Cancer Center, London, United Kingdom) presented the final analysis of EV-302/KEYNOTE-A39, which evaluated the Nectin-4 directed antibody-drug conjugate enfortumab vedotin (EV) combined with pembrolizumab in patients with previously untreated locally advanced metastatic urothelial carcinoma (la/mUC) who were eligible for platinum-based chemotherapy. EV combined with pembrolizumab (EV + P) has been granted FDA approval for patients with la/mUC who are ineligible for platinum-based chemotherapy. Patients were randomized to receive EV + P (n=442) or gemcitabine with cisplatin or carboplatin (chemo; n=444). The primary endpoints of the study were progression free survival (PFS) and overall survival (OS). Secondary endpoints included objective response rate (ORR) and safety. PFS significantly improved with EV+P compared to chemo, with median PFS 12.5 months and 6.3 months, respectively (HR 0.45). At a median survival follow-up of 17.2 months, median OS was 31.5 months for EV+P compared to 16.1 months for chemo (HR 0.47), and this increase was statistically significant. PFS and OS benefits with EV+P were consistently observed in all patient subgroups, including cisplatin eligibility, PD-L1 expression, and visceral metastases. ORR was significantly improved with EV+P (67.7%) compared to chemo (44.4%), and CR rates were 29.2% and 12.5%, respectively. 59% of patients in chemo arm received subsequent PD-(L)1 inhibitors. Treatment related adverse events of grade 3 or higher were observed in 55.9% of patients receiving EV+P and in 69.5% of patients receiving chemo, and no new safety signals were observed. The EV-301/KEYNOTE-A39 study marks the first time that a treatment surpassed platinum-based chemotherapy in OS as a first line treatment for la/mUC. The results presented strongly support enfortumab vedotin combined with pembrolizumab as a new standard of care for first line treatment of locally advanced metastatic urothelial carcinoma. The results are practice changing and will dramatically alter the standard frontline therapy. For the first time cisplatin eligibility will cease to be a factor is decision making for advanced urothelial cancer. Both cis eligible and ineligible cohorts showed significant benefit favoring EV + pembro arm.
Clinical benefits of nivolumab plus gemcitabine-cisplatin for first-line treatment of unresectable or metastatic bladder cancer
LBA7. Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: Results from the phase III CheckMate 901 trial
Michiel van der Heijden (Netherlands Cancer Institute, Amsterdam, Netherlands) reported the final results of an arm of the multi-arm phase 3 CheckMate 901 trial, comparing nivolumab (nivo) combined with gemcitabine-cisplatin versus gemcitabine-cisplatin alone in cisplatin-eligible patients with previously untreated unresectable or metastatic urothelial carcinoma (mUC). Cisplatin-based chemotherapy has been the standard of care for eligible patients with unresectable or mUC, but durable results with this regimen are rare. Patients were randomized 1:1 to receive nivo combined with gemcitabine-cisplatin followed by nivo monotherapy (Nivo + GC arm; n=304) or gemcitabine-cisplatin (GC arm; n=288). Primary endpoints were overall survival (OS) and progression-free survival (PFS), and median follow-up was 33.6 months. In total, 8% of patients in the Nivo + GC arm and 8% of patients in the GC arm discontinued treatment due to drug toxicity. CheckMate 901 met its primary endpoint of OS, with median OS of the Nivo + GC (21.7 months) significantly higher than median OS of the GC arm (18.9 months; HR 0.78). OS benefits associated with Nivo + GC were observed in all patient subgroups examined, except for a small subgroup of patients from the United States (n=40). Nivo + GC significantly improved PFS compared to GC, with median PFS of 7.9 and 7.6 months, respectively (HR 0.72). 24-month PFS rates were 23.5% for the Nivo + GC arm and 9.6% for the GC arm. Objective response rate was improved in the Nivo + GC arm (57.6%) compared to the GC arm (43.1%), with the complete response rate of the Nivo + GC arm almost twice that of the GC arm (21.7% and 11.8%, respectively). Complete responses with Nivo + GC were more durable, with a median duration of complete response of 37.1 months in the Nivo + GC arm and 13.2 months in the GC arm. Treatment-related adverse events were similar between both arms (97% in Nivo + GC arm and 93% in GC arm). Health-related quality of life was stable in both arm of the study. Nivo + Gc is the first immune checkpoint inhibitor + chemotherapy combination therapy to improve overall survival in the frontline setting, supporting nivolumab combined with platinum-based chemotherapy as a new standard of care for first line treatment of patients with unresectable or mUC.
Safety and early efficacy data of a DLL3 x CD3 T cell engager for neuroendocrine carcinoma
725MO. Phase I trial of the DLL3/CD3 IgG-like T cell engager BI 764532 in patients (pts) with DLL3-positive (+) tumours: Focus on neuroendocrine carcinomas
Valentina Gambardella (Hospital Clinico de Valencia, Valencia, Spain) presented results from an ongoing phase 1 dose-escalation study of BIBI764532 in adults with locally advanced/metastatic DLL3+ small cell lung cancer (SCLC), extrapulmonary neuroendocrine carcinomas (epNEC) or large cell neuroendocrine lung carcinoma. BI764532 is a DLL3 x CD3 T cell engager that redirects T cells to destroy DLL3-expressing cancer cells. DLL3 is highly expressed on SCLC and neuroendocrine carcinomas (NECs). 132 patients, including 54 patients with NECs, received one or more dose of BI 764532 in one of four different regimens. All four dosing regimens included step-in dosing to reduce the risk of toxicity, specifically cytokine release syndrome. Treatment related adverse events (TRAEs) were observed in 94% of the patient population, and 19% of patients experienced a TRAE of grade 3 or higher. Six patients experienced dose limiting toxicities, including one patient with grade 5 neurotoxicity. The maximum tolerated dose has not yet been reached. Responses occurred in patients receiving dose levels at 90 micrograms/kg or higher. The objective response rate among patients with epNEC receiving a clinically active dose was 29%, and disease control rate was 49%. Responses were durable and ongoing. BIBI764352 shows a manageable safety profile and promising clinical efficacy, especially against extrapulmonary neuroendocrine carcinoma. Dose optimization is ongoing.
Analysis of pathologic and radiographic responses in the SWOG S1801 trial of neoadjuvant-adjuvant pembrolizumab for melanoma
LBA48. Pathologic response and exploratory analyses of neoadjuvant-adjuvant versus adjuvant pembrolizumab (PEM) for resectable stage IIIb-IV melanoma from SWOG S1801
Sapna Patel (The University of Texas MD Anderson Cancer Center, Houston, United States of America) presented exploratory analyses of the SWOG S1801, which verified the improved clinical efficacy of neoadjuvant-adjuvant (NAT) pembrolizumab (PEM) compared to adjuvant PEM in patients with resectable melanoma. The goal of this analysis was to investigate pathological and radiologic response rates and their association with clinical outcomes, specifically recurrence-free survival (RFS). 88% (n=135) of patients from the NAT arm of S1801 underwent surgery. Samples from 78% of those patients underwent pathologic review. The major pathologic response (MPR) rate was 53%, and the pathological complete response (pCR) rate in this population was 38%. 11% of patients from the NAT arm who received surgery achieved a radiographic complete response (CR) and 39% had a partial response (PR). 24-months RFS rates segregated by pathologic response and radiographic response. 24-month RFS rates for patients with a pCR and MPR were 89% and 88%, respectively. With regards to patients with radiograph responses, 24-month RFS rates for patients with a CR and PR were 93% and 92%, respectively. Although these findings require validation with larger patient populations, results from S1801 support the use of pathologic and radiographic responses as surrogate markers of clinical outcomes.
Exploratory analyses of longitudinal circulating tumor DNA dynamics and patient subpopulations in the KEYNOTE-942 trial
LBA49. mRNA-4157 (V940) individualized neoantigen therapy + pembrolizumab vs pembrolizumab in high-risk resected melanoma: Clinical efficacy and correlates of response
Jeffrey S. Weber (NYU Langone Health, New York City, United States of America) presented clinical efficacy results and exploratory endpoint analysis from the phase 2 KEYNOTE-942 trial. Previous reports from KEYNOTE-942 indicate that adjuvant treatment with the customizable neoantigen vaccine RNA-4157 (V940) combined with pembrolizumab (pembro) significantly extends recurrence free survival (RFS) and distant metastasis-free survival (DMFS) compared with pembro alone in patients with high-risk resected melanoma. 107 patients received adjuvant therapy of V940 combined with pembro (V940 + pembro arm), and 50 patients received adjuvant pembro (pembro arm). V940 did not affect incidence of immune-mediated adverse events (AEs), with 10.6% of patients in the V940 + pembro arm and 14.0% of patients in the pembro arm experiencing immune-mediated AEs of grade 3 or higher. V940 +pembro improved RFS and DMFS regardless of baseline circulating tumor DNA (ctDNA) status. Longitudinal ctDNA measurements were classified into three categories: molecular responders (MR) were ctDNA positive at baseline or early in treatment but ctDNA negative at the last time point; molecular non-responders (MNR) were ctDNA positive throughout treatment; and ctDNA negative patients were ctDNA negative throughout treatment. The likelihood of disease recurrence was highest in MNR patients and lowest in ctDNA negative patients, with 94% of MNR patients, 57% of MR patients, and 17% of ctDNA negative patients experiencing recurrence. The risk of distant metastases among patients with recurrences were 60%, 37.5%, and 16%, indicating the prognostic potential of ctDNA detection. Improved RFS and DMFS correlated with favorable ctDNA longitudinal patterns, with the highest clinical benefits occurring in ctDNA negative patients. Improved RFS with V940 + pembro was observed in patients with mutated BRAF (HR 0.33) and, to a lesser degree, in patients with wild type BRAF (HR 0.81). RFS improvements with V940 + pembro were highest in ct DNA negative patients regardless of BRAF mutation status. Clinical benefits associated with V940 + pembro will be explored further in additional studies that are at various stages of planning. The phase 3 V940-001 study in patients with resected melanoma and the phase 3 V940-002 study in patients with resected NSCLC are open for enrollment.
Early safety and efficacy data of GCC-targeting CAR T cellular therapy for advanced colorectal cancer
1018O. Phase I study of GCC CAR-T therapy IM96 in patients with advanced colorectal cancer
Changsong Qi (Peking University Cancer Hospital and Institute, Beijing, China) presented results from a phase 1 study of the safety and efficacy of IM96, a guanylyl cyclase 2C (GCC)-targeted CAR T cells for advanced colorectal cancer. GCC is ectopically expressed in metastatic colorectal cancer (mCRC), and IM96 has exhibited strong anti-tumor activity in vitro and in mouse tumor models of mCRC. Nine patients with GCC-positive stage IV mCRC received IM96 after lymphodepletion. All patients had received three or more prior lines of therapy, and 8 patients received bridging therapies. No neurotoxicities or cytokine release syndrome of grade 3 or higher were observed, and no dose limiting toxicities have been reported. The disease control rate (DCR) was 66.7% (n=6). Tumor burden decreased in three patients, and one patient experienced a partial response of over 9 months. Decreases in CEA level correlated with tumor response, and in patients with moderate to strong GCC expression in more than 30% of tumor cells, DCR was 100%, and within this patient population, tumor reduction was observed in 100% of patients receiving IM96 doses of 6 x 108 cells or higher. IM96 is well tolerated and shows promising clinical efficacy. This dose escalation study is ongoing.
Next generation T cell receptor T cell therapy targeting MAGE-A4 in solid tumors
1019O. Clinical and translational data from the phase I SURPASS trial of ADP-A2M4CD8 T cell receptor (TCR) T cell therapy alone or combined with nivolumab in solid tumors
Victor Moreno Garcia (START Madrid-Fundacion Jimenez Diaz, Madrid, Spain) reported results from the phase 1 SURPASS trial of ADP-A2M4CD8 (ADP) in solid tumors. ADP is a next-generation T cell receptor (TCR) T cell therapy targeting melanoma –associated antigen A4 (MAGE-A4), modified with expression of a CD8 alpha coreceptor for increased potency. 56 patients with unresectable/metastatic solid tumors who received a median of 3 prior lines of systemic therapy received ADP monotherapy (n=46) or ADP combined with nivolumab or pembrolizumab (n=10) after lymphodepletion. A variety of solid tumors were repesented, including ovarian cancer (n=18), urothelial cancer (n=7), and head and neck cancer (n=4). The safety profile of the ADP + nivolumab arm was comparable to the profile of the ADP monotherapy arm. 75% of patients experienced cytokine release syndrome, with the majority of cases of grades 1 or 2, and 16% of patients experienced neurotoxicity. Overall response rate (ORR) of the ADP monotherapy arm was 34.8%, with a median duration of response of 21 weeks. One patient in the ADP + nivolumab arm responded to treatment, and their response lasted 30 weeks. ORR was 40% in patients with ovarian cancer, 75% in patients with head and neck cancer, and 57.1% in patients with urothelial cancer. Better response rates correlated with fewer lines of therapy; ORR among patients receiving three or fewer prior lines of therapy was 44%, compared to an ORR of 24% for patients receiving four or more prior lines. Tumor biopsies indicated that endogenous and engineered T cells infiltrated a variety of tumor types. ADP triggered innate and adaptive immune responses in a variety of tumor types, as indicated by a higher M1/M2 macrophage ratio and a lower M2/cytotoxic T cell ratio. ADP-A2M4CD8 exhibits an acceptable safety profile and encouraging anti-tumor activity in a variety of solid tumors. Increased response rates among patients with ovarian, head and neck, or urothelial cancers and among patients with fewer prior lines of systemic therapy indicate that earlier screening or apheresis of trial participants may increase clinical efficacy.
TGF beta cancer-associated fibroblast gene signature as a prognostic factor for disease free survival in early-stage lung cancer
1264MO. IMpower010: Exploratory analysis of disease-free survival (DFS) by TGF beta cancer-associated fibroblast (CAF) gene signature expression in patients (pts) with resected NSCLC treated with atezolizumab (atezo) or best supportive care (BSC)
Nasser K. Altorki (New York Presbyterian-Weill Cornell Medical Center, New York, United States of America) presented exploratory analysis of the IMpower010 clinical trial, in which atezolizumab showed significant gains in disease-free survival (DFS) compared to best supportive care (BSC) for resected early-stage non-small cell lung cancer (NSCLC) after chemotherapy. Results from this trial led to FDA approval of atezolizumab after adjuvant chemotherapy. Bulk RNA sequencing was performed on resected tumors to examine tumor microenvironment (TME) features predictive of DFS benefit with atezolizmab compared with BSC. 500 patients were included in the RNAseq biomarker-evaluable population, representing 50% of the intent-to-treat population. The TGF beta cancer associated fibroblast (CAF) gene signature was the gene signature most frequently associated with atezolizumab DFS benefit. TGF beta is generally associated with promotion of tumor growth and immune suppression of TME, and TGF-beta-induced CAFs are associated with poor prognosis. In the BSC arm, TGF beta CAF-high signature was associated with a worse prognosis than the TGF beta CAF-low signature (29.7 months vs 37.3 months, respectively; HR 1.6), suggesting high TGF beta CAF may be a predictor of poor DFS. In the atezolizumab arm, there was no difference in DFS of the two gene signature groups (HR 0.90). In the TGF beta CAF-high subgroup, atezolizumab was associated with DFS benefits, regardless of histology and PD0L1 expression level. These data indicate that high TGF beta CAF may be a potential prognostic factor for poor DFS with early-stage NSCLC and that patients with high TGF beta CAF may be associated with improved DFS after adjuvant atezolizumab compared to BSC. The sample size of this study was limited, and validation of the TGF beta CAF signature in additional NSCLC data sets is needed.
Circulating tumor DNA dynamics in patients receiving neoadjuvant chemoimmunotherapy and adjuvant immunotherapy for resectable lung cancer
LBA59. Associations of ctDNA clearance and pathological response with neoadjuvant treatment in patients with resectable NSCLC from the phase III AEGEAN trial
Martin Reck (Lung Clinic Grosshansdorf, Grosshansdorf, Germany) presented exploratory analysis of the AEGEAN trial, which previously reported perioperative durvalumab + neoadjuvant chemotherapy improved pathological complete response (pCR), major pathological response (MPR), and event-free survival (EFS) compared to neoadjuvant chemotherapy among patients with resectable non-small cell lung cancer (NSCLC). Results from the AEGEAN trial and others suggest pCR and MPR after neoadjuvant treatment are promising predictors for improved EFS and OS but can only be evaluated after surgical resection. This current study examined the association of circulating tumor DNA (ctDNA) clearance (CL) from patient plasma samples with pCR and MPR. Plasma samples had been collected during each cycle of neoadjuvant treatment and before surgery, and ctDNA was evaluated from 831 plasma samples from 186 patients (90 patients from durvalumab arm, 96 patients from placebo arm). Decreases in median ctDNA variant allele fractions (VAFs) were observed as early as Day 1 of Cycle 2 of neoadjuvant treatment. A greater reduction in median VAF was observed in the durvalumab arm versus the placebo arm. Among patients who were ctDNA-positive at baseline, all patients with a pCR and more than 90% of patients with an MPR had ctDNA clearance by Day 1 of Cycle 4 of neoadjuvant treatment. Patients without ctDNA clearance after neoadjuvant treatment were unlikely to achieve pCR. Data from this analysis indicate that ctDNA clearance after neoadjuvant treatment with durvalumab and chemotherapy may act as a biomarker of early response and identify patients who benefit from treatment prior to surgical resection. Further analyses of ctDNA from patients in the AEGEAN trial are planned.
CLDN6 CAR T cells combined with a CAR T cell-amplifying RNA vaccine in solid tumors
LBA35. BNT211-01: Interim results from a repeat dose escalation study of CLDN6 CAR-T cells manufactured with an automated process ± a CLDN6-encoding CAR-T cell-amplifying RNA Vaccine (CARVac)
John B. Haanen (Netherlands Cancer Institute, Amsterdam, Netherlands) reported interim results from BNT2111-01, which investigated CAR T cells targeting CLDN6 with and without a CAR T cell-amplifying RNA vaccine (CARVac). CLDN6 is an ideal target for CAR T cells in solid tumors, as it is absent in healthy adult tissues. Prior studies indicate treatment with manually manufactured CLDN6 CAR T cells and CARVac show promise against relapsed/refractory CLDN6+ tumors. In this study, 44 patients (17 with ovarian cancer and 16 with germ cell tumors) were dosed with CAR T cells at four dose levels, and CAR T cells were manufactured by an automated process. 68% of patients experienced treatment emergent adverse events of grade 3 or higher, and toxicities were more common at higher CAR T cell dose levels. 38 patients were evaluable for efficacy; the objective response rate (ORR) was 44.7%, and disease control rate (DCR) was 73.7%. Among patients who received dose level 2 (DL2) of 1 x 108 CAR T cells (n=27), ORR was 59% and DCR was 95%. Responses of patients in the DL2 cohort deepened over time, and CAR T cell persistence was improved in patients who received CARVac, with CAR T cells detected in several patients up to 100 days after infusion. CLDN6 CAR T cells combined with CAR Vac shows promising results with regards to safety and efficacy. Work to identify the recommended phase 2 dose of CLDN6 CAR T cells for a clinical trial in germ cell tumors is ongoing.