The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the ESMO Congress 2024 . Below is a recap of highlighted research presented from Friday, Sept. 13, 2024 and Saturday, Sept. 14, 2024.
Comparing overall survival associated with BCMA-targeting CAR T cell therapies vs. bispecific antibodies for multiple myeloma
802MO. Real-world comparison of overall survival between BCMA - bispecific and CAR-T therapies in multiple myeloma
Junmin Song (Albert Einstein College of Medicine, Bronx, NY, United States of America) presented a retrospective study comparing the overall survival rates and the frequencies of side effects of BCMA -targeting CAR T cellular therapies (ide-cel or cilta-cel) with BCMA-targeting bispecific antibodies (teclistamab). Patient data from the TriNetX US Collaborative Network were used in the study, and patients with multiple myeloma aged 18-90 who received CAR T cellular therapy (ide-cel or cilta-cel) or teclistamab were included in the study. Patient cohorts were matched, and all-mortality rates and adverse event rates were compared among patients who received CAR T cellular therapy (n=262) vs. teclistamab (n=262). All-cause mortality rates at the 12-month follow-up were significantly lower for patients who received CAR T cellular therapy compared to teclistamab (40/262 and 64/262, respectively; HR 0.52, p=0.001). A similar pattern was observed at the 1-month, 3-month, and 6-month follow-up, and significant differences were observed at 3 and 6 months. Patients who received CAR T cellular therapy had a significantly higher risk of developing cytokine release syndrome (CRS) at the 1-, 3-, 6-, and 12-month follow-up, compared to patients who received teclistamab (120/262 vs. 88/262; HR 1.4, p=0.013), and CRS usually occurred within the first month of initiating treatment. No significant differences were observed in the rates of immune effector cell-associated neurotoxicity syndrome (ICANS), which occurred in 49/262 patients who received CAR T cellular therapy compared to 42/262 patients who received teclistamab (HR 1.12). This is the first report comparing survival in a real-world setting between BCMA-targeting CAR-T cellular therapies and bispecifics. Although more time is needed to analyze patient data beyond the 12-month follow-up, these results indicate that for the first year following initiation of treatment for multiple myeloma, CAR-T cellular therapy is associated with a significantly higher survival rate compared to bispecifics, and patients who receive BCMA-targeting CAR-T cellular therapy have a higher risk of developing CRS compared to patients receiving bispecifics.
Clinical efficacy of an engineered oncolytic virus in combination with atezolizumab for advanced malignant melanoma
988O. A phase I/II trial (LOKON003) evaluating tumor microenvironment (TME) gene engineering using a viral vector combined with atezolizumab in advanced malignant melanoma
Gustav J. Ullenhag (Uppsala University, Uppsala, Sweden) presented results from a LOKON003, a clinical trial evaluating delolimogene mupadenorepvec (LOAd703), an oncolytic adenovirus that induces a systemic anti-tumor immune response, in patients with advanced melanoma. LOAd703 expresses membrane-bound CD40L and full-length 4-1BBL, which induce stromal inflammation and subsequent immune cell-mediated killing of tumor cells and tumor immunity. LOAd703, which is administered intratumorally, replicates selectively in tumor cells resulting in selective oncolytic cell death. Previous studies indicate LOAd703 exhibits clinical efficacy as monotherapy against pancreatic cancer and mixed solid tumors. As well as in combination with chemotherapy against advanced solid tumors. 24 patients with stage IV cutaneous malignant melanoma that had progressed on PD-(L)1 blockade were enrolled in the study. Patients received LOAd703 and atezolizumab every three weeks. The combination of LOAd703 and atezolizumab was overall well tolerated with 4 patients developing cytokine release syndrome. Median progression free survival (PFS) was 3.4 months, and 12-month PFS was 20.8%. The objective response rate was 16.7%, and 29% of patients exhibited disease control for six months or longer. Median overall survival (OS) was 9.3 months, and the 12-month survival rate was 58.3%. Median OS (26.3 months) was highest among patients who received the lowest dose of LOAd703 (1 x 1011 viral particles(VP), suggesting the lowest dose may be the most effective. This finding is supported by previous clinical studies of LOAd703 for pancreatic cancer with the same most effective dose. Tumor biopsies suggested LOAd703 induced Th1-dependent stroma inflammation and upregulation of biomarkers for T cell activation, recruitment, and killing. Biomarker screening in blood indicated upregulation of similar markers associated with immune activation. The data indicate that LOAd703 in combination with atezolizumab was well tolerated and produced encouraging clinical efficacy in patients with PD-(L)1 blockade refractory advanced metastatic melanoma. LOAd703 in combination with PD-1 and LAG-3 blockade is currently being considered for an upcoming trial.
Blockade of the immune checkpoint ILT2 as monotherapy and in combination with pembrolizumab or cetuximab for advanced solid tumors
990O. Final results from Phase 1, first-in-human, dose escalation study of a first-in-class anti-ILT2 antibody, SAR444881, alone and with pembrolizumab or cetuximab, in patients with advanced solid tumors
Ruth Perets (Rambam Medical Center, Haifa, Israel) presented final results of a Phase 1, first-in-human study of the anti-ILT2 antibody SAR444881 as monotherapy and in combination with pembrolizumab (anti-PD-1) or cetuximab (anti-EGFR) in patients with advanced solid tumors. SAR444881 is a first-in-class antibody against the immune checkpoint ILT2, which is found on macrophages, CD8+ T cells, and NK cells. Previous preclinical studies have indicated SAR444881 enhances the anti-tumor activity of macrophages, T lymphocytes, and NK cells. While in vitro studies indicate SAR444881 also enhances the pro-phagocytic activity of the anti-EGFR antibody cetuximab. 76 patients with advanced solid tumors were enrolled in the dose escalation phase of the study, and 31 patients received SAR444881 monotherapy, 23 received SAR444881 in combination with pembrolizumab, and 22 patients received SAR444881 in combination with cetuximab. 36 patients in the study had colorectal cancer, 12 patients had cholangicarcionma, and 8 patients had non-small cell lung cancer. Gastrointestinal, gynecological, and renal cancer were also represented in the study. SAR444881 monotherapy and combination treatment was well-tolerated. No dose limiting toxicities were observed in any of the arms, and the maximum tolerated dose was not reached. Overall response rates (ORR) in the SAR444881 monotherapy arm and SAR444881+pembrolizumab arm were 3.2% and 4.3%, respectively. In the SAR444881+cetuximab arm, the ORR was 9.1%, and the disease control rate was 50%. Two patients achieved partial responses that lasted 6.6 and 18 months. Tumor shrinkage was observed in 4 patients SAR444881+cetuximab arm who had previously progressed on prior anti-EGFR treatment. SAR444881 occupied over 90% of ILT2 receptors of monocytes at SAR444881 doses of 3 mg/kg or higher, and SAR444881 monotherapy induced upregulation of activation markers in monocytes and ILT2-expressing subsets of T cells and NK cells in a dose-dependent manner. SAR444881 was well-tolerated as a monotherapy and in combination with other therapeutic monoclonal antibodies. These data provide initial support for the targeting of ILT2 for the treatment of advanced solid tumors. A Phase 2 dose optimization and expansion study of SAR444881 for advanced solid tumors is currently enrolling patients.
Immune checkpoint inhibitors for chronic HPV-associated recurrent respiratory papillomatosis
992O. Pembrolizumab for HPV-associated recurrent respiratory papillomatosis
Sara Pai (Yale University School of Medicine, New Haven, CT, United States of America) reported results of a single-arm Phase II study of pembrolizumab for the treatment of recurrent respiratory papillomatosis (RRP), an orphan disease caused by infection with human papillomavirus (HPV) types 6 and 11. RRP affects both children and adults, with 3 to 5% of RRP lesions transforming to invasive cancer. There is no cure for RRP: it is usually treated by multiple surgeries over the lifetime of the patient to remove papillomas from the respiratory tract, underscoring an unmet need for systemic therapies in the treatment of RRP. Because chronic HPV infection is associated with a toleregenic immune response, the immune checkpoint inhibitor pembrolizumab was investigated as a potential treatment for RRP. 21 patients with confirmed HPV RRP who had undergone 3 or more procedures over a 12-month period received pembrolizumab every three weeks. 10 patients had juvenile onset RRP, and 11 patients had adult onset RRP. Treatment-related adverse events (TRAEs) were noted in five patients TRAEs of Grade 3 or higher observed in the study population. The partial response rate was 52%, with 60% of patients with juvenile onset and 45.5% of patients with adult onset experiencing a partial response, indicated by tumor regression. The median duration of response was 14 months for both patient subgroups, and the median number of required surgeries was reduced by 4 per year compared to baseline (p<0.01). Treatment with pembrolizumab increased IFN gamma secretion by HPV-specific T cells, suggesting pembrolizumab modulated patient immune responses. Responding patients exhibited increased levels of CD8 and CD4 T helper cells, increased clustering of T helper cells with LAMP3-positive dendritic cells, and subsequent increased CD8 T cell mobilization within papillomas. These data indicate pembrolizumab treatment was well-tolerated in a patient population with chronic HPV infection and was associated with durable clinical benefits and avoidance of surgery-based interventions.
Identifying patients most likely to benefit from LAG-3 checkpoint blockade for first line treatment of advanced non-small cell lung cancer
LBA53. Nivolumab (NIVO) plus relatlimab with platinum-doublet chemotherapy (PDCT) vs NIVO + PDCT as first-line (1L) treatment (tx) for stage IV or recurrent NSCLC: Results from the randomized phase 2 RELATIVITY-104 study
Nicolas Girard (Institut Curie, Paris, France) reported Phase 2 results from RELATIVITY-104, the first randomized phase 2 trial comparing PD-1 blocking antibody nivolumab (NIVO) in combination with LAG-3 blocking antibody relatlimab (RELA) and platinum-doublet chemotherapy (PDCT) versus NIVO in combination with PDCT as first line treatment for metastatic non-small cell lung cancer (NSCLC). Prior studies indicated NIVO + RELA significantly improved progression free survival (PFS) compared to NIVO monotherapy for advanced melanoma, leading to its approval by the U.S. Food and Drug Administration. 158 patients were treated with NIVO + RELA + PDCT, and 151 patients were treated with NIVO + PDCT. Safety was comparable between the two arms, with 54% of patients in the NIVO + RELA + PDCT arm and 55% of patients in the NIVO + PDCT arm experiencing Grade 3 or 4 treatment-related adverse events (TRAEs). 6 patients in the NIVO + RELA + PDCT arm died due to TRAEs, compared to 5 patients in the NIVO + RELA arm. At a median follow-up of 10.7 months, median PFS was 6.7 months in the NIVO + RELA + PDCT arm, compared to 6.0 in the NIVO + PDCT arm, and RELA was associated with a 7.6% increase in overall response rate (ORR; 51.3% in the NIVO + RELA + PDCT arm vs. 43.7% in the NIVO + PDCT arm). Median duration of response was 10.1 months in the NIVO + RELA + PDCT arm and 9.1 months in the NIVO + PDCT arm. Among patients with tumors expressing PD-L1 (TPS 1% or higher), NIVO + RELA + PDCT compared to NIVO + PDCT was associated with improvements in median PFS (9.8 months vs. 6.1 months, respectively, HR 0.63) and ORR (53.2% vs. 40.8%). This trend was not observed among patients with PD-L1 negative tumors (TPS less than 1%). NIVO + RELA + PDCT compared to NIVO + PDCT was also associated with PFS and ORR benefits among patients with a non-squamous tumor histology (PFS HR 0.86). When patients were stratified by PD-L1 expression and tumor histology, patients with PD-L1 expressing non-squamous tumors had a median PFS of 11.6 months and ORR of 58.0% if treated with NIVO + RELA + PDCT arm (n=50) compared to median PFS of 6.9 months (HR 0.55)and 39.6% ORR if treated with NIVO + PDCT (n=48). Improved PFS benefits with NIVO+RELA+PDCT were observed among those patients with tumors expressing PD-L1 measured at 1-49% and non-squamous histology (9.8 months for NIVO+RELA+PDCT (n=28) vs. 5.6 months for NIVO+PDCT (n=20), HR 0.45). These data provide the first proof-of-concept that adding LAG-3 inhibition to PD-1 blockade and chemotherapy improves clinical outcomes for patients with metastatic NSCLC, especially those with PD-L1-expressing tumors with non-squamous histology. RELATIVITY-1093, a phase 3 study of NIVO+RELA+PDCT as first line treatment for patients with metastatic NSCLC with PD-L1 expression 1 to 49% and non-squamous histology is ongoing. An additional phase 3 study for patients with metastatic NSCLC with non-squamous tumors expressing PD-L1 of 50% or is currently under development.
Distant metastasis-free survival results and final response rates for the NADINA trial comparing neoadjuvant therapy with adjuvant therapy for resectable macroscopic stage III melanoma
LBA42. Distant metastasis-free survival of neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in resectable, macroscopic stage III melanoma: the NADINA trial
Minke W. Lucas (Netherlands Cancer Institute, Amsterdam, Netherlands) presented distant metastasis-free survival (DMFS) data from the NADINA trial, which compared the efficacy of neoadjuvant nivolumab plus ipilimumab (nivo+ipi) with adjuvant nivolumab for resectable macroscopic stage III melanoma. The NADINA trial previously demonstrated that neoadjuvant nivo+ipi is associated with improved event free survival compared to adjuvant nivolumab. In the NADINA trial, patients with stage III resectable melanoma with at least one lymph node metastasis received neoadjuvant treatment with ipi+nivo (neoadjuvant arm) or no neoadjuvant treatment (adjuvant arm). Patients in both arms underwent total lymph node dissection (TLND). Patients in the adjuvant arm received adjuvant therapy with nivo with or without radiotherapy. Patients in the neoadjuvant arm who did not achieve a major pathologic response (MPR) after TLND received adjuvant therapy of dabrafenib and trametinib for BRAF mutants and nivolumab for BRAF wild type, with or without radiotherapy. Patients who achieved an MPR did not receive any adjuvant treatment after surgery. With a median follow-up of 15.4 months, the neoadjuvant arm exhibited significant increases in event-free survival (EFS) compared to the adjuvant arm (HR 0.32, p<0.001). The estimated 18-month EFS for the neoadjuvant arm and adjuvant arm were 80.8% and 53.9%, respectively. Significant gains in DMFS were also observed when comparing the neoadjuvant arm to the adjuvant arm (HR 0.37, p<0.001), with estimated 18-month rates of 85.7% and 62.4%, respectively. The first metastases in 29 patients in the neoadjuvant arm (n=212) and 65 patients in the adjuvant arm (n=211) were distant metastases, and the most common location for both treatment arms was the lungs. Neoadjuvant therapy significantly improved RFS compared to adjuvant therapy among patients with stage IIIB disease (HR 0.25, p<0.001) and stage IIIC disease (HR 0.29, p<0.001). DMFS was also improved for Stage IIIB disease (HR 0.23, p<0.001) and stage IIIC disease (HR 0.34, p<0.001). The final radiological response rate for the neoadjuvant arm was 37.2%, and 43% of patients had stable disease. The final major pathological response (MPR) rate for the neoadjuvant arm was 60.8%, with 49.1% of patients achieving a complete pathological response. Within the neoadjuvant arm, RFS and DMFS correlated with radiological response and with pathological response. Data from this interim report is consistent with previous reports. The final MPR and radiological response rates of 60.8% and 37.2%, respectively, providing further support for considering neoadjuvant treatment with nivolumab and ipilimumab over adjuvant treatment with nivolumab as the new standard of care for treating resectable, macroscopic stage III melanoma.
Neoadjuvant treatment with TROP2-targeting antibody drug conjugate in combination with durvalumab for treatment of stage II/III high risk HER2-negative breast cancer
LBA15. Rates of pathologic complete response (pCR) after datopotamab deruxtecan (dato) plus durvalumab (durva) treatment strategy in the neoadjuvant setting: Results from the I-SPY 2.2 trial
Meghna S. Trivedi (Columbia University Irving Medical Center, New York, NY, United States of America) presented results from an arm of the adaptive Phase 2 I-SPY 2.2 trial exploring the efficacy of neoadjuvant treatment with the TROP2-directed antibody drug conjugate datopotamab deruxtecan (dato) in combination with immune checkpoint inhibitor durvalumab (durva). In this adaptive trial design, 106 patients with stage II/III high risk (evaluated by MammaPrint) HER2-negative breast cancer received up to four cycles of dato+durva (Block A). Patients who responded went to surgery early. White remaining patients received taxane-based treatment regimens (Block B) that was specific to their biomarker-based response predictive subtype that included gene expression-based immune signatures (Immune), DNA repair deficiency (DRD), hormone receptor status, and HER2 status. Predicted non-responders after Block B proceeded to Block C of treatment to receive an anthracycline-based regimen. The overall pathologic complete response (pCR) rate was 50%, with the highest pCR rates observed in the Immune-positive and triple negative breast cancer subtypes at 79% and 62%, respectively. Patients with the hormone receptor (HR)-negative/HER2-negative/Immune-negative/DRD-negative subtype (n=23), a subtype with a historically low response rate, outperformed the control with a pathologic complete response (pCR) rate of 44%. Over half of all pCRs were achieved without receiving standard taxane-based chemotherapy (i.e. before Block B), and over 90% of all pCRs were achieved without anthracycline (i.e. before Block C). The toxicity profile was consistent with previous studies, and most adverse events were manageable. Although the patient population was relatively small, these data suggest that neoadjuvant treatment with dato + durva may allow for some patients with high risk HER2-negative breast cancer to avoid subsequent chemotherapy and chemotherapy-related adverse effects. Additional controlled clinical trials are needed to further investigate dato + durva treatment in the Immune-positive and the HR-negative/Immune-negative/DRD-negative subtypes.
Retifanlimab, an anti-PD-1 monclonal antibody, in combination with chemotherapy as a new standard of care for advanced squamous cell carcinoma of the anal canal.
LBA2. POD1UM-303/InterAACT 2: Phase 3 study of retifanlimab with carboplatin-paclitaxel (C-P) in patients (pts) With inoperable locally recurrent or metastatic squamous cell carcinoma of the anal canal (SCAC) not previously treated with systemic chemotherapy (chemo)
Sheela Rao (Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom) presented results from POD1UM-303, a phase 3 trial investigating the addition of humanized anti-PD-1 monoclonal antibody retifanlimab to standard of care chemotherapy for previously untreated/metastatic squamous cell carcinoma of the anal canal (SCAC). SCAC is an orphan disease, and relapse after primary standard of care chemoradiotherapy is common, indicating an unmet medical need. Results from the prior POD1UM-303/InterAACT 2 study indicated that retifanlimab exhibits anti-tumor activity against advanced SCAC that previously progressed on platinum-based chemotherapy. 308 patients participated in the study. Patients in the R arm (n=154) received standard dose carboplatin-paclitaxel (C-P) plus retifanlimab, and patients in the P arm (n=154) received standard dose C-P plus placebo every four weeks for up to one year. If patients in the P arm experienced progressive disease, crossover from the P arm was possible following observed progression; at the time of data cutoff, 69 patients in P arm had crossed over to the R arm. The study met its primary endpoint of progression free survival (PFS). Addition of retifanlimab to chemotherapy significantly improved PFS, with median PFS of 9.3 in the R arm compared to 7.4 months in the P arm (HR 0.63, p=0.0006). Overall survival (OS) on interim analysis (immature) indicated a strong trend of OS favoring the R arm compared to the P arm (median OS 29.2 months vs 23.0 months, respectively, HR 0.70, p=0.0273). Similar trends were observed after adjusting for patient crossover from the P arm to the R arm (R arm median OS 29.2 months vs. P arm 19.1 months, HR 0.63, p=0.0055). Overall response rates in the R arm and P arm were ORR 56% and 44.2%, respectively (p=0.0129), disease control rates were 87% and 80%, respectively, , and median durations of response were 14.0 months and 7.2 months, respectively. More adverse events (AEs) and immune-related AEs re associated with retifanlimab, which is consistent with prior phase 2 data, and at data cutoff, 90 patients (58.4%) in the R arm remain in the study. These results indicate that addition of retifanlimab to standard of care chemotherapy provides significant clinical benefits to patients with advanced SCAC, representing a potential new reference treatment and standard of care for patients with advanced SCAC.
Overall survival data for ENGOT-cx11/GOG-3047/KEYNOTE-A18: Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer
709O. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: Overall survival results from the randomized, double-blind, phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study
Domenica Lorusso (Fondazione Policlinico Universitario A. Gemelli IRCCS, Milan, Italy) presented overall survival (OS) results from the second interim analysis of the phase 3 ENGOT-cx11/GOG-3047/KEYNOTE-A18 study investigating pembrolizumab (pembro) with concurrent chemoradiotherapy (CCRT) for patients with high-risk locally advanced cervical cancer (LACC). The first interim analysis of the study indicated that pembro +CCRT showed a significant improvement in progression free survival (PFS) compared to placebo (pbo) + CCRT, leading to approval of pembro + CCRT for patients with FIGO 2014 Stage III-IVA cervical cancer. Treatment-naïve patients with locally advanced cervical cancer (FIGO stage IB-IIB or III-IVA) were treated with pembro + CCRT (pembro arm; n=528) or with pbo + CCRT (pbo arm; n=530). At the time of data cutoff, 42% of patients in the pembro arm and 39% of patients in the pbo arm had completed treatment, and 16% of patients from each arm were continuing treatment. Updated PFS data indicated a sustained benefit with pembrolizumab: 36-month PFS was 69% in the pembro arm, compared to 57% in the pbo arm (HR 0.68), and median PFS was not reached in either arm. A consistent benefit with pembro was observed across patient subgroups, especially among patients with FIGO 2014 stage III to IVA disease. The addition of pembrolizumab to CCRT also significantly improved OS. At a median follow-up of 29.9 months, the 36-month OS rate was 83% in the pembro arm, compared to 75% in the pbo arm (HR 0.67, p=0.0040), and median OS was not reached for either arm. Survival benefit with pembro + CCRT was consistently observed across all patient subgroups. Overall response rates were 88% and 84% in the pembro and pbo arms, respectively, and responses lasted 24 months or longer in 77% of patients in the pembro arm and 67% of patients in the pbo arm. No new safety signals were reported, and 69% of patients in the pembro arm experienced a treatment related adverse event of Grade 3 or higher, compared to 61% of patients in the pbo arm. The updated survival and safety data support previous reports indicating that pembro + CCRT provides significant survival benefits to this patient population and further support pembrolizumab in combination with CCRT as a new standard of care for patients with newly diagnosed, previously untreated LACC.