The Society for Immunotherapy of Cancer (SITC) is pleased to present highlights of the latest advances in immunotherapy emerging from the ASCO 2024 Annual Meeting. Below is a recap of highlighted research presented from Friday, May 31, 2024.
2024 Scientific Highlights
Phase I study of immune checkpoint inhibition for advanced secondary angiosarcomas
11513. Cemiplimab in locally advanced and/or metastatic secondary angiosarcomas (CEMangio): A phase II clinical trial.
Stefan van Ravensteijn (Radboud UMC, Nijmegen, Gelderland, Netherlands) presented a single-arm multicenter phase II clinical trial investigating the efficacy and safety of cemiplimab, an anti-PD-1 immune checkpoint inhibitor, for locally advanced or metastatic secondary angiosarcomas (sAS). sAS usually arises from DNA damaging factors such as radiotherapy, UV radiation, or chronic lymphedema. sAS are associated with poor prognosis (survival of 5-10 months) and limited treatment options, but its immunologic and genomic profiles indicate it could potentially respond to immunotherapy. 18 patients with locally advanced or metastatic sAS were included in the study. Cemiplimab represented first line treatment for 10 patients, second line treatment for 6 and third line for 2. At a median follow-up of 8.0 months, the best overall response rate (BORR) was 27.8%, with a partial response (PR) in 3 patients and 2 ongoing complete responses. Median time to response was 2.6 months, and median duration of response was 6.2 months, Median progression free survival 3.1 months, and median overall survival was 11 months. All patients experienced adverse events, with 10 patients (55.6%) experiencing an adverse event of grade 3 or higher. Next generation sequencing was conducted on tumor tissue from 17 patients. 3 patients (17.6%) exhibited a high tumor mutation burden of over 10 mutations/Mb, and 2 of those patients experienced a partial response to cemiplimab. Mutations in DNA damage response genes were identified in 9 patients (52.9%) and were not associated with a clinical response. Further translational studies of the patient population are ongoing. Cemiplimab shows promising clinical efficacy and a manageable safety profile against secondary angiosarcomas, in a patient population largely receiving first-line treatment. Larger single-arm or randomized phase II/III clinical trials are necessary to further explore the efficacy and safety of immune checkpoint inhibitors for secondary angiosarcomas.
A TROP2-targeting antibody drug conjugate combined with immune checkpoint inhibitor for advanced non-small cell lung cancer produces promising clinical results
8502. Sacituzumab tirumotecan (SKB264/MK-2870) in combination with KL-A167 (anti-PD-L1) as first-line treatment for patients with advanced NSCLC from the phase II OptiTROP-Lung01 study.
Wenfeng Fang (Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China) reported results from the phase II OptiTROP-Lung01 study, investigating the efficacy of sacituzumab tirumotecan (sac-TMT), an antibody drug conjugate combined with KL-A167, an anti-PD-L1 immune checkpoint inhibitor, in patients with advanced non-small cell lung cancer (NSCLC). Sac-TMT targets the transmembrane glycoprotein TROP2, which is overexpressed in approximately 70% of NSCLC cases. Sac-TMT features a novel linker that permits the release of the payload drug in the TME and within the tumor cell, providing a balance between safety and efficacy. Patients enrolled in cohort 1A (n=40) received sac-TMT 5 mg/kg and KL-A167 1200 mg every three weeks, and patients enrolled in cohort 1B (n=63) received sac-TMT 5 mg/kg and KL-A167 900 mg every two weeks. The overall response rates for cohorts 1A and 1B were 48.6% and 77.6%, respectively, and median progression free survival (PFS) for cohort 1A was 15.4 months for cohort 1A and not reached for cohort 1B. (6-month PFS rates were 69.2% and 84.6%, respectively.) Based on its increased clinical efficacy, the dosing protocol for cohort 1B was chosen for future studies. Although clinical benefits were observed in subgroups regardless of PD-L1 expression and histology, higher ORR was associated with higher levels of PD-L1 expression (ORR in PD-L1 TPS <1, 1-49%, and >= 50% were 63.2%, 81.3%,and 87.0%, respectively) and with squamous histology (ORR in non-squamous and squamous subgroups were 72.7% and 84.0%, respectively). The 6-month progression free survival rate was 84.6%. The safety profile of sac-TMT plus KL-A167 was manageable and consistent with the known profiles of each individual drug. Hematologic adverse events of grade 3 or higher were more frequently observed with the cohort 1A dosing regimen than the cohort 1B dosing regimen. These data suggest that the TROP2-targeting antibody drug conjugate sacituzumab tirumotecan combined with immune checkpoint inhibitor produces promising clinical results in patients with advanced NSCLC, and 3 phase III trials of this combination therapy are ongoing.
For a study of immune-related pneumonitis associated with immune checkpoint inhibitors in lung cancer authored by Dr. Feng and colleagues, read this research article from Chen et al in JITC.
CAR T cell persistence is associated with improved event free survival among patients in remission after treatment with obecabtagene autoleucel for refractory B-cell acute lymphoblastic leukemia
6504. Obecabtagene autoleucel (obe-cel, AUTO1) in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL): Overall survival (OS), event-free survival (EFS) and the potential impact of chimeric antigen receptor (CAR)-T cell persistency and consolidative stem cell transplantation (SCT) in the open-label, single-arm FELIX phase Ib/II study.
Elias Jabbour (The University of Texas MD Anderson Cancer Center, Houston, TX) presented overall survival (OS) and event-free survival (EFS) from the single arm FELIX phase Ib/II clinical trial, investigating obecabtagene autoleucel (obe-cel) for relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL). Obe-cel is an autologous CAR-T cell designed with a fast off-rate CD19 binder to mitigate toxicity and improve persistence. Patients received bridging therapy as needed and underwent lymphodepletion followed by obe-cel split dose infusions on Days 1 and 10 at a target dose of 410 x 10^6 CAR T cells. 127/153 patients received obe-cel infusion. At a median follow-up of 16.6 months, the overall complete remission or complete remission with incomplete count recovery rate among infused patients was 78% (n=99). Among the 99 responders, 40% retained remission without subsequent therapy or stem cell transplantation (SCT), and 18% of responders received SCT. All patients who received SCT were measurable residual disease (MRD)-negative at the time of transplant. SCT did not significantly affect event free survival (EFS) or overall survival (OS). The 12-month EFS rate was 49.5% and 44.0% with and without censoring for consolidative SCT, respectively. 12-month OS rate was 61% and 59% with and without censoring for consolidative SCT, respectively. Ongoing CAR T persistence correlated with long-term EFS, with a 12-month EFS rate of 87.3% among patients with ongoing CAR T cell persistence compared to 59.3% among patients with a loss of persistence. These data indicate that SCT consolidation for patients in remission after obe-cel does not significantly improve survival, and persistence of CAR T cells is associated with improved event-free survival, supporting obe-cel as a potential standard of care for patients with R/R B-ALL.
Preliminary safety and efficacy data of a CD3 x CD19 bispecific antibody for relapsed or refractory B-cell acute lymphoblastic leukemia
6505. Phase I study of CN201, a novel CD3xCD19 IgG4 bispecific antibody, in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia.
Ying Wang (Institute of Hematology and Blood Disease Hospital, CAMS & PUMC, Tianjin, China) reported data from the dose escalation and expansion stage of a phase I trial of CN201, a novel CD3- and CD19-targeting bispecific T cell engager for relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). CN201 exhibits adjusted CD3 affinity to minimize risk of cytokine release syndrome (CRS). Patients with B-ALL refractory to primary induction therapy or salvage therapy or relapse received CN201 intravenously once per week with step-up dose approach. 51 patients enrolled in the study, and 40 patients received their target dose. Clinical efficacy was dose-dependent, with 67% of patients receiving a target dose of 10 mg or above achieving a complete response (CR), compared to 75% (12/16) of patients receiving 20 mg and above as a target dose achieving a complete response. Efficacy was also achieved in patients with high tumor burden: all three patients who received a target dose of 60 mg had more than 50% blasts in baseline bone marrow, and all 3 achieved a complete response. The longest response has lasted more than 8 months. CN201 is well-tolerated, with all cases of CRS being managed and no reported neurotoxicities. These preliminary data indicate that CN201 exhibits promising clinical activity among patients with R/R B-ALL, and additional analyses are ongoing.
For a study of cardiovascular toxicities associated with bispecific T cell engagers, read this article from Sayed et al in JITC.
Safety and clinical efficacy of a PD-1 x VEGF bispecific antibody combined with chemotherapy for non-small cell lung cancer that progressed on EGFR tyrosine kinase inhibitor treatment
8508. Ivonescimab combined with chemotherapy in patients with EGFR-mutant non-squamous non-small cell lung cancer who progressed on EGFR tyrosine-kinase inhibitor treatment (HARMONi-A): A randomized, double-blind, multi-center, phase 3 trial.
Li Zhang (Sun Yat-sen University Cancer Center, Guangzhou, China) presented safety and efficacy results from HARMONi-A, a phase III trial comparing ivonescimab combined with chemotherapy to chemotherapy alone for EGFR-mutated non-small cell lung cancer (NSCLC) that progressed on EGFR tyrosine kinase inhibitor (TKI) treatment. Ivonescimab is a bispecific antibody targeting PD-1 and VEGF. Previous phase II studies indicate ivonescimab plus chemotherapy exhibits a promising safety and efficacy profile in patients with NSCLC. Patients were randomized 1:1 to receive ivonescimab plus pemetrexed and carboplatin (ivonescimab plus chemotherapy arm, n=161) or placebo plus pemetrexed and carboplatin (chemotherapy arm; n=161). At a median follow-up time of 7.89 months, progression free survival (PFS) was significantly improved in the ivonescimab plus chemotherapy arm compared to the chemotherapy arm, with median PFS of 7.1 months and 4.8 months, respectively (HR 0.46, p<0.0001). Subgroup analysis indicated PFS benefit favoring ivonescimab plus chemotherapy across almost all subgroups, including patients whose disease progressed on treatment with third generation EFGR-TKIs (HR 0.48), those with brain metastases (HR 0.40), those with EFGR deletion 19 (HR 0.22). Overall response rate was 50.6% for the ivonescimab plus chemotherapy arm and 35.4 % for the chemotherapy arm, and median duration of response was 6.6 months in the ivonescimab plus chemotherapy arm, compared to 4.2 months in the chemotherapy arm. Disease control rates for the ivonescimab plus chemotherapy arm and the chemotherapy arm were 93.1% and 83.2%, respectively. Survival data for both arms are not yet mature, but early analyses indicate a favorable trend for the ivonescimab plus chemotherapy arm. Combination treatment with ivonescimab and chemotherapy was tolerable, and treatment-related adverse events were manageable and caused no deaths. Ivonescimab combined with chemotherapy has been approved in China, and the HARMONi-A trial is being expanded globally, thus ivonescimab plus chemotherapy may represent a new treatment option for patients with NSCLC that progresses after EGFR TKI therapy.