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 Saturday, June 1, 2024.
2024 Scientific Highlights
Safety and efficacy of a cell-based immunotherapeutic vaccine combined with durvalumab for second-line treatment of HPV 16- or 18-positive cervical cancer
5513. An open label, single arm phase II, multicenter trial of durvalumab and BVAC-C, in patients with HPV 16- or 18-positive cervical cancer and failure of first-line platinum-based chemotherapy (DURBAC).
Chel Hun Choi (Department of Obstetrics and Gynecology, Samsung Medical Center, Seoul, South Korea) presented results from an ongoing phase II clinical trial investigating the potential synergistic effects of combining BVAC-C, an immunotherapeutic vaccine, with durvalumab, an anti-PD-L1 immune checkpoint inhibitor, to enhance the anti-tumor immune response against HPV-positive recurrent cervical carcinoma. BVAC-C, a novel vaccine consisting of autologous B cells and monocytes transfected with recombinant E6/E7 gene of HPV type 16/18, has been shown to activate innate and adaptive immunity. Additionally, it has demonstrated clinical efficacy as monotherapy against HPV-positive cervical cancer in a prior phase I/IIa study. In the current trial, 40 patients enrolled in the study, and 31 received at least one dose of BVAC-C + durvalumab. Among the 29 patients available for interim analysis, the 6-month progression free survival (PFS) rate was 50%. The objective response rate was 38%, with 4 patients (14%) achieving a complete response and 7 patients (24%) achieving a partial response. Responses were observed among patients with HPV 16- and HPV 18-positive disease and with squamous cell carcinoma and adenocarcinoma histological subtypes. Median PFS was 8.7 months and median OS was not reached in the entire patient population. Among patients who responded to BVAC-C + durvalumab, the median PFS was 16.3 months. Patients exhibited elevated serum levels of IFN gamma and TNF alpha one day after BVAC-C treatment, which may indicate activation of NKT and NK cells. Adverse events were clinically manageable. Given its durable anti-tumor activity and manageable safety profile, combination therapy with BVAC-C and durvalumab holds promise as a second-line treatment option for recurrent HPV 16- or HPV 18-positive cervical cancer.
Interim results of SURE-01: neoadjuvant monotherapy with antibody drug conjugate sacituzumab govitecan for muscle-invasive urothelial bladder cancer
LBA4517. Perioperative sacituzumab govitecan (SG) alone or in combination with pembrolizumab (Pembro) for patients with muscle-invasive urothelial bladder cancer (MIBC): SURE-01/02 interim results.
Antonio Cigliola (Medical Oncology Department, IRCCS San Raffaele Hospital, Milan, Italy) reported interim results from the phase II SURE-01 trial evaluating neoadjuvant sacituzumab govitecan (SG) for muscle invasive urothelial bladder cancer (MIBC). SG, a TROP2-targeting antibody drug conjugate, recently received FDA accelerated approval for the treatment of locally advanced or metastatic urothelial carcinoma. Among the 21 patients who received at least one dose of SG, 12 patients experienced a treatment-related adverse event (TRAE) of grade 3 or higher, 1 patient experienced a grade 5 TRAE, and 2 patients experienced TRAEs leading to SG discontinuation. 18 of the 21 patients completed all 4 cycles of SG and underwent surgery, with 11 of the 18 patients undergoing a radical cystectomy (RC) and 7 refusing RC and receiving restage transurethral resection of the bladder tumor (reTURBT). 6 of the 7 patients did not receive RC after the evidence of a pathologic complete response (pCR). The median duration of neoadjuvant treatment was 11.7 weeks, and the median time between the end of SG treatment and surgery was 6.9 weeks. At a median follow-up of 7.1 months, among the 11 patients who received RC, 4 achieved a pathologic complete response (pCR), evidenced by the absence of cancer cells in surgical specimens (ypT0N0), and 3 patients experienced a major pathologic response (mPR; ypT<=1N0). In the total intent-to -treat population (n=21), 10 patients achieved a pCR, and 11 patients achieved an mPR. Among the 7 patients who did not receive RC, 6 achieved a clinical complete response and circulating tumor DNA (ctDNA) negativity. All patients with residual disease tested negative for ctDNA post-RC, and none have relapsed. Biomarker analyses of the patient population are ongoing. Results from SURE-01 support further investigation of the use of perioperative SG for MIBC, and among a subpopulation of patients, neoadjuvant SG may represent a bladder-saving option. SURE-02, a clinical trial of neoadjuvant SG in combination with pembrolizumab followed by adjuvant pembrolizumab alone for MIBC is ongoing.
Circulating tumor DNA dynamics can be influenced by the mechanism of treatment: Retrospective analysis of the KEYNOTE-361 trial
4518. Quantitative circulating tumor DNA (ctDNA) assessment in patients (pts) with advanced urothelial carcinoma (UC) treated with pembrolizumab (pembro) or platinum-based chemotherapy (chemo) from the phase 3 KEYNOTE-361 trial.
Thomas Powles (Barts Cancer Institute, Queen Mary University of London, London, United Kingdom) reported an analysis of pre-treatment and on-treatment circulating tumor DNA (ctDNA) dynamics and clinical outcomes with pembrolizumab versus chemotherapy in patients with advanced urothelial carcinoma (UC). Data from the phase III KEYNOTE-361 trial were used for the study, and ctDNA samples from 131 patients who had been treated with chemotherapy and 132 patients who had been treated with pembrolizumab were analyzed. Lower baseline levels of ctDNA were associated with response to therapy and improved survival outcomes for both arms. Stronger, statistically significant associations were observed with the pembrolizumab arm compared to the chemotherapy arm, and these associations were similar when accounting for tumor size, tumor mutation burden, and PD-L1 status. Among patients with baseline ctDNA levels less than the median ctDNA level, the overall survival (OS) rate was higher in the pembrolizumab arm (n=63) compared to the chemotherapy arm (n=62), with a hazard ratio (HR) of 0.65. Among patients with baseline ctDNA levels greater than or equal to the median ctDNA level, OS rates of the pembro arm (n=62) and chemotherapy arm (n=63) were similar (HR 1.06). By cycle 2 of treatment, ctDNA clearance occurred in 41% of patients in the chemotherapy arm, compared to 11% of patients in the pembrolizumab arm, but ctDNA clearance was more closely associated with tumor reduction at 9 weeks in the pembrolizumab arm compared to the chemotherapy arm. On-treatment decreases in ctDNA were associated with survival benefits in both arms, but the strongest correlation was observed in the pembrolizumab arm. Among patients with a large reduction in ctDNA levels on-treatment, the OS HR was 0.25 (n=78 for the chemotherapy arm and n=19 for the pembrolizumab arm), while among patients with smaller reductions in ctDNA on-treatment the OS HR was 0.82 (n=24 for the chemotherapy arm and n=72 for the pembrolizumab arm). ctDNA changes observed with response to pembrolizumab correlated with high tumor mutation burden and high PD-L1 expression, further supporting these data. This study, one of the few investigations of ctDNA dynamics in advanced disease, indicates ctDNA dynamics can be influenced by the mechanism of treatment. While baseline and on-treatment ctDNA levels were associated with outcomes for both treatment arms, stronger associations with long-term clinical outcomes were observed with pembrolizumab.
For more information on ctDNA assays and methodologies, read this review by Vellanki et al in JITC.
SACI-IO HR+, a phase II trial investigating the effect of an immune checkpoint inhibitor on the anti-tumor activity of a topoisomerase inhibitor antibody drug conjugate in metastatic breast cancer
LBA1004. SACI-IO HR+: A randomized phase II trial of sacituzumab govitecan with or without pembrolizumab in patients with metastatic hormone receptor-positive/HER2-negative breast cancer.
Ana Christina Garrido-Castro (Dana-Farber Cancer Institute, Boston, MA) reported results from SAC-IO a phase II study comparing the safety and efficacy of sacituzumab govetican (SG) with or without pembrolizumab (pembro), an anti-PD-1 immune checkpoint inhibitor, in hormone receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (mBC). SG is a TROP2-targeting antibody drug conjugate that has been approved for previously treated triple negative HR+/HER2- mBC. The topoisomerase inhibitor payload of SG, SN-38 has been shown to enhance cytotoxic T cell effector function and deplete regulatory T cells. The hypothesis of this study was SG and pembro would synergistically restore T cell effector function, and this combination therapy would improve the efficacy of SG against HR+HER2- mBC. 104 patients with HR+HER2- mBC started study therapy and were included in the analysis. 52 patients in Arm A received SG plus pembro, and 52 patients in Arm B received SG alone. Addition of pembro to SG numerically improved progression free survival (PFS) and overall survival (OS), but the improvement was not statistically significant. Median PFS was 8.12 months in Arm A and 6.22 months in Arm B (HR 0.81, p=0.37), and at a median follow-up of 12.5 months, median overall survival (OS) was 18.52 months in Arm A and 17.96 months in Arm B (HR 0.65, p=0.21). With regards to the PD-L1 positive (CPS>=1) subgroups (n=16 in Arm A and n=24 in Arm B), addition of pembro to SG improved PFS by 4.4 months (11.1 months vs 6.7 months, p=0.23) and OS by 6 months (18.5 months vs 12.5 months, p=0.42), but this difference was not significant. Objective response rates did not significantly differ between the Arm A and Arm B (21.2% and 17.3%, respectively, p=0.80), regardless of PD-L1 expression. No new safety signals were reported, and all adverse events could be attributed to SG or pembro. SAC-IO HR+ is the first randomized clinical trial to report the efficacy of a topoisomerase inhibitor antibody drug conjugate in combination with an immune checkpoint inhibitor for breast cancer. Although the combination of SG with pembro did numerically improve PFS and OS of patients with HR+/HER2- mBC, especially among patients with PD-L1-positive tumors, no statistically significant differences were observed. One limitation of the study was the smaller patient population and the relatively small proportion of patients with PD-L1-positive tumors. More efforts are needed to identify predictors for benefit from this combination therapy.
To learn more about other TROP2-targeting immunotherapies for breast cancer, read this article by Liu et al in JITC.
Glofitamab, a CD20 x CD3 bispecific antibody for relapsed or refractory mantle cell lymphoma
7008. Glofitamab monotherapy in patients with heavily pretreated relapsed/refractory (R/R) mantle cell lymphoma (MCL): Updated analysis from a phase I/II study.
Tycel Jovelle Phillips (City of Hope National Medical Center, Duarte, CA) reported updated efficacy and safety data from a phase I/II trial of fixed-duration glofitabmab monotherapy for patients with relapsed or refractory mantle cell lymphoma (R/R MCL). Glofitamab is a CD20 x CD3 bispecific antibody with a novel two CD20 : one CD3 format to promote high avidity binding to CD20 on B cells. Previous studies indicate that glofitamab shows a high level of durable complete responses, and glofitamab has been approved for third-line treatment or later of diffuse large B cell lymphoma. 61 patients enrolled in the study, and 60 patients received treatment. Patients had received a median of 2.4 prior lines of therapy, and 73.3% of patients were refractory to the most recent line of therapy. 31 patients had received prior Bruton’s tryrosine kinase inhibitor (BTKi) therapy, and 27 (87.1%) of those patients were BTKi refractory. Overall response rate (ORR was 85% for the entire patient population, and the complete response (CR) rate was 78.3%. Among patients who were BTKi-refractory, ORR was 74.2%, and CR rate was 71.0%. The median time to first response among responding patients was 42 days. At a median follow-up on 19.6 months, the median progression free survival (PFS) was 16.8 months, and the 15-month PFS rate was 54.0%. At a median overall survival (OS) follow-up of 21.8 months, median OS was 29.9 months, and the 15-month OS rate was 71.4%. Among patients who had achieved a CR at the end of treatment (n=30), median PFS was not reached, and the 15-month PFS rate was 59.2%. The median OS in this patient population was not reached, and the 15-month OS rate was 72.7%, indicating that the majority of patients who achieved a complete response by the end of treatment survived and remained progression-free 15 months after treatment. Incidence and severity of adverse events aligned with the known safety profile of glofitamab. Cytokine release syndrome (CRS) occurred in 70.0% of patients, and the majority of these cases (58.4%) were grade 1 or 2. Given the high levels of long-lasting remissions in patients with R/R MCL, including those refractory to BTKi, and its manageable safety profile, glofitamab may represent a new treatment option for patients with R/R MCL. GLOBRYTE, a phase III trial of glofitamab monotherapy for R/R MCL is underway.