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 Sunday, June 2, 2024.
2024 Scientific Highlights
Blockade of TIGIT improves the anti-tumor efficacy of pembrolizumab for previously treated advanced mismatch repair-deficient endometrial cancer
5502. Vibostolimab coformulated with pembrolizumab (vibo/pembro) for previously treated advanced mismatch repair–deficient (dMMR) endometrial cancer: Results from cohort B1 of the phase 2 KEYVIBE-005 study.
Carlos Rojas (Bradford Hill Clinical Research Center, Santiago, Chile) presented data from the B1 cohort of the phase 2 KEYVIBE-005 study investigating the combinate of two immune checkpoint inhibitors, vibostolimab (anti-TIGIT) and pembrolizumab (anti-PD-1) (vibo/pembro) in patients with previously treated advanced mismatch repair defective (dMMR) endometrial cancers. In the previous KEYNOTE-158 study, pembro exhibited durable antitumor activity in patients with microsatellite instability-high (MSI-H) /dMMR endometrial cancer. However, 30 to 50% of patients experience disease progression on immunotherapy so more options are needed to treat this patient population. Both the immune checkpoints TIGIT and PD-L1 are upregulated in endometrial tumors and dMMR tumors, thus dual blockade of TIGIT and PD-1 maybe an effective therapeutic approach for dMMR endometrial cancer. In the KEYVIBE-005 study, 40 patients with advanced dMMR endometrial cancer with progressive disease after one platinum-based chemotherapy and no prior PD-(L)1 therapy received vibo/pembro. The median time from first dose to data cutoff was 17.2 months. At the time of data cutoff, 23 patients had discontinued treatment, and treatment was ongoing in 17 patients. The overall response rate (ORR) was 65%, with 5 patients (13%) achieving a complete response and 21 (53%) achieving a partial response. The median duration of response was 13.7 months, and 75% of responders had a duration of response for 12 months or longer. 76% of patients exhibited at least 30% tumor regression. Median progression free survival (PFS) was 15.0 months, and 12-month PFS rate was 58%. Median overall survival (OS) was not reached, and the 12-month OS rate was 82%. Treatment-related adverse events (AE) occurred in 38 patients (95%), and grade 3 or grade 4 treatment-related AEs occurred in 14 patients (35%). Immune-mediated AEs or infusion reactions occurred in 21 patients (53%) and 7 patients (18%) experienced grade 3 or 4 immune-mediated AEs. Co-formulated vibostolimab/pembrolizumab demonstrated durable anti-tumor activity and a manageable safety profile in patients with previously treated advanced dMMR endometrial cancer. These results build upon the results of the previous KEYNOTE158 trial and indicate that addition of anti-TIGIT vibostolimab to pembrolizumab may improve the efficacy of pembrolizumab monotherapy for advanced dMMR endometrial cancer. These results also support additional studies of vibostolimab/pembrolizumab for advanced immunotherapy-sensitive tumors.
Efficacy and safety of neoadjuvant pembrolizumab for high-risk, resectable mismatch repair deficient colorectal cancer
LBA3504. NEOPRISM-CRC: Neoadjuvant pembrolizumab stratified to tumour mutation burden for high risk stage 2 or stage 3 deficient-MMR/MSI-high colorectal cancer.
Kai-Keen Shiu, PhD, FRCP, FCRP (University College Hospital, NHS Foundation Trust)
NEOPRISM-CRC is the first multicenter phase II trial to determine the safety and efficacy of neoadjuvant pembrolizumab stratified to tumor mutation burden (TMB) for mismatch repair deficient (dMMR) /microsatellite instability-high (MSI-High) colorectal cancer (CRC). TMB is being evaluated as a biomarker of clinical benefit to immunotherapy for advanced cancers, but less is known about its predictive value for earlier-stage disease or in the neoadjuvant setting. 32 patients with operable high-risk stage 2 or stage 3 dMMR/MSI-high CRC received one cycle of neoadjuvant pembrolizumab. Patients with TMB-high tumors (n=31) received a second cycle of neoadjuvant pembrolizumab, while patients with TMB-low tumors (n=1) received surgery without a second cycle of neoadjuvant therapy. The pathologic complete response (pCR) rate was 53% (17/32), and all patients with a pCR had TMB-high tumors. Among 33 evaluable tumors, the pCR rate was 58% (19/33), and all tumors with a pCR were TMB-high. The majority of patients had complete response in the primary tumor and lymph nodes. No relapses had occurred at the 9.7 month follow-up, and 2 patients had received adjuvant chemotherapy. 20 patients (62.5%) experienced immune-related adverse events (irAE), and 2 patients experienced irAE of grade 3 or higher. Extensive translational biomarker studies are ongoing, and longer follow-up is needed to assess relapse and progression free survival. Results of this study indicate that neoadjuvant pembrolizumab is safe and effective in downstaging high-risk for early-stage dMMR/MSI-High CRC. More time is needed to determine if neoadjuvant pembrolizumab prevents relapse and maximizes the chances of a cure for early-stage disease. Of note, NEOPRISM-CRC has been expanded to a three-year relapse-free survival endpoint.
PATHdata: a pan-tumor scoring system to assess tumor regression after neoadjuvant therapy
2515. Pan-tumor harmonization of pathologic response assessment for standardized data collection in neoadjuvant IO trials (PATHdata): Final analysis of a multi-institutional reproducibility study.
Julie S. Deutsch (Johns Hopkins University, Baltimore, MD) presented the final analysis of PATHdata, a multi-institutional international study led by the Society for Immunotherapy of Cancer (SITC) to harmonize pan-tumor pathologic response assessment for standardized data collection in clinical trials of neoadjuvant immunotherapy. Given that pathologic response is increasingly being used as a surrogate for survival in the neoadjuvant setting, and features of pathologic response are similar across different tumor types receiving neoadjuvant treatment, there is a need for a pan-tumor scoring system for percent residual viable tumor (%RVT) to assess tumor regression after neoadjuvant therapy. These pathologic response criteria were used in CheckMate819, a phase III trial of neoadjuvant immunochemotherapy for resectable lung cancer. 14 pathologists from multiple institutions in academia and industry participated in PATHdata and were trained with online lecture-based learning modules to score hematoxylin and eosin (H&E) stained slides from the primary tumor (PT) and lymph node in both resection specimens and biopsies. After scoring, pathologists completed a survey to facilitate improvement of the training module for dissemination to the wider immuno-oncology community. Pathologists scored 42 pathology cases from resection specimens and on-treatment biopsies from more than 10 different tumor types. Each pathologist scored a total of 362 slides for %RVT in the PT and LN from patient specimens. High reproducibility for %RVT assessment was observed using pan-tumor response criteria, with an overall intraclass correlation coefficient (ICC) of 0.86. Similar reproducibility was also observed for scoring the PT (ICC=0.85), LN (ICC=0.87), and biopsy specimens (ICC=0.93). Reproducibility was also observed among scoring different tumor types, including melanoma (n=6; ICC=0.79), non-small cell lung cancer (n=10; ICC=0.88), renal cell carcinoma (n=3; ICC=0.98), breast carcinoma (n=7; ICC=0.86), Merkel cell carcinoma (n=2; ICC=0.96), and head and neck squamous cell carcinoma (n=4; ICC=0.95). When surveyed, 80% of pathologists reported a preference for using one scoring system versus individualized approaches for each tumor type. The PATHdata program indicates that a pan-tumor scoring system for %RVT is desired by pathologists and that scoring such as that done is PATHdata can be highly reproducible. Dissemination and implementation of this system will enhance the role of pathologic response as a surrogate endpoint for clinical trials of immunotherapy in the neoadjuvant setting.
For a case report on tumor pathology after combination therapy with PD-L1/LAG3 inhibitors, read this article by Deutsch et al in JITC.
Fecal microbiota transplantation for the treatment of refractory immune-mediated colitis after treatment with immune checkpoint inhibitors
2517. Effect of fecal transplantation on patient reported outcomes after immune checkpoint inhibitor colitis.
Yinghong Wang (The University of Texas MD Anderson Cancer Center, Houston, TX) presented a prospective study of the efficacy and safety of fecal microbiota transplantation (FMT) for refractory immune-mediated colitis (IMC) which arises as a side effect of immune checkpoint inhibitor therapy. IMC is associated with diarrhea and colitis-related features, and standard treatment of IMC with immunosuppressant medication such as steroids has high risk of complications, including infection and cancer progression. 59 adult patients with a diagnosis of immune-mediated colitis with symptoms of grade 2 or higher participated in the study. All cases of IMC were refractory to treatment with steroids and/or biologics, and FMT was administered as compassionate treatment. Prior to FMT, 56 patients (94.9%) had diarrhea grade 3 or higher, and 54 patients (91.5%) had colitis grade 2 or higher. 40 patients (67.8%) had been hospitalized for IMC. The response rate for the entire patient population was 84.7%, and for patients receiving FMT as front-line treatment (n=12), the response rate was 83.3%. The median time to response was 4 days for the entire patient population and 5 days for patients receiving front-line treatment. 18.6% of all patients and 25% of patients receiving front-line treatment experienced adverse events from FMT. There was a favorable trend of significant reductions in patient-reported symptoms of diarrhea (p<0.0001), abdominal pain (p=0.0365), fatigue (p=0.0260), rectal bleeding (p=0.0044), and abdominal bloating (p<0.0001) during the 12 weeks after FMT. This study indicates fecal microbiota transplant is a safe and effective means to address refractory immune-mediated colitis in patients receiving immune checkpoint inhibitors for cancer. Patient-reported outcomes showed significant improvement in symptoms, and use of FMT avoids immunosuppressive treatment regimens which can limit the effectiveness of cancer immunotherapies. More studies are needed to elucidate the role of gut microbiome in cancer and the implications of FMT on patient resumption of and response to therapy.
Preliminary results of a phase I trial of a CD137 x PD-L1 bispecific antibody as monotherapy and in combination with pembrolizumab for advanced solid tumors
2520. Phase I study of MCLA-145, a bispecific antibody targeting CD137 and PD-L1, in solid tumors, as monotherapy or in combination with pembrolizumab.
Chrisann Kyi (Memorial Sloan Kettering Cancer Center, New York, NY) reported interim results from an ongoing phase I dose escalation study of MCLA-145 for advanced or metastatic solid tumors. MCLA-145 is a bispecific antibody targeting CD137 and PD-L1. MCLA-145 enhances T cell activation by stimulating CD137, which is dependent on simultaneous binding to PD-L1 expressed on neighboring cells. 72 patients with PD-L1-positive advanced or metastatic solid tumors representing 26 cancer types received MCLA-145 as monotherapy or in combination with pembrolizumab. 53 patients received MCLA-145 monotherapy, with 47 patients receiving 25 mg, 50 mg, or 75 mg MCLA-145 every two weeks, and 6 patients receiving 40 mg MCLA-145 every three weeks. 19 patients received MCLA-145 combined with the anti-PD-1 immune checkpoint inhibitor pembrolizumab. Patients on the combination therapy cohort received 40 mg MCLA-145 every three weeks. 6 dose-limiting toxicities were observed in the monotherapy cohort and none in the combination cohort. Given that treatment-emergent adverse events of grade 3 or higher occurred less frequently among patients receiving 40 mg MCLA-145 every three weeks, the recommended dose for expansion (RDE) was 40 mg MCLA-145 every three weeks as monotherapy and 40 mg MCLA-145 with 200 mg pembrolizumab every three weeks as combination therapy. The overall response rate (ORR) for the monotherapy cohort was 10% (5/52), and ORR among patients receiving the RDE was 33% (2/6). The ORR for the combination therapy cohort was 11% (2/19), and one of 9 patients with non-small cell lung cancer responded to combination therapy. The median durations of response for the monotherapy and combination therapy cohorts were 2 months and 3 months, respectively, with disease control rates of 37% with monotherapy and 68% with combination therapy. Pharmacodynamic data indicate improved anti-tumor activity of MCLA-145 occurred at the RDE of 40 mg every three weeks, including increased T cell proliferation and more sustained T cell stimulation. 3 of 6 evaluable patients with baseline tumor CD8 T cell density of 250 cells per cubic mm responded to MCLA-145 treatment. MCLA-145 exhibited clinical activity and a manageable safety profile as monotherapy and as combination therapy at the RDE of 40 mg every three weeks. More investigation is needed to elucidate the mechanisms underlying the increased T cell proliferation and activation at less frequent dosing, especially in tumors with high levels of T cell infiltration at baseline.
Neoadjuvant immune checkpoint inhibitors as the new standard of care for macroscopic resectable stage 3 melanoma
LBA2. Neoadjuvant nivolumab plus ipilimumab versus adjuvant nivolumab in macroscopic, resectable stage III melanoma: The phase 3 NADINA trial.
Christian U. Blank (Netherlands Cancer Institute (NKI-AVL), Amsterdam, Netherlands) presented event-free survival (EFS) results from the phase III NADINA trial investigating the benefit of the combination of neoadjuvant ipilimumab with nivolumab (ipi + nivo) followed by response-driven adjuvant therapy compared to the standard of care (SOC) adjuvant nivolumab (nivo) in patients with stage III macroscopic melanoma. The current SOC for resectable macroscopic stage III melanoma is therapeutic lymph node dissection (TLND) followed by adjuvant therapy with nivo, pembrolizumab (pembro), or dabrafenib and trametinib (DAB/TRAM) for melanoma with BRAF mutations. Adjuvant therapy has been shown to improve relapse-free survival (RFS) in this patient population, but the 5-year overall survival (OS) rate for patients with macroscopic stage III melanoma is only 50% (5-year RFS rate is 30%). The recent SWOG S19-801 trial showed superior event-free survival (EFS) of neoadjuvant and adjuvant pembrolizumab compared to adjuvant pembrolizumab, and other phase II trials have demonstrated safety and efficacy of neoadjuvant ipi + nivo for other indications. Patients with resectable, macroscopic, nodal stage III melanoma that was naïve to ICI and BRAF/MEK inhibitors and at least one lymph node metastasis were randomized 1:1 to treatment arms. Patients assigned to the neoadjuvant group (n=212) received neoadjuvant ipi + nivo followed by TLND. If a major pathologic response (MPR) was not achieved, patients received adjuvant DAB/TRAm or adjuvant nivo with or without parallel adjuvant radiotherapy (RT). Patients who did in the neoadjuvant group who did achieve a MPR received no additional treatment. Patients assigned to the adjuvant group (n=211) received TLND followed by adjuvant therapy with nivo with or without adjuvant RT. Of the 212 patients in the neoadjuvant group, 198 underwent surgery, 120 achieved an MPR and did not start adjuvant treatment, and 66 started adjuvant treatment. Of the 211 patients in the adjuvant group, 208 underwent surgery, and 170 started adjuvant treatment with nivo. Neoadjuvant therapy significantly improved EFS, with 12-month EFS rates of 83.7% in the neoadjuvant group vs 57.2% in the adjuvant group (HR 0.32, p<0.0001). A similar trend was observed in BRAF mutational patient subgroups. Among patients with BRAF-mutated melanoma, 12-months EFS rates were 83.5% and 52.2% in the neoadjuvant and adjuvant groups, respectively (HR 0.29, p<0.0001). 12-month EFS rates of patients with non-mutated BRAF melanoma were 83.9% in the neoadjuvant group and 62.4% in the adjuvant group (HR 0.35, p=0.0014). 59.0% of patients in the NADINA trial achieved an MPR. 12-month recurrence-free survival rates among patients with a pathologic complete response (pCR) was 95.4%, 94.1% in patients with a near pCR, 76.1% in patients with a partial response, and 57.0% in patients with a non-response. Treatment-related adverse events (TRAEs) of grade 3 or higher seen in 29.7% of patients in neoadjuvant group and 14.7% of patients in the adjuvant group, and 1 patient in the adjuvant group died of a TRAE. NADINA is the first phase 3 trial of neoadjuvant checkpoint inhibitors in melanoma, and it is the first phase 3 trial testing a neoadjuvant immune checkpoint inhibitor combination without chemotherapy for a solid tumor. Results from the SWOG 1801 trial, combined with the statistically significant gains in EFS observed in NADINA strongly support neoadjuvant combination immunotherapy of ipi + nivo as the new standard of care for macroscopic stage III melanoma.
For a position article on the use of combination therapy to address resistance to anti-PD-(L)1 therapy, read this article by Zhang et al in JITC.
Durvalumab as consolidation therapy for patients with limited-stage small-cell lung cancer
LBA5. ADRIATIC: Durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC).
David R. Spigel (Sarah Cannon Research Institute, Nashville, TN) presented the first planned interim analysis of ADRIATIC, a phase III global study assessing the anti-PD-L1 immune checkpoint inhibitor durvalumab as consolidation therapy for patients with limited stage small-cell lung cancer (LS-SCLC) whose disease did not progress after concurrent platinum-based chemoradiotherapy (cCRT). The current standard of care (SOC) for LS-SCLC is cCRT with or without prophylactic cranial irradiation (PCI). ADRIATIC builds upon the recent PACIFIC and CASPIAN clinical trials, which support the use of durvalumab for consolidation therapy for unresectable stage III non-small cell lung cancer (NSCLC) and first-line treatment of extensive stage SCLC, respectively. Patients with inoperable stage I-III LS-SCLC were randomized after cCRT to receive durvalumab (D; n=264) or placebo (PBO; n=266). (Results from a third treatment arm of ADRIATIC, durvalumab + tremelimumab, will be reported in the next analysis.) 88 patients in the D group and 70 patients in the PBO group completed the maximum 24 months of treatment. The most common cause for not completing treatment was disease progression, and 95 patients in the D group and 127 patients in the PBO group went on to receive subsequent systemic therapy. At a median follow-up of 37.2 months, durvalumab significantly improved overall survival (OS) by almost 2 years, with median OS of 55.9 moths in the D group, compared to 22.4 months in the PBO group(HR 0.73, p=0.0104). 36-month OS rates for the D and PBO groups were 56.5% and 46.6%, respectively. At a median follow-up of 27.6 months, durvalumab was also associated with statistically significant improvements in progression-free survival (PFS). Median PFS for the D group and PBO group were 16.6 months vs 9.2 months, respectively (HR 0.76, p=0.0161), and 24-month PFS rates were also higher in D (46.2%) compared to PBO (34.2%). Survival benefits were observed across all patient subgroups. Consolidation therapy with durvalumab was well tolerated, and no new safety signals were observed. Grade 3/4 adverse events (AEs) occurred in 24.3% of patients in the D group and 24.2% in PBO group, and AEs led to treatment discontinuation in 16.3% and 10.6%of patients in the D group and PBO group, respectively. Given the statistically significant and clinically meaningful improvements in OS and PFS that are associated with durvalumab consolidation compared to placebo, these results strongly support consolidation durvalumab as the new standard of care for patients with LS-SCLC whose disease has not progressed after cCRT.
For a study of durvalumab combined tremelimumab with or without radiotherapy for relapsed SCLC, read this article by Pakkala et al in JITC.