Nivolumab-based neoadjuvant chemoimmunotherapy followed by response-adapted chemoradiation therapy is associated with deep responses and favorable survival for HNSCC
6007. Neoadjuvant nivolumab, paclitaxel, and carboplatin followed by response-stratified chemoradiation in locoregionally advanced HPV negative head and neck squamous cell carcinoma (HNSCC): The DEPEND trial.
Ari Rosenberg (University of Chicago, Chicago, IL – SITC Member) reported results from the phase II DEPEND trial of neoadjuvant chemoimmunotherapy followed by chemoradiation therapy (CRT) for advanced HPV-negative head and neck squamous cell carcinoma (HNSCC). One goal of this trial was to determine whether patient response to neoadjuvant therapy could lead to stratification of CRT dosing, potentially reducing long-term toxicities associated with CRT. 36 patients received neoadjuvant nivolumab with carboplatin and paclitaxel, and tumor response was assessed radiographically by RECIST v1.1 . Patients exhibiting a deep response to neoadjuvant therapy, defined as tumor reduction >= 50% (i.e., partial response by RECIST v1.1) received adapted CRT to 66 Gy with elimination of elective nodal volumes (n=19). Patients with < 50% tumor reduction received standard dose CRT to 70 –75 Gy (n=16). Post CRT nivolumab was administered to all eligible patients. Deep response rate to neoadjuvant chemoimmunotherapy was 54%, and objective response rate was 89%. PD-L1 expression (CPS >= 1) was associated with significantly higher deep response rates compared to PD-L1 CPS < 1 (78.9% vs 21.1%, respectively). 24-months estimates of progression free survival (PFS) and overall survival (OS) for the full cohort was 64% and 76%, respectively. For patients receiving response-adapted CRT compared to standard CRT, 24-month PFS was 79% vs 46%, respectively, 24-month OS was 86% and 67%, respectively, 24-month locoregional control (LRC) was 85% vs 92%, and 24-month distant control was 100% vs 63%. No nodal failures were observed in the response-adapted CRT group. Neoadjuvant therapy was tolerated and adverse events were similar to previous studies of neoadjuvant chemoimmunotherapy. Lower rates of acute adverse events (grade 3-5) were observed among patients receiving response-adapted CRT. These findings indicate that neoadjuvant nivolumab-based chemoimmunotherapy led to deep responses among patients with HPV-negative HNSCC, and response-adapted CRT was associated with a lower rate of acute adverse events with favorable survival and locoregional control. Analyses of late toxicity and biomarkers are ongoing and will be reported at a later date.
Long-term follow-up of KEYNOTE-426: pembrolizumab with axitinib for advanced clear cell renal cell carcinoma
LBA4501. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma: 5-year analysis of KEYNOTE-426.
Brian I. Rini (Vanderbilt-Ingram Cancer Center, Nashville, TN – SITC Member) presented long-term, five-year analyses of KEYNOTE-426, an open-label phase III trial of first line pembrolizumab combined with axitinib (pembro + axi; n=432) compared to sunitinib (sun; n=429) for advanced clear cell renal cell carcinoma (ccRCC). The first interim analysis of KEYNOTE-426 reported significant gains in overall survival (OS), progression free survival (PFS), and overall response rate (ORR) associated with pembro + axi. The five-year follow-up data continued this trend, with the pembro + axi arm associated with positive long-term outcomes compared to the sun arm. OS were rates of 41.9% and 37.1%, respectively (HR 0.84); PFS rates were 18.3% and 7.3%, respectively (HR 0.69); and ORR were 60.6% and 39.6%, respectively. Median duration of response was 23.6 months compared to 15.3 months, respectively, and 26% of responders in the pembro + axi arm remain in response, compared to 14.4% in the sun arm. In patients who discontinued therapy, 237/381 patients (62.2%) in pembro + axi arm and 300/406 (73.9%) of patients in sun arm received subsequent anti-cancer treatment, and 80% of these patients from the sun arm received anti-PD-(L)1 therapy. The hazard ratio for OS when adjusted for subsequent therapy was 0.67. Among patients who completed two years (35 cycles) of pembrolizumab-based therapy (n=120), ORR was 85%, and 5-year OS and PFS were 70.5% and 32.8%, respectively. These data comprise the longest follow-up to date of an immune checkpoint inhibitor combined with a VEGF TKI for first-line treatment of ccRCC. A substantial proportion of patients were able to complete 35 cycles of pembrolizumab-based therapy and exhibited positive long-term outcomes. These data continue to support the use of pembrolizumab with axitinib as the standard of care for first-line treatment of advanced clear cell renal cell carcinoma.
For a related commentary on combination therapy for renal cell carcinoma, see this JITC article by Rini and colleagues.
Anti-LAG3 antibody fianlimab combined with cemiplimab for advanced melanoma is associated with clinical benefits in a variety of patient populations
9501. Significant durable response with fianlimab (anti-LAG-3) and cemiplimab (anti-PD-1) in advanced melanoma: Post adjuvant PD-1 analysis.
Omid Hamid, MD (The Angeles Clinic & Research Institute, A Cedars-Sinai Affiliate, Los Angeles, CA – SITC Member) reported results study of three independent expansion cohorts (n=98) examining the clinical efficacy and safety of fianlimab (anti-LAG-3 antibody) combined with cemiplimab (anti-PD-1 antibody) for advanced melanoma. Two cohorts (n=80) were PD-(L)1-naïve and received fianlimab + cemiplimab for first- or second-line therapy of melanoma, and the third cohort (n=18) had received prior (neo)adjuvant systemic therapy, with 13 of these patients receiving anti-PD-1 therapy. The overall response rate among this PD-(L)1-naïve patient population was 64%. Overall response rate (ORR) was 61%, with 12 complete responses and 48 partial responses. Median duration of response (DOR) was not reached, and disease control rate was 78%, indicating a rapid, deep, and durable response. KM-estimated progression free survival (PFS) was 15 months, and estimated event-free probability at 12 months was 52%. Responses were similar among patients who had not received prior adjuvant therapy compared to those who had received prior (neo)adjuvant therapy. ORR was 60.9% and 61.5%, respectively, median DOR was not reached for either group, and median PFS was 13.3 months and 11.8 months. For patients with prior PD-1 therapy (n=13), ORR was 62%. Clinical benefits were also observed in all prognosis subgroups and at all levels of PD-L1 and LAG-3 expression. The safety profile was similar to prior studies of cemiplimab monotherapy and other anti-PD-(L)1 agents. Immune-related adverse events occurred in 65.3% of patients, and 16.3% of patients discontinued treatment due to treatment-emergent adverse events. Combination therapy of fianlimab + cemiplimab for advanced melanoma has produced consistent, reproducible results in PD-(L)1-naïve and PD(L)-1-experienced patient cohorts. Phase III trials of fianlimab + cemiplimab for advanced melanoma and in the adjuvant setting are ongoing.
For related research on LAG-3 inhibitors, read this article from Schöffski et al in JITC.
Two-year follow-up for RELATIVITY-047: Nivolumab + relatlimab vs Nivolumab monotherapy for advanced melanoma
9502. Nivolumab (NIVO) plus relatlimab (RELA) vs NIVO in previously untreated metastatic or unresectable melanoma: 2-year results from RELATIVITY-047.
Hussein A. Tawbi (University of Texas MD Anderson Cancer Center, Houston, TX – SITC Member) reported the two-year follow-up and updated descriptive analyses of RELATIVITY-047, which compared nivolumab + relatlimab (anti-LAG-3; NIVO + RELA) combination therapy with nivolumab monotherapy (NIVO) for metastatic or unresectable melanoma. Previous results from RELATIVITY-047 indicated a significant progression free survival (PFS) benefit associated with NIVO + RELA compared to NIVO. Overall survival (OS) benefits were also observed, but the difference between the two groups was not significant. 355 patients were assigned to the NIVO + RELA arm, and 359 patients were assigned to the NIVO arm. At a median follow-up of 25.3 months (minimum follow-up of 21 months), NIVO + RELA continued to demonstrate consistent clinical benefits over NIVO for advanced melanoma. Median PFS was significantly higher at 10.2 months vs 4.6 months, respectively (hazard ratio (HR), 0.81), OS was not reached vs 33.2 months, respectively (HR 0.82), and overall response rate was 44% vs 34%, respectively. Median melanoma-specific survival (MSS) was not reached for NIVO + RELA arm and 46.6% for the NIVO arm (HR 0.82). 131 patients in the NIVO + RELA arm (36.9%) and 136 patients (37.9%) received subsequent systemic therapy after disease recurrence, and responses to subsequent second-line systemic therapy were similar between both arms, although the sample sizes for each subsequent therapy were small. 48-month PFS2, defined as the time from randomization to disease progression after the next line of therapy or death was also similar between the two arms, at 42% for the NIVO + RELA arm and 35% for the NIVO arm. Safety data were similar to prior reports, with a favorable risk/benefit profile. NIVO + RELA continues to deliver clinical benefits over NIVO monotherapy for advanced melanoma, and exploratory results from this study suggest that prior exposure to RELA does not affect response to subsequent systemic therapies.
For more research by Tawbi and colleagues, read this article in JITC.
mRNA-4157/V940, an mRNA-based individualized neoantigen cancer vaccine, is associated with distant metastasis-free survival benefits in high-risk melanoma
LBA9503. Distant metastasis-free survival results from the randomized, phase 2 mRNA-4157-P201/KEYNOTE-942 trial.
Adnan Khattak (One Clinical Research and Edith Cowan University, Perth, Western Australia, Australia) presented the first analysis of distant metastasis-free survival (DMFS) in the open-label randomized phase II mRNA-4157-P201/KEYNOTE-942 trial comparing mRNA-4157/V940 + pembrolizumab (combination arm; n=107) to pembrolizumab (monotherapy arm; n=50) for resected high-risk stage IIIB/C/D and IV melanoma. V940 is a novel mRNA-based personalized cancer vaccine that encodes up to 34 patient-specific tumor neoantigens, and previous reports indicate that V940 + pembrolizumab combination therapy is associated with significant gains in recurrence free survival compared to pembrolizumab monotherapy (18-month RFS 78.6% vs 62.2%, HR 0.56). The combination arm was associated with significant improvement in DMFS compared to the monotherapy arm, with 18-month DMFS rates of 91.8% vs 76.8%, respectively (HR 0.347, p=0.0063). Fewer distant relapses or deaths occurred in the combination arm (9/107) compared to the monotherapy arm (12/50), suggesting addition of V940 to adjuvant immunotherapy delays distant relapse events. Exploratory analyses of circulating tumor DNA (ctDNA) suggests ctDNA negative status is associated with DMFS benefits for both treatment arms, but more strongly with the combination arm. mRNA-4157-P201/KEYNOTE-942 is the first trial to demonstrate the association of an individualized neoantigen therapy with significant gains in RFS and DMFS. A phase III study to confirm these results will begin in the near future, and expanded studies to include additional tumor types are being planned.
Exploratory analysis of biomarkers associated with survival benefits from nivolumab in the adjuvant setting for melanoma.
9504. Association of biomarkers (BMs) with efficacy of adjuvant nivolumab (NIVO) vs placebo (PBO) in patients with resected stage IIB/C melanoma (CA209-76K).
Georgina V. Long (Melanoma Institute Australia, The University of Sydney, and Royal North Shore and Mater Hospitals, Sydney, NSW, Australia) presented exploratory biomarker analyses of the CHECKMATE-76K trial, which previously showed adjuvant treatment with nivolumab (NIVO) significantly prolonged recurrence free survival (RFS) over the placebo (PBO) for stage IIB/C melanoma. Patients with Stage IIB/C melanoma are at similar risks of 5-year disease recurrence and death compared to patients with Stage IIIA/B melanoma, so it is important to identify patients at higher risk of recurrence as well as patients who are more likely to respond to adjuvant immunotherapy. Tumor and serum samples were analyzed, and six biomarkers were identified as being associated with prolonged RFS in the NIVO arm but not in the PBO arm: higher interferon gamma signatures, higher tumor mutation burden (TMB), higher percentage of CD8+ T cells, and lower CRP levels. There was not a clear association between PD-L1 expression and RFS, and no biomarker was associated with gains in RFS in the PBO arm. All identified biomarkers favored the NIVO arm regardless of expression levels, suggesting nivolumab treatment improves outcomes, but presence of the biomarker will enhance the improvement in outcomes. No prognostic biomarkers for RFS were identified in this study. Multivariate analyses to identify clinical and transitional factors that predict RFS and differentiate treatment effects are in development, and early results suggest TMB and interferon gamma signatures have the largest independent effect on the benefit of nivolumab. These results are exploratory in nature, but this study marks the first comprehensive analysis of biomarkers for adjuvant treatment of stage II melanoma and may eventually optimize the risk/benefit stratification for adjuvant immunotherapy in this patient population.
Final distant metastasis-free survival analysis of KEYNOTE-716: Pembrolizumab as adjuvant therapy for stage IIB/C melanoma
LBA9505. Pembrolizumab versus placebo as adjuvant therapy in stage IIB or IIC melanoma: Final analysis of distant metastasis-free survival in the phase 3 KEYNOTE-716 study.
Jason J. Luke (UPMC Hillman Cancer Center, Pittsburgh, PA – SITC Member) reported final distant metastasis-free survival (DMFS) and updated recurrence free survival (RFS) analyses from KEYNOTE-716, which compared pembrolizumab (pembro; n=487) vs placebo (pbo; n=489) in patients with resected stage IIB or IIC cutaneous melanoma. Interim analyses of KEYNOTE-716 have indicated that adjuvant pembro improves distant metastasis-free survival and recurrence-free survival. At a median follow-up of 39.4 months, 320 patients in the pembro arm completed treatment, and 163 patients discontinued treatment. 367 patients in the pbo arm completed treatment, and 119 discontinued treatment. 36-month DMFS was significantly higher in the pembro arm compared to the pbo arm, at 84.4% vs 74.7%, respectively, and the Hazard Ratio (HR) was 0.59. Pembrolizumab was associated with DMFS benefits in patients with IIB and IIC disease (HR 0.62 and 0.57, respectively), though the differences between treatment arms were not significant. DMFS favored pembrolizumab in all subgroups examined. Updated RFS analyses were similar, with 39.4 months RFS rates of 76.2% for the pembro arm and 63.4% for the pbo arm (HR 0.62). RFS also favored pembrolizumab in all subgroups examined. No new safety signals were reported. This final DMFS analysis supports pembrolizumab as the standard of care of adjuvant therapy patients with resectable stage IIB or IIC melanoma. Biomarker analyses of KEYNOTE-716 are pending and will be reported at a later date.