Perioperative pembrolizumab is associated with survival benefits for early-stage NSCLC
LBA100. KEYNOTE-671: Randomized, double-blind, phase 3 study of pembrolizumab or placebo plus platinum-based chemotherapy followed by resection and pembrolizumab or placebo for early stage NSCLC.
Heather A. Wakelee (Stanford University, Stanford, CA) presented an interim analysis of KEYNOTE-671, a randomized, double-blind phase III trial investigating a perioperative approach that includes immune checkpoint inhibition before and after surgical resection of stage II, IIIA or IIIB(N2) non-small cell lung cancer (NSCLC) per AJCC v8. Patients were randomized to receive pembrolizumab with cisplatin-containing chemotherapy prior to surgery followed by adjuvant pembrolizumab therapy (pembro arm; n=397) or placebo with chemotherapy prior to surgery followed by adjuvant treatment with the placebo (placebo arm; n=400). At a median follow-up of 25.2 months, event-free survival (EFS) for the pembrolizumab arm was significantly better than the placebo arm, with a hazard ratio of 0.58. Median EFS for the placebo arm was 17.0 months and not reached for the pembro arm. Pembrolizumab was associated with EFS benefits across all stages and histologies examined. Benefits were observed in all PD-L1 subgroups, and the most benefit was observed in the high PD-L1 subgroup (TPS >= 50%). Overall survival (OS) was also higher in the pembro arm (median OS not reached) compared to the placebo arm (median OS 45.5 months), with a hazard ratio of 0.73. Pathologic response rates were significantly higher in the pembro arm compared to the placebo arm with major pathologic response rates of 30.2% vs 11.0%, respectively, and pathologic complete response rates of 18.1% and 4.0%, respectively. Exploratory analyses indicate pembrolizumab is associated with EFS benefits regardless of pathologic response. Adverse event rates were expected based on the profiles of the individual treatment components. These data support perioperative pembrolizumab as a new promising treatment option for patients with resectable stage II to III NSCLC.
Using pathologic response to neoadjuvant immunotherapy as a guide for developing further treatments for melanoma
101. The impact of response-directed surgery and adjuvant therapy on long-term survival after neoadjuvant ipilimumab plus nivolumab in stage III melanoma: Three-year data of PRADO and OpACIN-neo.
Irene L.M. Reijers (Netherlands Cancer Institute, Amsterdam, Netherlands) presented post-hoc analysis of three-year data from the PRADO and OpACIN-neo trials to determine the benefits associated with extensive surgery and with adjuvant therapy among patients with stage IIII melanoma. The OpACIN-neo trial (n=86) featured a one-size-fits-all approach, in which patients were treated with neoadjuvant nivolumab + ipilimumab (nivo + ipi) followed by therapeutic lymph node dissection (TLND) without adjuvant systemic therapy, although some patients received adjuvant radiotherapy. The PRADO trial (n=99) featured a personalized approach, in which patients were treated differently based on their pathologic response. Patients who achieved a major pathologic response (MPR; <=10% viable tumor) after neoadjuvant nivo + ipi did not undergo TLND and adjuvant therapy, while patients who achieved a partial pathologic response (pPR) or pathologic non-response (pNR) underwent TLND and adjuvant systemic therapy, with some patients receiving adjuvant radiotherapy. Baseline characteristics and pathologic response rates were comparable for both cohorts. Extensive surgery (TLND) did not affect survival outcomes among patients with an MPR who underwent TLND (OpACIN-neo trial; n=53) compared to those who did not receive TLND (PRADO trial, n = 59), with recurrence free survival rates (RFS) of 96% and 93%, respectively, and distant metastasis-free survival rates (DMFS) of 98% for both groups. None of the patients in these groups received adjuvant therapy, suggesting that adjuvant therapy may also be unnecessary for patients who achieve an MPR. Adjuvant therapy was associated with survival benefits among pNR patients, with 36-month RFS of 64% for patients who did receive adjuvant systemic therapy (n=17) compared to 36% for patients who did not receive adjuvant systemic therapy (n=17), and 36-month DMFS of 70% vs. 52%, respectively. Preliminary data from the small groups of patients who received adjuvant nivolumab therapy (n=7) compared to patients who received adjuvant targeted therapy of dabrafenib/trametinib (n=10) suggest immunotherapy may be associated with better long-term survival outcomes for patients with pNR. Adjuvant radiotherapy was also associated with survival benefits among patients pNR who did not receive adjuvant therapy, although the sample sizes for these groups were very small. The data indicate that for patients with a major pathologic response to neoadjuvant immune checkpoint blockade, TLND and adjuvant systemic therapy may not be necessary for positive survival outcomes. For patients who do not respond to neoadjuvant immune checkpoint blockade, adjuvant systemic therapy improves survival outcomes, and adjuvant immune checkpoint blockade may provide more benefits over targeted therapy. This analysis supports the practice of personalizing adjuvant therapy based on a patient’s pathologic response to neoadjuvant immune checkpoint blockade, thus scaling therapy to only what is needed for long-term disease control.
For related information on neoadjuvant immunotherapy, read this review article from Ahern et al in JITC.
The ImPrint classifier to predict response to neoadjuvant immunotherapy for early-stage breast cancer
102. Biomarkers predicting response to 5 immunotherapy arms in the neoadjuvant I-SPY2 trial for early-stage breast cancer (BC): Evaluation of immune subtyping in the response predictive subtypes (RPS).
Denise M. Wolf (University of California San Francisco, San Francisco, CA) reported on a study to identify predictive biomarkers of response or non-response to neoadjuvant immunotherapy for early-stage triple negative breast cancer (TNBC). The study focused on five arms of the I-SPY 2 trial for high-risk early-stage breast cancer. All arms featured anti-PD(L)1 immunotherapy, two arms consisted of anti-PD1 monotherapy, one arm consisted of anti-PD-L1 therapy combined with PARP inhibitors, and two arms consisted of anti-PD-1 combined with other immunotherapy agents (TLR9 agonist and anti-LAG3). 32 gene expression profiles associated with response to immunotherapy were identified, and these profiles included 30 immune signatures and targets. More predictive signals were identified in HR+/HER2- breast cancers compared to TNBC. Tumor-immune signatures dominated by chemokine and cytokine signaling were consistently associated with pathologic complete response (pCR) across all five arms and across tumor receptor status. These specific immune signatures also correlated with high spatial colocalization of PD-1+ tumor cells and PD-L1+ immune cells. The clinical grade ImPrint immunotherapy classifier was developed and evaluated in the five immunotherapy arms. 29% of HR+ HER2- breast cancers were ImPrint+, and 76% of ImPrint+ patients achieved pCR, compared to 16% of ImPrint- patients. For TNBC, 51% were ImPrint+, 75% of ImPrint+ patients achived pCR, compared to 37% of ImPrint- patients. 75% of ImPrint+ patients with HER2- (HR+ and triple negative) breast cancers achieved pCR, compared to 23% of ImPrint- patients with HER2- disease. The ImPrint classifier is a strong predictor of response to a range of immunotherapy-based treatment regimens, especially for HR+ HER2-disease, and could be used in the future to inform development of breast cancer treatment plans.
Final overall survival results of KEYNOTE-826, a study of pembrolizumab combined with chemotherapy for cervical cancer
5500. KEYNOTE-826: Final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer.
Bradley J. Monk (University of Arizona College of Medicine, Phoenix and Creighton University School of Medicine, Phoenix, AZ) presented final survival analysis results of the KEYNOTE-826 trial, which previously showed that first line pembrolizumab + platinum-based chemotherapy with or without bevacizumab (pembro + chemo; n=307) provided significant and meaningful improvements in overall survival (OS) and progression free survival (PFS) versus placebo + chemotherapy with our without bevacizumab (placebo + chemo; n=309) for patients with persistent, recurrent, or metastatic cervical cancer. At a median follow-up of 39.1 months, pembro + chemo significantly improved survival in all PD-L1 subgroups examined compared to placebo + chemo. For PD-L1 CPS >= 1, median OS was 28.6 months for pembro + chemo, compared to 16.5 months for placebo + chemo (HR 0.60). In the PD-L1 CPS >=10 population, median OS was 29.6 months for pembro + chemo vs 17.5 months for placebo + chemo (HR 0.58). In the all-comer population, median OS was 26.4 months for pembro + chemo and 16.8 months for placebo + chemo (HR 0.63). Similar trends were seen with regards to progression free survival (PFS). Median PFS for pembro + chemo vs placebo + chemo were 10.5 months vs 8.2 months, respectively, for the PD-L1 CPS >= 1 population (HR 0.58), 10.4 months vs 8.2 months, respectively, for the all-comer population (HR 0.61), and 10.4 months vs 8.1 months, respectively, in the PD-L1 CPS >= 10 population. The safety profile for pembro + chemo was manageable, and observed adverse events were consistent with the known safety profiles of individual components. These results are consistent with the previous interim data from the KEYNOTE-826 trial and provide more support for pembrolizumab combined with chemotherapy with or without bevacizumab as the new standard of care for persistent, recurrent, or metastatic cervical cancer.
For related research on cervical cancer, read this article from Huang et al in JITC.
Bispecific antibody elranatamab demonstrates clinical efficacy against multiple myeloma among patients with prior BCMA-directed therapies
8008. Efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma (RRMM) and prior B-cell maturation antigen (BCMA)-directed therapies: A pooled analysis from MagnetisMM studies.
Ajay K. Nooka (Emory University Hospital, Atlanta, GA) presented a pooled analysis of four MagnetisMM studies, investigating the efficacy and safety in patients with relapsed/refractory multiple myeloma (RRMM) and prior exposure to BCMA-directed therapy. Elranatamab is a humanized bispecific antibody that targets BCMA on multiple myeloma cells and CD3 on T cells. The study involved 87 patients representing a highly pre-treated population, having experienced a median of 7.0 prior lines of therapy. Average duration of treatment was 3.5 months, with 39.1% of patients receiving treatment for more than 6 months. 20% of patients were receiving ongoing treatment. Overall response rate (ORR) among this patient population was 46%; ORR of patients who had previously received prior BCMA-targeting antibody-drug conjugates (ADC) or BCMA-targeted CAR T cellular therapy (CAR T) were 42.4% and 52.8%, respectively. Responses were deep and durable, with a median duration of response (DOR) of 17.1 months, and 50% of objective responses were ongoing at the data cutoff. Median DOR of patients with prior ADC treatment was 13.6 months, and it was not reached among patients with prior CAR T treatment. Median progression free survival (PFS) was 5.5 months, and median overall survival (OS) was 12.1 months. Median PFS was 3.9 months and 10.0 months among patients with prior ADC therapy and CAR T therapy, respectively, and median OS was 12.1 months for both subgroups. The safety profile among this patient population was similar to a BCMA-naïve population. 75 (65.5%) patients experienced cytokine release syndrome (CRS), and 2 cases were grade 3-4. Infections were reported in 73.6% of patients and led to permanent discontinuation of therapy in 6.9% of patients. 3 cases of grade 2 and 2 cases of grade 3 ICANS were reported. These results provide evidence supporting elranatamab as an option for patients with RRMM who have received prior BCMA-directed therapies.
Blinded independent central review of the RUBY trial of dostarlimab for endometrial cancer
5500. Dostarlimab for primary advanced or recurrent (A/R) endometrial cancer (EC): Outcomes by blinded independent central review (BICR) of the RUBY trial (ENGOT-EN6-NSGO/GOG-3031/RUBY).
Matthew A. Powell (Washington University School of Medicine, St Louis, MO) reported outcomes determine by blinded independent central review (BICR) of the RUBY trial, which investigated the efficacy and safety of dostarlimab combined with standard of care (SOC) carboplatin and paclitaxel (CP) versus CP alone in advanced or recurrent endometrial cancer (A/R EC). Previous reports of RUBY indicated that the primary endpoint of progression free survival (PFS), determined by investigator assessment (INV), was significantly improved with dostarlimab + CP compared to placebo (PBO) + CP in a mismatch repair deficient/microsatellite instability-high ((HR 0.28) and in the overall overall population (HR 0.64). Dostarlimab + CP was also associated with an early trend in improved overall survival (OS) compared to placebo. 494 patients participated in the study. 245 patients received dostarlimab + CP, and 249 received PBO + CP. 118 patients made up the dMMR/MSI-H) subpopulation, with 53 receiving dostarlimab + CP and 65 receiving PBO + CP. PFS by BICR showed high concordance with PFS by INV. PFS by BICR was longer for dostarlimab + CP compared to PBO + CP for the overall population (42.5% vs 25.4%; HR 0.66) and for the dMMR/MSI-H subgroup (24 month PFS 66.3% vs 26.0%, respectively; HR 0.29). Response rates by BICR were similar to those by INV. Overall response rates by BICR for dostarlimab + CP vs PBO + CP was 68.2% vs 59.4%, respectively, for the overall population and 77.1% vs 63.3%, respectively, for the dMMR/MSI-H subgroup. Compete response rates were 20.6% vs 14.8% and 22.9% vs 13.3% for the overall population and the dMMR/MSI-H subgroup, respectively. Clinical efficacy assessments by BICR reinforce prior assessments by INV and further support the use of dostarlimab + CP in patients with primary advanced or recurrent endometrial cancer.
Addition of durvalumab and olaparib to the current standard of care produces significant progression free survival benefits for patients with advanced ovarian cancer
LBA5506. Durvalumab with paclitaxel/carboplatin (PC) and bevacizumab (bev), followed by maintenance durvalumab, bev, and olaparib in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) without a tumor BRCA1/2 mutation (non-tBRCAm): Results from the randomized, placebo (pbo)-controlled phase III DUO-O trial.
Philipp Harter (Kliniken Essen-Mitte and AGO, Essen, Germany) presented interim progression free survival (PFS) data from the DUO-O trial, which evaluated the efficacy of durvalumab with paclitaxel/carboplatin (PC) and bevacizumab (bev) followed by maintenance durvalumab, bev, and olaparib in patients with advanced ovarian cancer without a tumor BRCA1/2 mutation. Immunotherapy for ovarian cancer has not yet demonstrated a clinical benefit, but data from the MEDIOLA trial have indicated that durvalumab combined with bevacizumab and olaparib have shown promising clinical benefits. Patients were randomized to Arm 1: PC + bev , followed by maintenance bev (n=378), Arm 2: PC + bev + durvalumab followed by maintenance bev + durvalumab, or Arm 3: PC + bev + durvalumab followed by maintenance bev + durvalumab + olaparib. Approximately 90% of patients completed all planned cycles of chemotherapy and continued with maintenance therapy. At interim analysis, PFS for Arm 3 was significantly improved over Arm 1 in the intent to treat population (ITT), with median PFS 24.2 months and 19.3 months, respectively (HR 0.63) and in the homologous recombination deficiency (HRD) population, with median PFS 37.3 months and 23.0 months, respectively (HR 0.49). Improved PFS was observed in all subgroups, including patients with HRD-negative disease (HR 0.68). Improvement in PFS was observed in Arm 2 compared to Arm 1 of the ITT population (20.6 months vs 19.3 months, respectively; HR 0.87), but this difference was not significant. Serious adverse events were observed in 34% of patients in Arm 1, 43% of patients in Arm 2, and 39% of patients in Arm 3, and frequency and grade of observed adverse events were similar with other trials of multi-drug regimens. PC + bev + durvalumab followed by maintenance bev + durvalumab + olaparib for newly diagnosed non-tBRCAm advanced ovarian cancer produced statistically significant benefits in PFS, compared to PC + bev with maintenance bev and a manageable safety profile. DUO-O is ongoing, and final PFS, overall survival data, and other secondary endpoints will be reported at later times.
For related research on ovarian cancer, read this article from Xia et al in JITC.