FROM JUNE 3, 2022
Does chemotherapy improve the efficacy of first-line immunotherapy for non-small cell lung cancer?
9000: Outcomes of anti–PD-(L)1 therapy with or without chemotherapy (chemo) for first-line (1L) treatment of advanced non–small cell lung cancer (NSCLC) with PD-L1 score ≥ 50%: FDA pooled analysis.
Oladimeji Akinboro (U.S. Food and Drug Administration) reported results of an exploratory analysis to determine whether chemotherapy improves clinical outcomes when added to immunotherapy for patients receiving first-line treatment of PD-L1 high (>=50%) advanced non-small cell lung cancer (NSCLC). Data from 12 randomized controlled clinical trials that investigated anti-PD-(L)1 regimens with or without chemotherapy for first line treatment of patients with advanced NSCLC were pooled, representing 3,189 patients. Median OS for patients who received chemotherapy with immunotherapy (n=455) was 25.0 months, compared to 20.9 months for patients receiving immunotherapy alone (n=1,298); the hazard ratio was 0.82. Median PFS was 9.6 months for chemotherapy + immunotherapy, compared to 7.1 months for immunotherapy alone. Overall response rate for chemotherapy + immunotherapy was also higher (61% vs. 43%), although this difference was not significant. These data suggest that combining chemotherapy with immunotherapy for first-line treatment of NSCLC with PD-L1 score >=50% is comparable or slightly more favorable than immunotherapy alone. Most patient subgroups exhibited slightly better outcomes with chemotherapy + immunotherapy compared to immunotherapy alone, except patients aged 75 years or older, who seemed to benefit more from immunotherapy monotherapy. These results underscore the importance of shared decision making between a patient and their oncologist when choosing an individualized therapeutic approach.
Efficacy of immune checkpoint inhibitors as monotherapy or as combination with chemotherapy for first-line treatment of KRAS-mutated non-small cell lung cancer
9001: Outcomes of first-line immune checkpoint inhibitors with or without chemotherapy according to KRAS mutational status and PD-L1 expression in patients with advanced NSCLC: FDA pooled analysis.
Erica C. Nakajima (U.S. Food and Drug Administration) presented findings from a pooled retrospective analysis to determine the outcomes of immune checkpoint inhibitors (ICIs) for first-line treatment of non-small cell lung cancer (NSCLC) with mutated Kirsten rat sarcoma oncogene (KRAS). Past studies suggest that patients with KRAS mutations exhibit favorable outcomes when receiving ICI monotherapy in the first line setting. Data from 12 randomized controlled clinical trials were pooled and evaluated for the efficacy of ICI combined with chemotherapy (ICI + chemo), ICI alone, and chemotherapy alone. KRAS mutation status was reported in 16% of all patients (n = 1430): 61% of patients were KRAS wild type and 39% were KRAS mutant. Patients were further sub-divided by PD-L1 staining; 60% of patients were PD-L1 positive (combined positivity score [CPS] >=1) and 40% were PD-L1 negative (CPS <1). Median overall survival (OS) for patients who received ICI + chemo was 22.4 months for patients with KRAS mutations, compared to 18.7 months for KRAS wild type. The KRAS G12C mutants were reported at 11% of patients with a KRAS mutation (157/555), and median OS in this subpopulation who received ICI + chemo was 20.8 months (n= 58). Median OS and ORR was highest for patients who received ICI + chemo, regardless of KRAS mutation status and PD-L1 status. Some patient groups included in this analysis were relatively small, specifically patients receiving ICI monotherapy and patients with the KRAS G12C mutation, so survival benefits in these groups may not be completely represented in this study. Furthermore, the KRAS wild type group contained patients with EGFR/ALK mutations, which may negatively impact survival benefit. While larger patient groups and more analysis is needed for further investigation, preliminary analysis suggests that patients with KRAS-mutated NSCLC benefit from first line treatment with ICI + chemo, similarly to those with that are KRAS wild type and that treatment of ICI + chemo may be the optimal control arm for future clinical trials of first-line treatment for NSCLC.
Evaluating the safety of a soluble LAG-3 protein to augment the anti-tumor activity of pembrolizumab
9003: A phase II study (TACTI-002) in first-line metastatic non–small cell lung carcinoma investigating eftilagimod alpha (soluble LAG-3 protein) and pembrolizumab: Updated results from a PD-L1 unselected population.
Enriqueta Felip (Vall d’Hebron Institute of Oncology (VHIO)) reported on the efficacy of eftilagimod alpha (E), a soluble LAG-3 protein fused to human IgE backbone, in increasing the anti-tumor activity of pembrolizumab against metastatic non-small cell lung cancer. E binds to a subset of MHC class II molecules, stimulating antigen presentation and T cell recruitment, leading to the hypothesis that E could increase the anti-tumor activity of pembrolizumab compared to pembrolizumab alone. A specific cohort from the Phase II TACTI-002 trial received E once every two weeks for 8 three-week cycles and then E every three weeks for up to 1 year with pembrolizumab once every three weeks for up to two years. 114 patients were enrolled in the study, and 88% of patients were at stage IV disease at the start of the study. 17% (n = 19) patients discontinued treatment due to adverse events. At data cut-off in January 2022, 114 patients were evaluated for efficacy. 11 patients (9.6%) permanently discontinued treatment due to adverse events (AEs) related to study treatment. ORR (iRECIST) was 38.6%, and disease control rate with 73.7%. Two patients exhibited a complete response, and only 9% of patients who responded to treatment exhibited disease progression within 6 months. Response rate (iRECIST) for patients with squamous pathology was 35.0% and 38.9% for patients with non-squamous pathology. Results were similar to RESCIST 1.1. Median progression free survival (PFS) for all patients was 6.9 months, and median PFS was 11.8 months for patients with high PD-L1 status (>=50%) was 11.8 months, 9.3 months for patients with PD-L1 between 1 to 49%, and 4.2 months for PD-L1 negative patients (<1%). These early data indicate that E + P is safe, and its antitumor activity, regardless of PD-L1 status, warrants further investigation.
Assessing real-world outcomes of CAR-T cell therapy by race and ethnicity
7571. Real-world outcomes of axicabtagene ciloleucel (Axi-cel) for the treatment of large B-cell lymphoma (LBCL) by race and ethnicity.
Frederick L. Locke (H. Lee Moffitt Cancer Center & Research Institute) provided results from a study investigating the outcomes by race and ethnicity of patients who received axicabtagene ciloleucel (Axi-cel) to treat large-B cell lymphoma (LBCL). The study consisted of 1389 patients, and race and ethnicity were self-reported. 81% (1127) of patients were White, 5% (70) were African American, 6% (81) were Asian, and 152 (11%) were Hispanic. No significant differences were seen in overall survival, duration of response, or progression free survival across races or between Hispanic and non-Hispanic patients. Multivariate analyses indicated that the overall response rate (ORR) and complete response (CR) rate for African American patients (57% and 45% respectively) was significantly lower than rates for White patients (ORR 74%, CR 57%). Asian patients had a higher duration of response (DOR) compared to White and African American patients (HR 0.46 and 0.39, respectively). Rates of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS) were similar across races and ethnicities. Asian and Hispanic patients had a lower risk of ICANS >= grade 3, compared to White patients. Overall, treatment of LBCL with axi-cel showed favorable OS, PFS, and safety profiles in patients regardless of race and ethnicity. Lower response rates among African American patients warrant further investigation to determine if these rates are associated with higher disease burden and/or differential access to care.
Determining the optimal timing of immunotherapy with chemoradiotherapy
6007. A randomized phase II study evaluating concurrent or sequential fixed-dose immune therapy in combination with cisplatin and intensity-modulated radiotherapy in intermediate- or high-risk, previously untreated, locally advanced head and neck cancer (LA SCCHN).
David Anthony Clump (UPMC Hillman Cancer Center) presented results from a randomized phase II trial investigating the optimal timing of combining anti-PD-1 therapy with cis-platin chemoradiotherapy (CRT) for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). 80 patients participated in the study; patients in the concurrent treatment arm (n=41) received 7 weeks of CRT, which began at week 2 of a 24-week course of pembrolizumab, and patients in the sequential treatment arm received 7 weeks of CRT followed by a 24-week course of pembrolizumab. Both arms of the study met the predefined endpoints of dose-limiting toxicity rate < 20%, 1-year local failure rate < 60%, and one-year progression free survival (PFS) > 60%. One- and two-year PFS for sequential treatment was 89%, compared to 82% and 78% for concurrent treatment, respectively. Three-year PFS for sequential treatment was 84%, compared to 74% for concurrent treatment. A similar trend was observed for three-year overall survival (90% for sequential treatment vs 74% for concurrent treatment). Grade 3 toxicity rate for sequential treatment was 87.2% compared to 95% for concurrent treatment. Although the differences between the two treatment arms are not statistically significant, these early data suggest that sequential treatment with pembrolizumab in combination with CRT is the preferable care regimen for LA SCCHN. Tissue and peripheral blood samples were taken pre-operatively and two weeks into treatment, and correlative studies to identify cellular and immunological mechanisms related to outcome, as well as a Phase III trial, are ongoing.
Combining immune checkpoint inhibitors with receptor tyrosine kinase inhibitors to treat HNSCC
6008. A phase II trial of pembrolizumab and cabozantinib in patients (pts) with recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC).
Nabil F. Saba (Winship Cancer Institute, Emory University) reported results from a phase II, single arm trial investigating the tolerability and benefits of the immune checkpoint inhibitor (ICI) pembrolizumab (pembro) combined with the receptor tyrosine kinase inhibitor cabozantinib (cabo) to treat recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). 32 patients who had not received prior immune checkpoint inhibitor therapy received treatment of pembrolizumab combined with cabo. 16 (50%) patients reported adverse events (AE), most commonly fatigue. 6 (18.7%) patients reported adverse events of grade 3 or 4. The rate of AEs corresponded were within the range of AEs associated with pembro and cabo monotherapies. AEs were mitigated by reduction of cabo dose, which did not alter clinical benefits. Overall response rate was 45.2%, with all responses characterized as partial responses, and an overall clinical benefit of 90.4% was observed. One-year overall survival was 67.7%, and one-year PFS was 54%. CPS scores and T cell infiltration of tumors corresponded with response. These results indicate that pembro + cabo is well-tolerated and exhibits encouraging clinical results and that combination of ICIs with cabozantinib, which is already used for treatment of renal cell carcinoma, may also be relevant for treatment of HNSCC.