Immune checkpoint inhibitors (ICI) dramatically improved outcomes of patients with non-small cell lung cancer (NSCLC). The gut microbiome has emerged as a biomarker of response to ICI in NSCLC and a potential therapeutic target. High fiber and Mediterranean diets were associated with prolonged response in patients with melanoma treated with ICI. The objective of this study was to assess the effect of diet on outcome and microbiome composition. Prospective collection of clinical and dietary data were assessed in 102 patients with NSCLC amenable to ICI. We employed a standardize food frequency questionnaire (FFQ) specific to the NSCLC population designed by a clinical nutritionist. FFQ answers were recorded electronically and analyzed using a calculation tool to estimate the median daily fiber (g/day), and surrogate markers of the Mediterranean diet; Monounsaturated fatty acids (MUFA) and Polyunsaturated fatty acids (PUFA) intake (g/1000kcal). Then correlated with progression-free survival (PFS) and overall survival (OS). Microbiome was profiled in a sub-group of 76 patients using shot-gun metagenomic, MetaPhlan4 pipeline was used to detect species, diversity index and LefSe were calculated. Among the 102 patients with NSCLC the median fiber intake was 16 g/day and did not correlate with outcome. However, Spearman correlation showed a significant association between increased PUFA or MUFA intake and longer OS (p<0,001 and p<0,001). Moreover, MUFA dietary intake correlated with a prolonged PFS (median PFS high MUFA intake: 20.0 months versus low MUFA intake: 9.1 months, p=0.02). Additionally, MUFA and PUFA intake correlated with the increase abundance of Eubacterium, Alistipes and Bifidobacterium. In this cohort, patients had a very low fiber diet, however a high MUFA and PUFA intake was associated with beneficial response and an overrepresentation of known beneficial immunogenic bacteria. These results raise the possibility that evidence-based dietary recommendations counseling using educational tools may represent an important strategy to employ the gut microbiome as a potential therapeutic target in improving the response to ICI.
Abstract The eventual development of resistance to single-agent targeted therapies in lung adenocarcinomas (LUAD) is inevitable, and new strategies are needed. We hypothesize that combination therapies aimed at a known driver and a distinct targetable alteration could prolong time on oral targeted therapy. In an analysis of 7636 patients with LUAD who underwent MSK-IMPACT large panel NGS testing, 5.5% (416/7636) harbored MDM2 amplification (MDM2amp), a known mechanism of TP53 inactivation. MDM2amp was over-represented among tumors with alterations in METex14 (34.4%, p<0.001), EGFR (10%, p<0.001), RET (11%, p<0.05), and ALK (9.9%, p<0.002). The small molecule MDM2 inhibitor milademetan (mila) caused growth inhibition as a single-agent in MDM2amp patient-derived cell lines with concurrent kinase alterations including ECLC5-GLx (MDM2amp/TRIM33::RET/TP53 wildtype (WT)) and LUAD12c (MDM2amp/METex14/KRASG12S/TP53 WT). Mila also caused growth inhibition in a cell line with KRASG12C and WT TP53 without MDM2amp (SW1573 (KRASG12C/TP53WT)), but not in cell lines with TP53 mutations (LUAD-002AS1 (KIF5B::RET/TP53P128fs, H1792 (KRASG12C/TP53 splice site mut)). Treatment of ECLC5-GLx and LUAD12c with mila resulted in restoration of ERK phosphorylation, confirming a previous report of ERK activation upon MDM2 inhibition. At 48 hours, ERK phosphorylation was suppressed by concurrent mila and MEK inhibition using trametinib (tram). In contrast, ERK phosphorylation was not suppressed by concurrent mila and KIF5B::RET inhibition using selpercatinib (in ECLC5-GLx) or MET inhibition using capmatinib (in LUAD12c). The combination of mila+tram was synergistic in slowing growth of ECLC5-GLx, LUAD12c, and SW1573 cells, and increased expression of pro-apoptotic proteins PUMA and BIM, beyond that achieved by either agent alone. In ECLC5-GLx, mila+tram also caused increased apoptotic cells measured by Annexin-V compared to either agent alone (combination p<0.01 compared to mila, p<0.001 compared to tram). In vivo, combination mila+tram was more effective than mila or tram alone in ECLC5-GLx (p<0.0001 and p<0.0001, respectively), LX-285 (EGFRex19del/MDM2amp) (p<0.0001 and p<0.0001, respectively), and L-13BS1 (model resistant to capmatinib) (METex14/MDM2amp) (p<0.05 and p<0.0001, respectively). These results suggest that combined MDM2/MEK inhibition is effective in patient-derived LUAD models harboring MDM2amp. This combination, potentially applicable to LUADs with a wide variety of oncogenic driver mutations and kinase fusions will be investigated as part of a phase 1/2 clinical trial. Citation Format: Arielle Elkrief, Vladimir Markov, Álvaro Quintanal-Villalonga, Rebecca Caeser, Pawel Sobczuk, Emily Cheng, Alexander Drilon, Gregory J. Riely, William W. Lockwood, Elisa de Stanchina, Charles M. Rudin, Igor Odintsov, Romel Somwar. MDM2 inhibition in combination with MEK inhibition in pre-clinical models of lung adenocarcinomas with MDM2 amplification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6127.
Abstract Colitis induced by treatment with immune-checkpoint inhibitors (ICI), termed irColitis, is a substantial cause of morbidity complicating cancer treatment. We hypothesized that abnormal fecal microbiome features would be present at the time of irColitis onset and that restoring the microbiome with fecal transplant from a healthy donor would mitigate disease severity. Herein, we present fecal microbiota profiles from 18 patients with irColitis from a single center, 5 of whom were treated with healthy-donor fecal microbial transplantation (FMT). Although fecal samples collected at onset of irColitis had comparable α-diversity to that of comparator groups with gastrointestinal symptoms, irColitis was characterized by fecal microbial dysbiosis. Abundances of Proteobacteria were associated with irColitis in multivariable analyses. Five patients with irColitis refractory to steroids and biologic anti-inflammatory agents received healthy-donor FMT, with initial clinical improvement in irColitis symptoms observed in four of five patients. Two subsequently exhibited recurrence of irColitis symptoms following courses of antibiotics. Both received a second “salvage” FMT that was, again, followed by clinical improvement of irColitis. In summary, we observed distinct microbial community changes that were present at the time of irColitis onset. FMT was followed by clinical improvements in several cases of steroid- and biologic-agent-refractory irColitis. Strategies to restore or prevent microbiome dysbiosis in the context of immunotherapy toxicities should be further explored in prospective clinical trials.
3125 Background: MAP2K1 (MEK1) mutations are potentially actionable driver mutations in cancer. MAP2K1 mutations can be classified into 3 classes according to molecular characteristics. The efficacy of MAPK inhibitors (MAPKi) for the treatment of MAP2K1 mutant tumors is not well understood. We sought to characterize the genomic and clinical landscape of MAP2K1 mutant tumors, and to evaluate the relationship between MAP2K1 mutation class and clinical activity of MAPKi in patients with MAP2K1 mutant metastatic solid tumors. Methods: We interrogated AACR GENIE (v13) to identify all tumors with Class 1/2/3 MAP2K1 mutant solid tumors. We performed a systematic review and meta-analysis of individual patient data from patients with MAP2K1 mutant cancer published between 2010-22. Key inclusion criteria were: MAP2K1 mutation, solid tumor, metastatic disease, treatment with MAPKi and available treatment response data. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall response rate (RR) and duration of response (DOR). Chi-squared and Log-Rank tests were used to evaluate statistical significance of differences between groups. Results: MAP2K1 driver mutations were present in 917/167,423 (0.5%) tumors in the AACR GENIE dataset. MAP2K1 mutants were most commonly identified in melanoma, colorectal (CRC) and non-small cell lung cancer (NSCLC). In solid tumors, Class 2 mutations were the most prevalent (n=310, 63%) followed by Class 1 (n=119, 24%) and Class 3 (n=66, 13%). Co-occurring MAPK pathway activating mutations (KRAS, NRAS, HRAS, NF1, BRAF, RAF1, or EGFR) were significantly more likely (P<0.0001) to occur in Class 1 (82.3%), versus Class 2 (30.9%) or Class 3 (10.6%) MAP2K1 mutant tumors. We identified 55 patients with MAP2K1 mutant tumors who received MAPKi (n=16/30/6/3 for Class 1/2/3/unclassified, respectively). Of these, (n=22, 18, 12, 3) had melanoma, CRC, NSCLC, or other cancers, respectively. Patients were treated with BRAFi (n=12), MEKi (n=24), BRAF+MEKi (n=2), ERKi (n=1) or EGFRi (n=16). Co-occurring MAPK pathway mutations were present in 51% of tumors. In the entire cohort, the RR was 24% and median PFS was 3.3 months. The RR did not differ according to mutation class, cancer type or MAPKi regimen. However, patients with Class 2 mutations experienced longer PFS (4.0 months) and DOR (23.8 months) compared to patients with Class 1, 3 or unclassified MAP2K1 mutations (PFS 3.0 months, P=0.035; DOR 4.2 months, P=0.04). Conclusions: Class 2 MAP2K1 mutations are RAF-regulated oncogenic mutations with a relatively low incidence of co-occurring MAPK pathway activating mutations. Some patients with Class 2 MAP2K1 mutations may derive durable therapeutic benefit from MAPKi. Prospective clinical studies with MAPK inhibitors are warranted in patients with MAP2K1-mutated metastatic cancer.
BackgroundNon-small cell lung cancer (NSCLC) patients aged ≥80 years [y] are underrepresented in clinical trials. We evaluated whether age correlates with a distinct immunophenotype or impacts outcomes to first-line pembrolizumab in patients with advanced NSCLC, PD-L1 Tumor Proportion Score (TPS) of ≥50%, and aged ≥80y.MethodsThree NSCLC cohorts were retrospectively analyzed to assess the impact of age (<80y versus ≥80y) on pembrolizumab efficacy and the tumor microenvironment (TME). Cohort A encompassed patients receiving first-line pembrolizumab for advanced NSCLC with PD-L1 ≥50%. Cohort B comprised patients with tumor profiling using multiplexed immunofluorescence (ImmunoPROFILE). Cohort C included The Cancer Genome Atlas (TCGA) and Stand Up To Cancer (SU2C) databases for gene expression analysis.ResultsIn Cohort A (N=669), patients ≥80y (N=111) showed no significant differences in objective response rate or median progression-free survival compared to younger patients (N=558), but had shorter median overall survival and were less likely to receive second-line therapy after progression on pembrolizumab. In Cohort B (N=567), tumors from patients ≥80y (N=45) exhibited higher intratumoral FOXP3+ T cells and closer vicinity of PD-1+ immune cells to tumor cells compared to <80y (N=522). Cohort C revealed a distinct immunophenotype in samples from patients ≥ 80y, with elevated specific immune cell subsets and up-regulated immune checkpoint proteins.ConclusionPatients ≥ 80y with PD-L1-high NSCLC displayed a distinct immunophenotype in the TME but achieved similar ORR and mPFS to first-line pembrolizumab compared to younger patients. OS was shorter in older patients, who were less likely to receive second-line therapy.
This prospective observational study assesses changes in treatment plans for patients with lung cancer and qualifies the types of changes observed as a direct result of the coronavirus disease 2019 pandemic.
<p>Supplementary Figure 27. Tumor mutational burden in NSCLC samples which underwent NGS at the DFCI and MSK according to ATM/TP53 co-mutation status.</p>
