Lungenkarzinom (inkl. Pleura) II
V158 Young Investigator Award: Repression von RIPK3 in Lungenkrebs begünstigt die Tumorprogression durch Umbau des Tumor assoziierten Immunsystems
Fabian Allmendinger, München, D
Introduction: Receptor-Interacting Serin/Threonin-Protein Kinase 3 (RIPK3) is a key player in a highly inflammatory programmed cell death pathway, namely necroptosis. Necroptosis induction elicits the release of intracellular contents and cytokines, which attract and activate anti-tumoral immune cells. In lung adenocarcinomas (LUAD) RIPK3 is a tumor suppressive aberrational target, which has been shown to induce immune suppression in the tumor microenvironment.
Methods: To elucidate RIPK3 involvement in LUAD, we took advantage of an in vivo LUAD mouse model and The Cancer Genome Atlas program (TCGA).
We used genetically modified mice, carrying KrasG12D oncogene (under a floxed stop codon) and floxed p53tumor suppressor. Tumor induction was obtained through Cre recombination, which induced KrasG12Dactivation as well as p53 deletion.
Results: Analysis at 16 weeks post-induction revealed that advanced-stage lung tumors (Adenoma, Adenocarcinoma - Ad/AC) have lower RIPK3 expression than early-stage tumors (bronchial hyperplasia, Fig. 1A-C). Furthermore, high RIPK3 expressing tumor lesions showed an enrichment of anti-tumoral inducible nitric oxide synthase (iNOS)-positive M2-macrophages and a reduction in Arginase-1 positive anti-inflammatory M1 macrophages (Fig. 1D). This difference in macrophage polarization suggests that RIPK3 may initiate an anti-tumoral immune microenvironment. To evaluate this hypothesis in human settings, we analyzed the TCGA datasets and found that tumors with higher RIPK3 expression showed higher total infiltrating leukocytes, specifically T-cells, B-cells, macrophages, and dendritic cells.
Conclusion: Taken together our data clearly point to RIPK3 as a tumor suppressor in LUAD. This effect may be driven by the inhibition of necroptotic cell death, which in turn alters immune cell recruitment. Leveraging the crosstalk between inflammatory cell death and immune micro-environment may be a possible immunogenic therapeutic target.
V495 Pacific-R Real-World-Studie: Behandlungsdauer und Zwischenanalyse des progressionsfreien Überlebens bei nicht resezierbaren NSCLC-Patienten im Stadium III, die nach einer Radiochemotherapie mit Durvalumab behandelt wurden
Daniel C. Christoph, Essen, D
Background: Durvalumab consolidation therapy for up to 12 months (PACIFIC regimen) is now standard of care in patients (pts) with unresectable Stage III non-small-cell lung cancer (NSCLC) without disease progression after platinum-based chemoradiotherapy (CRT). PACIFIC-R assesses the effectiveness of durvalumab in this pt population in a real-life setting.
Methods: PACIFIC-R (NCT03798535) is a large international, observational study in pts who received ≥1 dose of durvalumab (10 mg/kg Q2W) as part of an AstraZeneca-initiated expanded access program. Pts had completed platinum-based chemotherapy concurrent or sequential to radiotherapy within the previous 12 weeks without evidence of disease progression.
Results: Outcomes were assessed in the full analysis set (N=1155). Median time to durvalumab initiation after the end of RT was 52 days. Overall median durvalumab treatment duration was 337 days (11 months); 232 (20.1%) pts received treatment for >12 months (50 [4.3%] for >14 months). Pts received a median of 22 infusions. Reasons for/median time to treatment discontinuation included completion of treatment (47.6%/11.8 months; investigator decision per country protocol), disease progression (25.8%/5.1 months) and adverse event (AE; 17.5%/2.8 months). Pneumonitis was the most common AE leading to discontinuation (temporary: 5.1%; permanent: 8.7%). 214 (18.5%) pts had any- grade pneumonitis and/or interstitial lung disease (median time from durvalumab start: 74 days [2.4 months]). Of these, most events were moderate (8.8%) in severity; 2 (0.2%) and 1 (0.1%) pts had a life- threatening or fatal event, respectively. Interim analysis (51.8% of events) showed a median real-world PFS (rwPFS) of 22.5 months (95% CI, 19.7-25.5). rwPFS by baseline PD-L1 status and prior CRT will be included in the final presentation.
Conclusions: These results demonstrate the effectiveness of consolidation durvalumab after CRT in a real-world cohort of pts with unresectable Stage III NSCLC; pneumonitis events were mostly moderate in severity. Additional data from an externally sponsored study with similar enrolment criteria in Spain will be included in the final presentation.
V160 Nivolumab (NIVO) + Ipilimumab (IPI) + 2 Zyklen Chemotherapie (Chemo) versus Chemotherapie (4 Zyklen) als Erstlinientherapie bei Patienten mit fortgeschrittenem nicht-kleinzelligen Lungenkarzinom (NSCLC): 2-Jahres-Update der Studie CheckMate 9LA
Niels Reinmuth, München, D
Introduction: In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line (1L) NIVO+IPI combined with 2 cycles of chemo significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemo alone (4 cycles). Clinical benefit was observed regardless of programmed-death-ligand 1 (PD-L1) expression level and histology. Here we report 2 years' (yr) minimum follow-up (FU) data from this study.
Methods: Adults with stage IV/recurrent NSCLC, ECOG performance status ≤1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥1%), sex, and histology (squamous vs non-squamous) and were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles; n=361) or chemo alone (4 cycles; n=358). Patients (pts) with non-squamous NSCLC in the chemo-alone arm could receive pemetrexed maintenance. The primary endpoint was OS. Secondary endpoints included PFS and ORR by blinded independent central review, and efficacy by different PD-L1 levels. Safety was exploratory.
Results: At a minimum FU of 24.4 months (mo) for OS (database lock: Feb 18, 2021), pts treated with NIVO+IPI+chemo continued to derive OS benefit vs chemo, with a median OS of 15.8 mo vs 11.0 mo, respectively (HR, 0.72 [95% CI, 0.61-0.86]); 2-yr OS rates were 38% vs 26%. Median PFS with NIVO+IPI+chemo vs chemo was 6.7 mo vs 5.3 mo (HR, 0.67 [95% CI, 0.56-0.79]); 8% and 37% of pts who had disease progression received subsequent immunotherapy, respectively. ORR was 38% with NIVO+IPI+chemo vs 25% with chemo. Similar clinical benefit with NIVO+IPI+chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level (Table) or histology. Any grade and grade 3-4 treatment-related adverse events were reported in 92% and 48% of pts in the NIVO+IPI+chemo arm vs 88% and 38% in the chemo arm, respectively.
Conclusion: With 2 yr minimum FU, 1L NIVO+IPI+chemo demonstrated durable survival and benefit versus chemo in pts with advanced NSCLC; no new safety signals were identified.
(Accepted/previously presented at the 2021 ASCO Annual Meeting. Reused with permission.)
V241 Durvalumab ± Tremelimumab + Platinum-Etoposid in der 1L beim ES-SCLC: Eine explorative Analyse des HLA Genotyps und des Gesamtüberlebens in der CASPIAN-Studie
Jürgen Alt, Mainz, D
Introduction: In the Phase 3, open-label CASPIAN study, 1L durvalumab (anti-PD-L1; D)+etoposide and cisplatin or carboplatin (EP) significantly improved OS vs EP alone in patients with extensive-stage small- cell lung cancer (ES-SCLC) HR 0.73 (95% CI 0.59-0.91; p=0.0047). This benefit was sustained with >2 years of median follow-up: HR 0.75 (95% CI 0.62‒0.91; nominal p=0.0032). Although not statistically significant, a numerical improvement in OS was observed with D+tremelimumab (anti-CTLA-4; T)+EP vs EP: HR 0.82 (95% CI 0.68‒1.00; p=0.0451). Biomarkers that predict efficacy of immunotherapy (IO) are not well characterized in SCLC. As HLA expression and genotype have previously been associated with IO response, in this post-hoc exploratory analysis, we assessed the association of HLA-I/II genotype with OS.
Methods: 805 treatment-naïve patients (ECOG 0/1) with ES-SCLC were randomized 1:1:1 to D+T+EP, D+EP, or EP. The primary endpoint was OS. A subset of patients consented to provide a blood sample (collected at Day 1 pre-dose) for genetic research. Germline whole exome sequencing data was generated from which four-digit resolution HLA data was obtained using next generation sequencing.
Results: In CASPIAN, 414 patients (52% of all treated patients) were evaluable for HLA-I/II genotype (biomarker evaluable population [BEP]). In the BEP, the HR for OS was 0.71 (95% CI 0.55-0.93) with D+T+EP vs EP and was 0.65 (0.49-0.84) with D+EP vs EP. DQB1*03:01, an MHC class II allele (prevalence of 37% in the BEP), was associated with larger treatment effect in the D+T+EP arm (HR 0.59) but not in the D+EP (HR 0.93) or EP (HR 0.94) arms (Table). Presence of DQB1*03:01 was enriched in patients with OS ≥18 months in the D+T+EP arm (odds ratio 2.28).
Conclusion: In CASPIAN, the presence of the HLA-DQB1*03:01 allele was associated with improved OS in the D+T+EP arm but not in the D+EP or EP arms. MHC class II and CTLA-4 cooperate to determine the range of antigens the immune system can respond to and complement the antitumor mechanism of PD- L1 blockade. Further investigation is warranted to understand the role of the DQB1*03:01 allele in the tumor microenvironment.
V285 Capmatinib bei Patienten mit METex14-mutiertem fortgeschrittenen nicht-kleinzelligen Lungenkrebs (NSCLC): Neue Ergebnisse aus der GEOMETRY mono-1 Studie
Jürgen Wolf, Köln, D
Introduction: Capmatinib, a selective MET inhibitor, is approved in the USA and Japan for the treatment of patients (pts) with MET exon 14 skipping mutation(METex14) advanced non-small-cell lung cancer (NSCLC) based on the multi-cohort phase II GEOMETRY mono-1 study. This is the first report on expansion Cohort 7 in first line (1L) METex14 NSCLC pts, with updates to previously reported results (Wolf et al, NEJM 2020) for METex14 pts.
Methods: In GEOMETRY mono-1, pts were assigned to cohorts based on previous lines of therapy and MET status (METex14 or MET amplification). This efficacy analysis includes patients with METex14 NSCLC who were treatment-naive (Cohort 5b and 7) and those who had previously received 1L or 2L of therapy (Cohort 4 and 6) for their advanced disease (data cutoff: Sep 18, 2020). Evaluated outcomes included ORR, DOR, and PFS, all by BIRC; and OS. The safety analysis includes all patients enrolled.
Results: In total, 160 pts with METex14 who received capmatinib 400 mg BID were analyzed. ORR of 65.6% (95% CI 46.8-81.4) for the treatment-naive expansion Cohort 7 was in line with that previously reported for Cohort 5b. Though Cohort 7 data are still immature, median PFS was 10.8 mo (95% CI 6.87-NE). Mature median OS was 20.8 mo (95% CI 12.4-NE) in Cohort 5b and 13.6 mo (95% CI 8.6-22.2) in Cohort 4. Median OS for Cohorts 6 and 7 and DOR for Cohort 7 are not yet reached. The safety profile remained unchanged across all study cohorts (N = 373): 98.4% of pts reported AEs (68.6% G3/4) regardless of causality and 16.1% reported AEs leading to discontinuation (10.5% G3/4). The most common AEs (≥20% all G) were peripheral edema (54.2%), nausea (45.0%), vomiting (28.2%), increased blood creatinine (26.5%), dyspnea (23.3%), fatigue (22.3%), and decreased appetite (21.2%).
Conclusions: Results of Cohort 7 confirm those previously reported for Cohort 5b showing higher efficacy of capmatinib when used as 1L in METex14 NSCLC pts. A clinically meaningful median OS of 20.8 mo in 1L (Cohort 5b) and of 13.6 mo in relapse (Cohort 4) was also observed and, together with the continued manageable toxicity profile, the data support capmatinib as a valuable targeted treatment option for METex14 NSCLC pts.