Gastrointestinale Tumoren

V149 Nivolumab plus Chemotherapie in der Erstlinienbehandlung von fortgeschrittenen Adenokarzinomen des Magens, gastro-ösophagealen Übergangs oder Ösophagus: weitere Daten zur Wirksamkeit und Verträglichkeit aus CheckMate 649

Markus Möhler, Mainz, D

Introduction: CheckMate 649 is the largest randomized, global phase 3 study of 1L programmed death (PD)-1 inhibitor-based therapy in GC/GEJC/EAC. 1L NIVO+chemo demonstrated superior overall survival (OS) vs chemo, with progression-free survival (PFS) benefit and an acceptable safety profile in patients (pts) whose tumors expressed PD-ligand (L)1 at combined positive score (CPS) ≥5 and ≥1, and in all randomized pts (Moehler et al. Ann Oncol 2020). We report additional data for all randomized pts.

Methods: Eligible pts had previously untreated, unresectable advanced or metastatic GC/GEJC/EAC. Known HER2-positive pts were excluded. Pts were randomized to receive NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO+chemo vs chemo were OS and PFS by blinded central review in PD-L1 CPS ≥5 pts. Hierarchically tested secondary endpoints were OS in PD-L1 CPS ≥1 and all randomized pts.

Results: At 12-month minimum follow-up for 1581 randomized pts, NIVO+chemo had a statistically significant OS benefit vs chemo (HR 0.80 [99.3% CI 0.68-0.94; P = 0.0002]) in all randomized pts; PFS benefit was also seen (HR 0.77 [95% CI 0.68-0.87]). OS benefit was observed in multiple prespecified subgroups, consistent with the primary population. Grade 3-4 treatment-related adverse events (TRAEs) were reported in 59% (NIVO+chemo) and 44% (chemo) of pts. TRAEs with potential immunologic etiology (select TRAEs; sTRAEs) are shown in the Table. Pts in the NIVO+chemo arm had decreased risk of symptom deterioration on treatment vs those in the chemo arm (HR 0.77 [95% CI 0.63-0.95; P = 0.0129]). Tolerability as measured by the FACT-Ga GP5 item was similar in both treatment groups.

Conclusions: The addition of NIVO to chemo demonstrated improved OS and PFS benefit in all randomized pts, along with an acceptable safety profile and maintained tolerability as well as QoL, providing further support for NIVO+chemo as a standard 1L treatment for advanced GC/GEJC/EAC.

(This abstract was accepted/previously presented at the 2021 ASCO Annual Meeting. Reused with permission. All rights reserved)


V132 Adjuvantes Nivolumab (NIVO) bei resezierten Karzinomen des Ösophagus oder des gastroösophagealen Übergangs (EC/GEJC) nach neoadjuvanter Chemoradiotherapie (CRT): erweiterte Wirksamkeits- und Sicherheitsanalysen aus der Studie CheckMate 577

Thomas Zander, Köln, D

Introduction: In CheckMate 577 (NCT02743494), NIVO demonstrated a significant and clinically meaningful improvement in disease-free survival (DFS; primary endpoint) vs placebo (PBO) and was well tolerated in patients (pts) with resected (R0) stage II/III EC/GEJC who received neoadjuvant CRT and had residual pathologic disease. Median DFS doubled with NIVO vs PBO (22.4 vs 11.0 months; HR 0.69; 96.4% CI 0.56-0.86; P = 0.0003). Serious treatment-related adverse events (TRAEs) and TRAEs leading to discontinuation were reported for < 10% of pts with NIVO and 3% with PBO.

Methods: Pts were randomized 2:1 to NIVO 240 mg or PBO Q2W for 16 weeks, followed by NIVO 480 mg or PBO Q4W. Here, we present additional efficacy, safety, and quality-of-life (QoL) data from CheckMate 577.

Results: 794 pts were randomized (NIVO, 532; PBO, 262). Distant recurrence was reported for 29% vs 39% and locoregional recurrence for 12% vs 17% of pts in the NIVO vs PBO groups, respectively. Median distant metastasis-free survival was 28.3 vs 17.6 months with NIVO vs PBO (HR 0.74; 95% CI 0.60-0.92). Median progression-free survival 2 (PFS2; time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death, whichever is earlier) was not reached with NIVO vs 32.1 months with PBO (HR 0.77; 95% CI 0.60-0.99). TRAEs with potential immunologic etiology (select TRAEs; sTRAEs) reported for NIVO are presented in the Table. Results for the FACT-ECS and FACT-G7 showed similar trends for QoL improvement from baseline for NIVO and PBO during treatment and maintained benefit post-treatment.

Conclusions: Adjuvant NIVO demonstrated clinically meaningful efficacy, an acceptable safety profile, and maintained QoL, providing further support for its use as a new standard of care for pts with resected EC/GEJC who received neoadjuvant CRT with residual pathologic disease.

(This abstract was accepted/previously presented at the 2021 ASCO Annual Meeting. Reused with permission. All rights reserved)


V218 Nivolumab (NIVO) plus Chemotherapie (Chemo) oder NIVO plus Ipilimumab (IPI) versus Chemotherapie als Erstlinientherapie (1L) bei fortgeschrittenem Plattenepithelkarzinom des Ösophagus (ESCC): Erster Bericht der
CheckMate 648 Studie

Richard Greil, Salzburg, A

Introduction: NIVO demonstrated superior overall survival (OS) vs chemo in previously treated patients (pts) with ESCC (ATTRACTION-3). We report OS and progression-free survival (PFS) from CheckMate 648, the first global phase 3 study to evaluate both an immuno-oncology (I-O)/chemo combination and an I-O/I-O combination in advanced ESCC (NCT03143153).

Methods: Adults with previously untreated, unresectable advanced, recurrent or metastatic ESCC were enrolled regardless of tumor cell PD-L1 expression. Pts were randomized to NIVO (240 mg Q2W) + chemo (fluorouracil + cisplatin Q4W), NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), or chemo alone. Primary endpoints for both comparisons: OS and PFS per blinded independent central review (BICR) in pts with tumor cell PD-L1 ≥1%. Hierarchically tested secondary endpoints included OS and PFS in all randomized pts.

Results: 970 pts were randomized to NIVO+chemo, NIVO+IPI, and chemo arms (49% with tumor cell PD-L1 ≥1%). With 13 months (mo) minimum follow-up, NIVO+chemo and NIVO+IPI led to statistically significant improvement in OS vs chemo in pts with tumor cell PD-L1 ≥1% and all randomized pts (Table). Statistically significant PFS benefit was also observed for NIVO+chemo vs chemo (HR 0.65 [98.5% CI 0.46-0.92]; P = 0.0023) in pts with tumor cell PD-L1 ≥1%. PFS in NIVO + IPI vs chemo in pts with tumor cell PD-L1 ≥1% did not meet the prespecified boundary for significance. Objective response rate (per BICR) was 53% (NIVO+chemo), 35% (NIVO+IPI), and 20% (chemo) in pts with tumor cell PD-L1 ≥1% and in all randomized pts was 47%, 28%, and 27%, respectively; longer duration of response was observed vs chemo for pts with tumor cell PD-L1 ≥1% and for all randomized pts (Table). No new safety signals were identified (Table).

Conclusions: NIVO plus chemo and NIVO plus IPI both demonstrated superior OS vs chemo, along with durable objective responses and acceptable safety, in pts with advanced ESCC, and each represents a potential new 1L treatment option.

© 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved.


V61 Sicherheit und Wirksamkeit des anti-PD-1 Antikörpers Dostarlimab in Patienten mit Mismatch-Repair-defizienten (dMMR) soliden Tumoren: Ergebnisse aus der GARNET Studie
Arndt Vogel, Hannover, D

Dostarlimab is a humanized anti-PD-1 monoclonal antibody that binds the PD-1 receptor, blocking interaction with its ligands. The phase 1 GARNET study (NCT02715284) evaluates dostarlimab in advanced solid tumors. Here we present safety and efficacy data from cohort F.
Cohort F enrolled pts with dMMR or POLεmut non-endometrial solid tumors. Pts must have progression per BICR following systemic therapy for advanced disease and had dMMR status by immunohistochemistry. Pts received 500 mg of dostarlimab Q3W for 4 cycles then 1000 mg Q6W until discontinuation. Objective response rate (ORR) and duration of response (DOR) were assessed by BICR per RECIST v1.1. Pts who received ≥1 dose were included in safety analysis and in efficacy analysis if they received ≥1 dose dostarlimab, had measurable disease at baseline, and had 6 mo of follow-up.
144 pts were included in safety analysis;106 dMMR pts in efficacy analysis (1 POLεmut pt with confirmed partial response [PR] not included). Of the 106 pts, 99 (93.4%) had GI tumors. Confirmed ORR was 38.7% (95% CI, 29.4-48.6); complete response rate 7.5%. ORR was consistent across tumor type (Table). At data cutoff, median follow-up time (n=107; dMMR and POLεmut pts) was 12.4 mo; median DOR was not reached. Kaplan-Meier estimated probability of maintaining response was 91% at 12 mo and 80.9% at 18 mo.

Treatment-related adverse events (TRAEs) were reported in 68.8%; 8.3% had ≥1 grade ≥3 TRAE, with lipase increased in 1.4% as most common. Treatment-related serious AEs were reported in 9 (6.3%) pts; 5 pts (3.5%) discontinued because of TRAE. No deaths were attributed to dostarlimab.
Dostarlimab demonstrated durable antitumor activity in dMMR solid tumor pts, the majority with GI cancers. Safety profile was consistent with other cohorts in GARNET, with immune-related TRAEs infrequent and low grade.

Disclosures: This study (NCT02715284) was sponsored by GlaxoSmithKline, Waltham, MA, USA. Encore Statement: These data are presented on behalf of the original authors with their permission. Presented at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, January 15-17, 2021, virtual meeting.

V65 Patienten mit RAS-mutiertem metastasiertem kolorektalem Karzinom - Daten aus der klinischen Routine von über 1000 Patienten aus dem Tumorregister Kolorektales Karzinom (TKK)
Roland Schnell, Frechen, D

Introduction: For patients (pts) with RAS mutant (mut) metastatic colorectal cancer (mCRC) the therapeutic benefit derived from established treatment regimens is still unclear. Guidelines recommend chemotherapy (CT; fluoropyrimidine, irinotecan, oxaliplatin) with or without anti-angiogenic agents for two treatment lines. There is no established standard of care for subsequent treatment lines. Real-world data on pts with RAS mut mCRC are scarce.

Methods: Since 2006, the Tumor Registry Colorectal Cancer (TKK) prospectively collects data on patient and tumor characteristics, treatment, outcome, and quality of life of CRC pts in routine clinical practice in Germany. The treating physicians decide treatments as per clinical routine and independently from the registry. Here we analyse patient and tumor characteristics, longitudinal treatment details and outcome of 1087 pts with (K)RAS mut mCRC from begin of palliative first-line therapy.

Results: Between 2010 and 2018, 1087 pts with (K)RAS mut mCRC were enrolled. Median age of pts was 68 years. Since 2010, KRAS testing could be documented. Since 2014 details on extended RAS mutation status testing (exons 2/3/4 for KRAS or NRAS) were documented (n=897). RAS mut is defined as any KRAS or NRAS mutations in exon 2,3, or 4. Of all pts with RAS mut mCRC, 94% of pts had KRAS mut and 18% of pts had NRAS mut tumors. 6% (n=49) of pts with wild-type KRAS tumor had additional NRAS mutations.

Between 2010 and 2018, pts with (K)RAS mut mCRC were mostly treated with a doublet CT and bevacizumab (BEV) as 1st-line therapy, with the most frequent treatment regimens being FOLFIRI+BEV (30%), FOLFOX+BEV (25%), FOLFOX (13%) and FOLFIRI (9%). No major changes were seen in choice of treatment over time. 747 pts (69%) received 2nd-line therapy, of those 18% of pts were treated with FOLFIRI+BEV followed by FOLFOX+BEV (16%). 439 pts (40%) received 3rd-line therapy, of those 12% of pts received FOLFIRI+BEV. The percentage of pts receiving 3rd-line trifluridine/tipiracil increased over time from 9% in 2016 to 38% in 2019.

Median overall survival for all evaluable pts with (K)RAS mut mCRC was 21.9 months (62% events, 95%-CI: 20.9 - 23.0 months).

Conclusions: This analysis of the RAS mut mCRC population enrolled prospectively in the TKK database provides important insights into treatment patterns, sequential treatments, and outcome of patients with RAS mut mCRC in routine clinical practice in Germany.