No abstract

Several evidences showed that patients with gastrointestinal stromal tumors (GISTs) develop additional malignancies. However, thorough incidence of second tumors remains uncertain as the possibility of a common molecular pathogenesis.A retrospective series of 128 patients with histologically proven GIST treated at our institution was evaluated. Molecular analysis of KIT and PDGFR-α genes was performed in all patients. Following the involvement of KRAS mutation in many tumors’ pathogenesis, analysis of KRAS was performed in patients with also second neoplasms.Forty-six out of 128 GIST patients (35.9%) had a second neoplasm. Most second tumors (52%) raised from gastrointestinal tract and 19.6% from genitourinary tract. Benign neoplasms were also included (21.7%). Molecular analysis was available for 29/46 patients with a second tumor: wild-type GISTs (n. 5), exon 11 (n. 16), exon 13 (n. 1), exon 9 (n. 1) KIT mutations, exon 14 PDGFR-α mutation (n. 2) and exon 18 PDGFR-α mutation (n. 4). KIT exon 11 mutations were more frequent between patients who developed a second tumor (P = 0.0003). Mutational analysis of KRAS showed a wild-type sequence in all cases. In metachronous cases, the median time interval between GIST and second tumor was 21.5 months.The high frequency of second tumors suggests that an unknown common molecular mechanism might play a role, but it is not likely that KRAS is involved in this common pathogenesis. The short interval between GIST diagnosis and the onset of second neoplasms asks for a careful follow-up, particularly in the first 3 years after diagnosis.

37 Background: NIVACOR trial is an open-label, multicentric Italian phase II trial of FOLFOXIRI/bevacizumab in association with an anti-PD1 antibody, nivolumab, in patients (pts) with metastatic colorectal cancer (mCRC). We report preliminary safety analysis by an Independent Monitoring Committee. Methods: Pts with mCRC RAS or BRAF mutated, regardless microsatellite status and eligible to receive a first line treatment will be enrolled. FOLFOXIRI/bevacizumab (BEV) in association with nivolumab (NIV) was administered every 2 weeks for 8 cycles (induction) followed by BEV plus NIV every 2 weeks (maintenance) until PD or unacceptable toxicities. BEV was administered intravenously at dose of 5 mg/kg and NIV intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint was the ORR. The safety is assessed after the inclusion of the 10th patient, receiving ≥1 dose. Results: As of September 20, 2020, 25/70 pts are enrolled. The first 10 pts were evaluated for preliminary safety analysis. Median age was 58 years (32-66), 60% of pts were male, median cycles of treatment was 5.5 (1-9). 100% were KRAS G12D mut and BRAF wild type, respectively, and 2% MSI-H/dMMR. 7/10 pts experienced at least one AE related to FOLFOXIRI/BEV and 2/10 related to NIV. The most frequent grade 1-2 AEs related to FOLFOXIRI/BEV were nausea and vomiting 4(57%), fatigue 5(71%), and diarrhea 5(71%); 3(43%) pts had grade 3-4 neutropenia, and 1(14%) febrile neutropenia. Only 2 pts developed grade 1-2 AEs related to NIV represented by rash (50%) and salivary gland infection (50%); no grade 3-4 was reported. One of pts with dose delay because of serious AES (proteinuria) BEV related, and one patient discontinued due to serious AEs (ileo-urethral fistula) not related to NIV. Conclusions: Combination of FOLFOXIRI/BEV and NIV was generally well tolerated and showed an acceptable toxicity profile. The final analysis will be scheduled at the end of enrollment. Clinical trial information: NCT04072198.

3509 Background: FOLFOXIRI plus bevacizumab (BEV) represents standard chemotherapy in first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC). The NIVACOR study evaluates the addition of nivolumab (NIV) to FOLFOXIRI/BEV as first-line therapy in mCRC RAS/BRAF mut pts regardless of MSS/MSI status. Methods: This is a single-arm, multicenter, open-label, phase II trial in first-line treatment of pts with mCRC RAS/BRAF mut. Pts received NIV at a flat dose of 240 mg q14 days, FOLFOXIRI (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, and 5-fluorouracil CI 3,200 mg/m2 for 48 hours) in combination with BEV at the dose of 5 mg/kg IV q14 days for eight cycles and then, the maintenance with BEV/NIV until PD or unacceptable toxicities. The primary endpoint was the ORR according to RECIST 1.1 Criteria. All images are reviewed by Independent Data Monitoring Committee. According to Fleming’s design with alpha and beta levels of 0.05 and 0.2 respectively, in a sample size of 73 pts (comprehensive of a 10% drop-out rate), at least 56 responses were necessary to not reject the alternative hypothesis of an ORR=0.80. Results: From October 2019 to March 2021, 73 pts were enrolled in 9 Italian centers. The median age was 60 (51-65) years and 50.7% were male; the main primary tumor side was right (50.7%). The molecular characterization was: 87.7% RAS mut, 16.2% BRAF mut, and 4.5% both RAS and BRAF mut; 10/62 were MSI (16.1%), 52/62 (83.9%) MSS, and 11 pts not assessed. Liver metastases were present in 56.2% pts. The median follow-up was 14.3 (IQR 11.5-16.5) months on December 31, 2021. The median (m) duration of treatment was 12 (8-17) cycles. The ORR was 76.7%, with 7(9.6%) CR and 49(67.1%) PR. SD were 15(20.6%) with a DCR of 97.3%; 2(2.7%) pts were not evaluable. The mDOR was 8.4 (95%CI, 7-NE) months. The mPFS was 10.1 months (95%CI, 9.4-NE) and 12-months PFS was 53.4%. At data cut-off, 65 (89.1%) pts are still alive. In subgroups analysis of MSS pts the ORR was 78.9% with a mDOR of 7.59 (95% CI 6.21 -11.43) months, DCR of 96.2%, and mPFS of 9.8 (95%CI 8.18-15.24) months. The surgery of the primary tumor, metastases, or both was performed in 6(8.2%), 9(9.6%), and 5(6.9%) of pts, respectively. The main grade (G) 3 -4 toxicities were: neutropenia (G3 21.9%, G4 15.1%), diarrhea (G3 17.8%, G4 1.4%), hypertension G3 (6.8%), fatigue G3 (6.8%), and febrile neutropenia G4 (4.1%). Conclusions: The primary endpoint ORR was met. These results show the preliminary efficacy and safety of NIV in combination with FOLOXIRI/BEV as first-line therapy in pts with mCRC RAS/BRAF mut. Also, promising activity was observed in MSS subgroup pts. These data support the conduction of phase III randomized-controlled study. Research Sponsor: Bayer, Bristol Myers-Squibb. Clinical trial information: NCT04072198.

The NIVACOR trial is a phase II study assessing the efficacy and safety of nivolumab in combination with FOLFOXIRI/bevacizumab in first-line setting in patients affected by metastatic colorectal cancer (mCRC) RAS/BRAF mutated. We report safety run-in results in the first 10 patients enrolled. Patients received triplet chemotherapy with FOLFOXIRI scheme plus bevacizumab, in association with nivolumab every 2 weeks for 8 cycles (induction phase) followed by bevacizumab plus nivolumab every 2 weeks (maintenance phase), until progression of disease or unacceptable toxicities. The first ten patients were evaluated: 7 experienced at least one adverse event (AE) related to FOLFOXIRI/bevacizumab and 2 related to nivolumab. The most frequent grade 1–2 AEs related to FOLFOXIRI/bevacizumab were diarrhea and fatigue (71%), nausea and vomiting (57%); 3 (43%) had grade 3–4 neutropenia, and 2 (20%) patients developed grade 1–2 AEs nivolumab related: skin rash and salivary gland infection. Two patients delayed the dose because of serious AEs, proteinuria and salivary gland infection; one patient discontinued experimental treatment due to the ileo-urethral fistula and concurrent Clostridium infection diarrhea. No treatment- related death occurred. The safety run-in analysis of NIVACOR trial reassured using co-administration of FOLFOXIRI/bevacizumab and nivolumab was well tolerated with an acceptable toxicity profile.Clinical Trial Registrationhttps://clinicaltrials.gov/, (NCT04072198).