Siena, Salvatore

3116 Background: Pralsetinib is an oral tyrosine kinase inhibitor that selectively and potently targets oncogenic RET fusion and mutation proteins. RET fusions or mutations are present in various tumor types. We report the final results from the phase 2 portion of ARROW, a phase 1/2, open-label, multi-cohort, dose-expansion study evaluating the efficacy and safety of pralsetinib (NCT03037385) in patients with RET fusion-positive solid tumors other than non-small-cell lung cancer (NSCLC) and thyroid cancer. Methods: Eligible pts were ≥18 years of age with a pathologically documented, definitively diagnosed advanced solid tumor with an oncogenic RET fusion or mutation, had previously received standard of care appropriate for their tumor type, and were not eligible for any other study groups. Overall response rate (ORR) and safety were primary endpoints of the study. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). The final database lock was May 20, 2024. Results: Twenty-nine patients were enrolled with 11 different solid tumor histologies. Twenty-six (90%) received prior systemic therapy. Median age was 58 years (range 25-75); 59% were female. Twenty-eight patients were included in the efficacy analysis. ORR (by RECIST) was 46.4% (13/28); 10.7% (3/28) achieved complete response (pancreatic cancer, n=2; cancer of unknown primary, n=1) and 35.7% (10/28) achieved partial response. Median PFS was 7 months (95% CI: 3.9, 12.8). Median DOR was 11.1 months (95% CI: 5.5, 25.1). Median OS was 10.3 months (95% CI: 6.8, 25.2). Twenty-five (86%) patients experienced treatment-related adverse events (TRAEs); 19/29 (66%) reported TRAEs ≥grade 3. The most common TRAEs included increased aspartate aminotransferase (11/29; 38%), increased alanine aminotransferase (10/29; 35%), and anemia (9/29; 31%). Four (13.8%) patients experienced hypertension, and 1 (3.4%) patient had ≥grade 3 hypertension. No new safety risks were identified; AEs remained manageable with supportive care and/or dose modifications. Conclusions: In the phase 2 portion of this trial, responses were observed in many tumor types (Table). Pralsetinib demonstrated robust and durable anti-tumor activity with an ORR of 46.4%. These data validate RET fusions as a tissue-agnostic target with sensitivity to RET inhibition and activity beyond NSCLC and thyroid cancer, further supporting the promising potential of pralsetinib to address the unmet medical need in these patients. Clinical trial information: NCT03037385 . Overall response rate by tumor type. Cancer Type (patient n) ORRn (%) Pancreatic (5) 5 (100) Cancer of unknown primary (1) 1 (100) Neuroendocrine (3) 2 (67) Sarcoma (3) 2 (67) Head and neck (2) 1 (50) Small cell lung (2) 1 (50) Hepatobiliary (4) 1 (25) Colorectal (5), gastric (1), ovarian (1), thymic (1) 0

3509 Background: HER2 overexpression/amplification (HER2+) occurs in ~3%-5% of pts with metastatic colorectal cancer (mCRC) and up to ~10% of pts with RAS/BRAF wild-type (WT) mCRC. The primary results of the MOUNTAINEER study (NCT03043313) demonstrated that the combination of tucatinib (TUC), a highly selective HER2-directed TKI, and trastuzumab (Tras) was well tolerated with clinically meaningful activity in pts with chemo-refractory HER2+ mCRC. Confirmed ORR was 38.1%, median DOR was 12.4 months, and median OS was 24.1 months. Here, we present results from the final analysis of MOUNTAINEER. Methods: MOUNTAINEER is a multi-center, open-label, randomized, phase 2 trial. Eligible pts had HER2+ and RAS WT mCRC with progression on or intolerance to last systemic therapy. Previous HER2-directed therapies were not permitted. The trial consisted of Cohort A, comprising pts treated with TUC (300 mg PO BID) + Tras (8 mg/kg IV then 6 mg/kg IV Q3W), as well as pts randomized 4:3 to receive TUC+Tras (Cohort B) or TUC monotherapy (Cohort C). Pts randomized to Cohort C were allowed to crossover and receive TUC+Tras on radiographic progression or if they did not achieve a complete or partial response by Week 12. Study endpoints evaluated at final analysis include DOR per BICR, PFS per BICR, OS, and safety. Results: The median duration of follow-up was 32.4 months (IQR, 25.1-46.7), with an additional 16.1 months of follow-up since the primary analysis (data cutoff, 02-Nov-2023). A total of 116 pts received at least 1 dose of study treatment (Cohorts A+B, N = 86; Cohort C, N = 30). In Cohorts A+B, median DOR per BICR was 15.2 months (95% CI, 8.9-20.5), median PFS per BICR was 8.1 months (95% CI, 4.2-10.2), and median OS was 23.9 months (95% CI, 18.7-28.3). In Cohort C post-crossover (N = 28), median DOR was not reached (95% CI, 2.8 months-NE). Median OS in Cohort C was 21.1 months (95% CI, 17.0-NE). The most common TEAEs in Cohorts A+B were diarrhea (66.3%), fatigue (44.2%), and nausea (34.9%). The majority of TEAEs were low grade, and rates were stable with longer follow-up. The most common grade ≥3 TEAE was hypertension (7.0%). TEAEs leading to TUC discontinuation in Cohorts A+B occurred in 5.8% of pts, which was unchanged from the primary analysis. In Cohort C, the most common TEAEs post-crossover were diarrhea (39.3%), back pain (21.4%), and pyrexia (21.4%); the most common grade ≥3 TEAE was AST increase (10.7%). No deaths resulted from TEAEs in any cohort and no new safety signals were identified. Conclusions: TUC+Tras continued to be well tolerated with sustained efficacy in pts with chemo-refractory RAS WT HER2+ mCRC, demonstrating clinically meaningful activity of the combination on longer follow-up. TUC+Tras is an important chemotherapy-free treatment option in HER2+ mCRC. TUC+Tras is being further evaluated in the first-line setting in combination with chemotherapy in the ongoing phase 3 MOUNTAINEER-03 trial (NCT05253651) for pts with HER2+ mCRC. Clinical trial information: NCT03043313 .

3528 Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved by the FDA in combination w/trastuzumab (Tras) for treatment (tx) of pts w/ RAS wild-type HER2+ unresectable or metastatic colorectal cancer (mCRC) that has progressed following tx w/ fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. There are currently no established best practices for HER2 testing/interpretation in mCRC. Here we present results of central HER2 testing across multiple platforms and response to tx for MOUNTAINEER pts treated w/ TUC + Tras based on central HER2 status. Methods: MOUNTAINEER (NCT03043313) enrolled pts w/ local HER2+ mCRC using ≥1 method: IHC, ISH, and/or NGS testing; retrospective central assessment of HER2 status was performed on multiple platforms. Pts in cohorts A+B were treated w/ TUC + Tras; pts in cohort C were treated w/ TUC monotherapy. Confirmed objective response rates (cORRs) using RECIST v1.1 per BICR, DOR, and PFS were calculated for pts treated w/ TUC + Tras based on each central testing method. Results: 114 pts were enrolled in cohorts A (n = 45), B (n = 39), and C (n = 30) w/ HER2+ tumors per ≥1 local testing method. Of samples submitted for central testing for Cohorts A and B, 70 per IHC/FISH, 50 per tissue NGS, and 71 per blood NGS had evaluable results. In all cohorts, there was 81.0% (95% CI, 68.6-90.1) agreement between blood and tissue NGS, 92.6% (95% CI, 83.7-97.6) between IHC/FISH and tissue NGS, and 79.5% (95% CI, 69.2-87.6) between IHC/FISH and blood NGS. In cohorts A and B, pts w/ HER2+ tumors by central IHC/ISH had a mDOR of 16.4 months (95% CI: 10.6-25.5) and mPFS of 10.1 months (95% CI: 4.2-15.2). cORR was 41.1% to 47.7% for the 3 assays. Detailed HER2 results are presented in the Table. Conclusions: Percent agreement of HER2 status was highest w/ tissue-based platforms. Detection of HER2 amplification by ctNDA NGS is useful; however, pts w/o HER2 amplification should be confirmed w/ a tissue-based assay. HER2 status by all 3 platforms predicted tx response to TUC + Tras. cORR in IHC2+/ISH+ was numerically lower but remained clinically relevant. These data support use of the above methods to identify HER2+ mCRC patients that may benefit from TUC + Tras. Clinical trial information: NCT03043313 . [Table: see text]

TPS3631 Background: The current standard of care (SOC) for the treatment of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, with or without a VEGF or EGFR inhibitor. Human epidermal growth factor receptor-2 (HER2) is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%–5% of patients with mCRC; the rate of HER2 amplification can increase to approximately 10% in patients with RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC)—a highly selective, HER2-directed tyrosine kinase inhibitor—is approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, approved in the US for HER2+ metastatic colorectal cancer, and under investigation in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in patients with treatment-refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity, with a confirmed objective response rate (ORR) per blinded independent central review (BICR) of 38.1% (95% confidence interval [CI] 27.7, 49.3) and median duration of response per BICR of 12.4 months (95% CI 8.5, 20.5). Results also demonstrated TUC + Tras was well tolerated, with a low discontinuation rate (5.8%) and no deaths due to adverse events. MOUNTAINEER-03 will further investigate TUC in combination with modified FOLFOX (mFOLFOX) and Tras in patients with RAS wild-type HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open-label, randomized, phase III study for first-line treatment of HER2+ and RAS wild-type mCRC. Approximately 400 patients will be randomized 1:1 to the TUC experimental arm (TUC [300 mg orally twice daily] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combination with either bevacizumab or cetuximab). HER2 status is determined centrally with tissue-based HER2 immunohistochemistry and in situ hybridization assays. Eligible patients must not have received prior treatment in the metastatic setting but may have received adjuvant treatment if completed > 6 months prior to enrollment. Patients must be ≥18 years old with an Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS wild-type mCRC. Patients with treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). The primary endpoint is progression-free survival per RECIST v1.1 assessed by BICR. Key secondary endpoints are overall survival and confirmed ORR per RECIST v1.1 assessed by BICR. Enrollment is ongoing in North America, Asia, Australia, and Europe. Clinical trial information: NCT05253651 .

TPS261 Background: Current standard of care (SOC) for treatment (tx) of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, w/ or w/o a VEGF- or EGFR-inhibitor. HER2 is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%-5% of patients (pts) w/ mCRC; the rate of HER2 amplification can increase to ~10% in pts w/ RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC), a highly selective, HER2-directed tyrosine kinase inhibitor, is approved in multiple regions for HER2+ metastatic breast cancer and is being investigated in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in pts w/ tx refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity (confirmed ORR of 38.1% and median DOR of 12.4 months) and demonstrated TUC + Tras was well tolerated with a low discontinuation rate (5.8%) and no deaths due to AEs. MOUNTAINEER-03 will further investigate TUC in combo w/ mFOLFOX and Tras in pts w/ RAS wild-type, HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open label, randomized, phase 3 study for 1L tx of HER2+ and RAS wild-type mCRC. Approximately 400 pts will be randomized 1:1 to the TUC experimental arm (TUC [300 mg PO BID] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combo w/ either bevacizumab or cetuximab). HER2 status is determined centrally w/ tissue based HER2 immunohistochemistry and in situ hybridization assays. Eligible pts must not have received prior tx in the metastatic setting but may have received adjuvant tx if completed > 6 months prior to enrollment. Pts must be ≥18 years of age w/ an ECOG performance status of ≤1 and RAS wild-type mCRC. Pts w/ treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). Primary endpoint is progression-free survival per RECIST v1.1, assessed by blinded independent central review (BICR). Key secondary endpoints are overall survival and confirmed objective response rate per RECIST v1.1 assessed by BICR. Enrollment is ongoing in the US, w/ global sites planned. Clinical trial information: NCT05253651 .

198 Background: HER2 overexpression/amplification (HER2+) occurs in 3%-5% of patients (pts) w/ metastatic colorectal cancer (mCRC). Rates of HER2+ can increase to ~10% in pts w/ RAS/BRAF wild-type mCRC tumors. The MOUNTAINEER trial (NCT03043313) evaluated the efficacy and safety of the investigational combination of tucatinib with trastuzumab in pts with HER2+ and RAS wild-type mCRC. Established regional guidelines for mCRC recommend HER2 testing and HER2-directed treatment options; however, there is currently no established best practice for HER2 testing and interpretation in mCRC. Here, we present data from a concordance analysis comparing breast and gastric HER2 testing algorithms in the mCRC setting. Methods: The MOUNTAINEER trial enrolled pts w/ HER2+ mCRC identified using ≥1 method: tissue-based local immunohistochemistry (IHC), in situ hybridization (ISH), and/or next-generation sequencing (NGS) testing. Archival or fresh tumor tissue was submitted to a sponsor-designated central laboratory for confirmatory HER2 testing w/ IHC/FISH per the package insert of the FDA approved assay and scored by both the breast and gastric algorithms for HER2 IHC. A positive result per the breast scoring criteria for IHC requires circumferential membrane staining for HER2, while the gastric criteria allows for circumferential, basolateral, or lateral staining patterns. Results: A total of 114 pts were enrolled with HER2+ tumors per ≥1 local testing methods; 69 pts were HER2+ by NGS, 46 by IHC 3+, and 36 by ISH. Of 105 pts who had tissue available for central HER2 testing w/IHC/FISH, 98 had valid HER2 results; 82/98 (83.7%) of pts had tumors centrally confirmed as HER2+ using both the breast and gastric algorithms. Tissue samples from pts in the MOUNTAINEER trial had 100% concordance between breast and gastric algorithms in HER2 status and 99% concordance in HER2 IHC score. Conclusions: Central pathology testing using both the breast and gastric criteria showed high concordance between these two commonly used algorithms. A high central confirmation rate of local HER2+ results was also observed. These data support the use of either the breast or gastric algorithms to identify HER2+ mCRC tumors until an FDA-approved HER2 assay is available for mCRC. Clinical trial information: NCT03043313 . [Table: see text]

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

TPS371 Background: Tucatinib (TUC), a highly selective HER2-directed tyrosine kinase inhibitor (TKI) approved in multiple regions for HER2+ metastatic breast cancer, is being developed as a novel therapy for patients (pts) with GI tumors including gastric or gastroesophageal junction adenocarcinoma (GEC). While trastuzumab (Tras) with chemotherapy is standard in the 1st-line setting for metastatic HER2+ GEC, no anti-HER2 therapy has demonstrated an OS benefit over chemotherapy as 2nd-line therapy, possibly due to loss of HER2 expression following Tras-based therapy. In GEC xenograft models, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone.(Kulukian 2020) Interim results from the MOUNTAINEER study have shown promising activity for TUC and Tras for HER2+ mCRC.(Strickler 2019) The MOUNTAINEER-02 study is evaluating the efficacy and safety of TUC with Tras, ramucirumab (Ram), and paclitaxel (Pac) in pts with HER2+ GEC in the 2nd-line setting. Methods: MOUNTAINEER-02 (NCT04499924) is a phase 2/3 study evaluating TUC + Tras with Ram and Pac. Pts receive TUC 300 mg or placebo PO BID, Tras (6 then 4 mg/kg) or placebo (IV on Days 1 and 15 of each 28-day cycle), Pac (IV on Days 1, 8, 15), and Ram (IV on Days 1 and 15). Eligible pts have locally-advanced unresectable or metastatic HER2+ GEC and have received a HER2-directed antibody and 1 prior line of therapy for advanced disease. Pts must be ≥18 years of age, with an ECOG ≤1, and have had no prior exposure to Ram, anti-HER2 or anti-EGFR TKI, HER2-directed antibody-drug conjugates, or taxanes ≤12 months before enrollment. Due to the potential impact of TUC on Pac metabolism, the study will include an initial Pac dose optimization stage. The open-label phase 2 part will determine the recommended dose of Pac (60 or 80 mg/m²) combined with TUC, Tras, and Ram in 6-18 pts, and evaluate safety and activity of the regimen in Cohorts 2A and 2B (30 pts each). The randomized, double-blind, phase 3 part will compare the efficacy and safety of TUC and Tras (Arm 3A; ̃235 pts) vs. placebo (Arm 3B; ̃235 pts), both in combination with Ram and Pac, and also evaluate activity of TUC with Ram and Pac (Arm 3C; ̃30 pts). The dual primary phase 3 endpoints are OS and PFS per investigator, with confirmed ORR as a key secondary endpoint. HER2 status is determined at baseline using a blood-based NGS assay, and IHC/ISH of fresh or archival tumor biopsies, if available. Pts must be HER2+ by blood-based NGS in Cohort 2A and phase 3; in Cohort 2B, pts must be HER2+ in a biopsy taken post-progression during/after 1st-line therapy, but HER2-negative by blood-based NGS. Disease assessments per RECISTv1.1 will occur q6 weeks for 36 weeks, then q9 weeks. The pharmacokinetics of TUC, Pac, and their metabolites will be evaluated in a subset of pts, including a cohort with gastrectomies. Enrollment in phase 2 is ongoing. Clinical trial information: NCT04499924.