Stecher, Michael

Background: HER2 amplification (HER2+) occurs in approximately 3% of patients with metastatic colorectal cancer (mCRC). Despite the recent addition of HER2-directed therapies to treatment recommendations in the NCCN Guidelines, until more recently there were no FDA-approved treatments. This study examined real-world treatment patterns in patients with HER2+ mCRC in the United States before and after the emerging awareness of HER2-directed therapies in 2018. Methods: This was a retrospective observational study of patients with HER2+ mCRC from the GuardantINFORM database, which contains claims data for patients with Guardant360 genomic testing results. Patients were aged ≥18 years, were diagnosed with mCRC between January 2014 and September 2020, and had confirmed ERBB2 amplification via the blood-based Guardant360 test. Treatment patterns and real-world time to next treatment (rwTTNT) were evaluated. Results: This study included 142 patients with a median age of 59 years; 31 (21.8%) patients with ERBB2 amplifications also had ERBB2 mutations. Treatment patterns were heterogeneous and evolved over time; before 2018, the most common regimen prescribed after detection of ERBB2 amplification was anti-VEGF therapy with or without chemotherapy (31.6%; n=25), and after 2018, HER2-directed therapies were the most commonly prescribed (36.5%; n=23). Median rwTTNT among the overall cohort was 8.4 months (95% CI, 6.5–10.0); rwTTNT was numerically longer in patients who received HER2-directed therapy compared with those who received non–HER2-directed therapies (11.0 months [95% CI, 6.3–12.3] vs 7.2 months [95% CI, 5.8–9.6]). Conclusions: This real-world study of the largest clinically annotated dataset of patients with HER2+ mCRC showed that many patients do not receive HER2-directed therapy despite its inclusion in NCCN Guidelines, with heterogeneous treatment patterns suggesting that standard of care remains undefined and targeted therapy remains underutilized. Greater awareness of the unmet need in this patient population, together with new effective therapies, will facilitate strategies for improved, targeted treatment approaches.

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]

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]

TPS153 Background: The clinical benefit of approved therapies in patients (pts) with metastatic colorectal cancer (mCRC) who progress on first- and second-line chemotherapy (FOLFOX and FOLFIRI) is limited. In pts with chemotherapy-refractory RAS wild type mCRC, antibodies targeting EGFR offer a monotherapy response rate of approximately 20% and a progression-free survival (PFS) of 4 months (Price 2014). HER2 is a validated target in gastric and breast cancers, with HER2 amplification occurring in ~3–5% of pts with mCRC. Tucatinib (TUC), recently approved for HER2+ metastatic breast cancer, is a tyrosine kinase inhibitor (TKI) highly selective for HER2 with minimal inhibition of EGFR. In pt-derived xenograft models of HER2+ mCRC, the combination of TUC + trastuzumab (TRAS) showed significantly greater antitumor activity compared with either agent alone (Kulukian 2020). The MOUNTAINEER trial was initiated to evaluate the efficacy and safety of TUC in combination with TRAS in pts with HER2+ RAS wild-type mCRC. Interim analysis of the initial 26 pts enrolled in MOUNTAINEER demonstrated an objective response rate (ORR) of 52.2% (12 partial responses [PRs] in 23 evaluable pts), median duration of response of 10.4 months, with a median PFS of 8.1 months and a median overall survival (OS) of 18.7 months (Strickler 2019). Based on these results, the trial was expanded to enable better estimation of ORR and safety. Methods: MOUNTAINEER (NCT03043313) is an open-label, pivotal phase 2 trial that initially consisted of a single cohort of up to 45 pts (Cohort A) treated with TUC (300 mg BID) and TRAS (8 mg/kg IV followed by 6 mg/kg IV every 3 weeks). The trial was expanded to include an additional 70 pts randomized 4:3 into 2 cohorts: Cohort B (N = 40) who will receive TUC + TRAS, and Cohort C (N = 30) who will receive TUC monotherapy. Pts in Cohort C will be treated with TUC (300 mg orally twice daily) with the option to crossover to TUC + TRAS if an objective response is not achieved by 12 weeks, or if progressive disease develops at any time. Eligible pts have RAS wild-type and HER2+ mCRC, and must have previously received regimens that include fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF therapy, and an anti-PD-1 if the tumor has dMMR proteins or is MSI-H. Pts who have received prior HER2-directed therapies are not eligible. Additionally, pts must have measurable disease and ECOG PS of 0 to 2. The primary endpoint of this trial is confirmed ORR (per RECIST v1.1) in Cohorts A + B as assessed by blinded independent central review. Secondary endpoints include duration of response, PFS, OS, and safety and tolerability. Enrollment is ongoing in the US and planned for the EU. Clinical trial information: NCT03043313.