Ciombor, Kristen K.

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]

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]

139 Background: The fibroblast growth factor receptor (FGFR) pathway plays a key role in cellular proliferation, migration, survival and angiogenesis. Aberrant signaling through FGFR in colorectal cancer and other malignancies results from gene amplification or mutation, chromosomal translocation or ligand-dependent activation of the receptors. Pemigatinib is an oral inhibitor of FGFR1-3 with proven efficacy in FGFR-altered cholangiocarcinoma and myeloid/lymphoid neoplasms, among others. We hypothesized that pemigatinib would improve response rates compared to historical controls in patients with refractory FGF/FGFR-altered mCRC. Methods: ACCRU-GI-1701 was a multicenter, single-arm, Simon’s two-stage phase II clinical trial (NCT04096417) of the FGFR inhibitor pemigatinib in patients (pts) with FGF/FGFR-altered mCRC. Eligible pts had received prior fluoropyrimidine, oxaliplatin, irinotecan, and anti-VEGF/anti-EGFR/anti-PD-1 if eligible. Pts received pemigatinib 13.5 mg once daily on d1-21 of each cycle, with option to escalate to 18 mg in c2 if well tolerated. The primary endpoint was (unconfirmed) objective response (OR). A sample size of 21 evaluable pts would provide 82% power to detect a true OR rate of 20% or greater compared to a historical control of 5 % with a one-sided type I error rate of 0.1. A prespecified interim analysis for futility was planned after 12 evaluable patients. Results: A total of 14 patients were enrolled in the first stage of the study, and all were evaluable for the primary endpoint. No OR were observed (out of 12) crossing the futility boundary and resulting in permanent closure of the study. Among all enrolled patients, median age was 60.5 years, 71.4% were male, 92.9% Caucasian, 42.9% with no prior exposure to TAS-102 or regorafenib, and 64.3% with left-sided primary tumors. Treated patients all had tumors with FGFR1-4 mutations and/or FGF/FGFR amplifications by tissue- and/or blood-based molecular testing; no FGFR translocations were present. OR rate for this study was 0% (95% CI, 0-23.2%), with one patient achieving stable disease as best response. Median progression-free survival was 9.1 weeks (95% CI, 7.9-not evaluable [NE]), and median overall survival was 7.9 months (95% CI, 3.4-NE). Grade 3+ adverse events (AE) were seen in 42.9% of treated patients (including 1 grade 5 AE). Most commonly occurring AEs of any grade were anemia, hyperphosphatemia, alkaline phosphatase increased, aspartate aminotransferase increase, and fatigue. Conclusions: Pemigatinib demonstrated evidence of safety but not clinical activity in this population of patients with FGF/FGFR-altered mCRC. It is unknown whether pemigatinib would be active in mCRC patients with FGFR translocations/fusions as these were not represented in our trial. Translational studies are planned to investigate mechanisms of resistance to this therapy. Clinical trial information: NCT04096417 .

AbstractData on diet and survival among people with metastatic colorectal cancer are limited. We examined dietary fat in relation to all‐cause mortality and cancer progression or death among 1149 people in the Cancer and Leukemia Group B (Alliance)/Southwest Oncology Group (SWOG) 80405 trial who completed a food frequency questionnaire at initiation of treatment for advanced or metastatic colorectal cancer. We examined saturated, monounsaturated, total and specific types (n‐3, long‐chain n‐3 and n‐6) of polyunsaturated fat, animal and vegetable fats. We hypothesized higher vegetable fat intake would be associated with lower risk of all‐cause mortality and cancer progression. We used Cox proportional hazards regression to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI). Over median follow‐up of 6.1 years (interquartile range [IQR]: 5.3, 7.2 y), we observed 974 deaths and 1077 events of progression or death. Participants had a median age of 59 y; 41% were female and 86% identified as White. Moderate or higher vegetable fat was associated with lower risk of mortality and cancer progression or death (HRs comparing second, third and fourth to first quartile for all‐cause mortality: 0.74 [0.62, 0.90]; 0.75 [0.61, 0.91]; 0.79 [0.63, 1.00];Ptrend: .12; for cancer progression or death: 0.74 [0.62, 0.89]; 0.78 [0.64, 0.95]; 0.71 [0.57, 0.88];Ptrend: .01). No other fat type was associated with all‐cause mortality and cancer progression or death. Moderate or higher vegetable fat intake may be associated with lower risk of cancer progression or death among people with metastatic colorectal cancer.

BRAF-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. BRAF alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I BRAF V600E mutation occurring most frequently in colorectal cancer. Functional categorization of BRAF mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with BRAF V600E -mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in BRAF V600E -mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in BRAF-mutated advanced colorectal cancer.

116 Background: Constitutively activating KRAS or NRAS muts occur in ̃50% of CRC, increasing RAF-MEK-ERK signaling and causing overexpression of cyclin D1, which binds to cyclin dependent kinase 4/6 (CDK4/6) to drive cell cycle progression. Combination MEK and CDK4/6 inhibitors caused tumor regression in patient-derived xenografts of KRAS mut CRC. We hypothesized that binimetinib and palbociclib (B+P) would improve progression-free survival (PFS) compared to TAS-102 in refractory KRAS/NRAS mut mCRC. Methods: ACCRU-GI-1618 was a multicenter, randomized phase II clinical trial (NCT03981614). Key inclusion criteria were KRAS/NRAS mut mCRC, with prior fluoropyrimidine/ oxaliplatin/ irinotecan/ anti-VEGF therapy. There was a 6-patient safety run-in with binimetinib 30 mg po BID D1-28 and palbociclib 100 mg po daily D1-21. After, patients were randomized 1:1 to B+P vs TAS-102 (stratified by KRAS mut type and prior regorafenib use), with optional crossover at progression. The primary endpoint was PFS; 73 PFS events (from a sample size of 112) provided 90% power to detect improvement of PFS (hazard ratio = 0.5, i.e. median PFS of 2 vs. 4 months) with 1-sided α = 0.05. A prespecified interim analysis for futility was planned after 37 PFS events were observed, with completion of accrual if 1-sided stratified log-rank p-value < 0.551. Hazard ratios (HR) and 95% confidence intervals (CI) are estimated by stratified Cox proportional hazards models. Results: After the safety run-in, 93 patients at 6 sites were randomized; 82 (41 B+P, 41 TAS-102) comprise the primary analysis population (eligible, consented, and started treatment). In this population, median age was 52 years, 50% female, 68% left-sided, 79% with KRAS codon 12/13 mut, 12% with prior regorafenib. Enrollment was halted at interim analysis as the futility boundary was crossed (1-sided p = 0.67). At final analysis, 68 subjects had a PFS event (34 in each arm). Median PFS was 2.1 mo (95% CI 2.0-3.0) with B+P vs 2.1 mo (2.0-2.4) with TAS-102; HR 0.86 (0.52-1.44). 4-mo PFS rate was 22.2% (11.9-41.6) with B+P vs 10.6% (3.8-30.0) with TAS-102. With 37 OS events (14 in B+P arm), median OS was 7.7 mo (5.1-NE) with B+P vs 6.6 mo (4.8-8.9) with TAS-102; HR 0.77 (95% CI 0.39-1.51). TAS-102 had greater grade 3-4 hematologic AEs (46% vs 22%), and B+P had more grade 3-4 non-hematologic AEs (47% vs 32%). Grade 3-4 AEs more common with B+P were fatigue (8% vs 0%), oral mucositis (6% vs 0%), and nausea (4% vs 2%). Though 63% of patients on B+P had acneiform rash, only 2% was grade 3-4. Grade 1-2 diarrhea occurred in 35% of B+P and 24% of TAS-102 patients. No new safety signal was observed. Conclusions: B+P did not significantly improve median PFS or OS compared to TAS-102 in KRAS/NRAS mut mCRC. Subgroup analyses and translational studies are ongoing to determine which subgroups may be more likely to attain 4-mo PFS or identify mechanisms of resistance. Clinical trial information: NCT03981614.

This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colon Cancer focuses on systemic therapy options for the treatment of metastatic colorectal cancer (mCRC), because important updates have recently been made to this section. These updates include recommendations for first-line use of checkpoint inhibitors for mCRC, that is deficient mismatch repair/microsatellite instability-high, recommendations related to the use of biosimilars, and expanded recommendations for biomarker testing. The systemic therapy recommendations now include targeted therapy options for patients with mCRC that is HER2-amplified, or BRAF V600E mutation–positive. Treatment and management of nonmetastatic or resectable/ablatable metastatic disease are discussed in the complete version of the NCCN Guidelines for Colon Cancer available at NCCN.org . Additional topics covered in the complete version include risk assessment, staging, pathology, posttreatment surveillance, and survivorship.

Abstract Background Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC. Materials and Methods Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test. Results A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p &lt; .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p &lt; .001). Patients aged &gt;65 had significantly worse PFS rates as compared with patients aged ≤65 (p &lt; .001). Conclusion BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age &gt;65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings. Implications for Practice The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.

Abstract Background Hand-foot skin reaction (HFSR) is the most common regorafenib-induced adverse event and is in need of effective prevention and palliation. Materials and Methods The Regorafenib Dose Optimization Study (ReDOS), a four-arm, previously published trial with a 1:1:1:1 randomization scheme, was analyzed in a manner in keeping with the original protocol to assess whether clobetasol 0.05% cream (a corticosteroid) applied to the palms and soles twice per day for 8 weeks was more effective when prescribed preemptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the first two cycles of regorafenib. Results Sixty-one patients received preemptive clobetasol, and 55 received reactive clobetasol. Groups were balanced on demographics. Over the first two cycles, no evidence of HFSR occurred in 30% with preemptive clobetasol versus 13% with reactive clobetasol (p = .03). During the first cycle, 54% and 45% of patients had no HFSR with preemptive and reactive clobetasol, respectively (p = .35). During the second cycle, 33% and 15% had no HFSR with preemptive and reactive clobetasol, respectively (p = .02). During the second cycle, rates of grade 1, 2, and 3 HFSR were 30%, 8%, and 3%, respectively, with preemptive clobetasol and 43%, 18%, and 7%, respectively, with reactive clobetasol (p = .12). Patient-reported outcomes showed HFSR compromised nearly all activities of daily living with worse quality of life in patients who received reactive versus preemptive clobetasol. No clobetasol-induced adverse events were reported. Conclusion Preemptive clobetasol might lessen regorafenib-induced hand-foot reactions compared with reactive therapy. Further confirmatory studies are needed in a larger patient cohort. Implications for Practice Regorafenib causes hand-foot skin reactions. Preemptive clobetasol, a high-potency topical corticosteroid, appears to lessen the severity of this adverse event. Although further study is needed, the favorable adverse event profile of this intervention might prompt clinicians to discuss this option with their patients.