Wu, Christina

Colorectal cancer (CRC) is the third most common malignancy worldwide. It is projected to increase by 3.2 million new cases and account for 1.6 million deaths by 2040. Mortality is largely due to limited treatment options for patients who present with advanced disease. Thus, the development of effective and tolerable therapies is crucial. Chemotherapy has been the backbone of systemic treatment of advanced CRC, but utility has been limited because of invariable resistance to therapy, narrow mechanisms of action, and unfavorable toxicity profile. Tumors that are mismatch repair-deficient have demonstrated remarkable response to immune checkpoint inhibitor therapy. However, most CRC tumors are mismatch repair-proficient and represent an unmet medical need. Although ERBB2 amplification occurs only in a few cases, it is associated with left-sided tumors and a higher incidence of brain metastasis. Numerous combinations of HER2 inhibitors have demonstrated efficacy, and antibody-drug conjugates against HER2 represent innovative strategies in this area. The KRAS protein has been classically considered undruggable. Fortunately, new agents targeting KRAS G12C mutation represent a paradigm shift in the management of affected patients and could lead the advancement in drug development for the more common KRAS mutations. Furthermore, aberrant DNA damage response is present in 15%-20% of CRCs, and emerging innovative combinations with poly (ADP-ribose) polymerase (PARP) inhibitors could improve the current therapeutic landscape. Multiple novel biomarker-driven approaches in the management of patients with advanced CRC tumors are reviewed in this article.

563 Background: RUB is an oral PARP1,2,3 inhibitor that demonstrated efficacy in patients (pts) with ovarian and prostate cancers harboring deleterious BRCA mutations. RUB exerts synergistic anti-tumor effect with IRI preclinically though the combination has overlapping toxicities. We previously published on the population PK of nal-IRI (Adiwijaya, Ma et al, Clin Pharm Ther 2017). We conducted a phase I study to evaluate a novel sequential dosing of RUB with nal-IRI/5FU in mGI cancer pts. Methods: Eligible pts had incurable mGI cancer previously received > 1 line of therapy (rx), ECOG PS 0-1, had RECIST measurable disease, adequate organ reserves and not received IRI for metastatic disease. Previous PARPi rx was excluded. The endpoints included dose limiting toxicity (DLT), maximum tolerated dose (MTD) and toxicity profile. The dose escalation utilized the 3+3 design. RUB was given oral bid on Day 4 to 13 and 18 to 27 with nal-IRI i.v. and 5FU i.v. 2400 mg/m2 over 46 hr on Day 1 and 15, every 28 day. Planned dose levels were RUB 400 mg/nal-IRI 50 mg/m2 (DL1), 400 mg/70 mg/m2 (DL2) and 600 mg/70 mg/m2 (DL3). Adverse events (AEs) were scored per CTCAE v4.03. Molecular profile was evaluated by CLIA-certified NGS testing. Results: Eighteen pts including 11 colorectal (CRC), 6 PANC, 1 gastroesophageal (GE) were enrolled and 12 were evaluable for DLTs. DL2 was not tolerable (DLT: G3 diarrhea, nausea and vomiting) and DL2A was added (RUB 600 mg/nal-IRI 50 mg/m2). DL2A enrolled 6 pts with no DLT and was determined as the MTD. Of DLT-evaluable pts, G3 and worse treatment-related AEs from all cycles were diarrhea (33%), fatigue (25%), leukopenia (25%), neutropenia (25%), anemia (8%) and nausea (8%). Four of 12 response evaluable pts had partial response: 2 CRC (1 had ATM mut), 1 PANC ( ATM mut), 1 GE ( BRCA2 mut) whilst 3 responders previously had platinum (PLA). Five pts had stable disease beyond 16 weeks (range 18.9 to 100.7 weeks), and all had prior PLA. Conclusions: The study successfully determined the MTD of RUB in combination with nal-IRI and 5FU. Encouraging efficacy was observed in PLA-treated mGI cancers including responses in those harboring ATM and BRCA alterations. The study is proceeding to evaluate the efficacy of the combination in metastatic pancreas cancer pts with and without BRCA1/2 or PALB2 alterations. Clinical trial information: NCT03337087.

92 Background: Since the publication of the MOSAIC trial, stage III CC has been treated with a six-month (mo) regimen of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Recently, the IDEA collaboration challenged this practice by demonstrating that the 3-year rate of disease-free survival (DFS) was non-inferior to 6mo of treatment (Rx) when given for low risk CC (83.1 vs. 83.3%) and resulted in significantly lower rates of grade 2 and higher neuropathy. In high risk (T4, N2) patients (pts) the DFS of 3mo of CAPOX was equivocal to 6mo (64.1 vs. 64.0%), while 3mo of FOLFOX was inferior to 6mo (61.5 vs. 64.7%). We hypothesized that trends in prescribing would favor shorter courses of Rx with a preference towards CAPOX given its efficacy across both high and low risk CC. Methods: We performed a retrospective analysis of stage III CC pts from 4 institutions. We evaluated prescribing patterns of 3mo or 6mo of Rx and CAPOX vs. FOLFOX over a period of 5 years from Jan 2016 to Jan 2021, a time period that traverses before and after the release of IDEA. Logistic and multinomial logistic regression models, with a linear time trend, were used to estimate the percentage of pts receiving CAPOX vs. FOLFOX and the combination of Rx and duration, respectively, while adjusting for baseline characteristics. The prescribing patterns in important subgroups were examined by incorporating the interaction term in the models. Results: A total of 366 pts met inclusion criteria. From 2016-2021, there was a significant increase per quarter in patients treated with CAPOX when compared to FOLFOX (OR 1.16 95% CI 1.11 – 1.21, p <.001). Prior to IDEA, 78.3% of pts received 6mo FOLFOX and 7.4% received 3mo CAPOX. Two years after IDEA, only 17.3% of pts were on 6mo FOLFOX compared to 67.5% of pts on 3mo CAPOX (Table). At present, high risk pts are more likely to receive 6mo FOLFOX (47.8%) than 3mo of FOLFOX (3.9%), 3mo CAPOX (25.8%), or 6mo CAPOX (22.4%). Low risk pts are more likely to receive 3mo of CAPOX (67.9%) than other Rx. Conclusions: Our findings suggest that since IDEA, physician practice has significantly changed in favor of CAPOX and shorter courses of Rx. The use of CAPOX has significantly increased overall, presumably due to its efficacy across all risk groups and relatively reduced toxicity.[Table: see text]

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.

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.

TPS143 Background: Patients with KRAS and NRAS ( RAS) wild-type mCRC benefit from the epidermal growth factor receptor (EGFR) monoclonal antibodies (Abs) panitumumab and cetuximab, but nearly all patients experience resistance. Blood-based profiling of cell free DNA (cfDNA) can identify genomic alterations that drive acquired EGFR Ab resistance. After discontinuation of anti-EGFR Abs, acquired genomic alterations decay over time to undetectable levels. Some studies have suggested clinical benefit from EGFR Ab rechallenge, but there is limited evidence that EGFR Ab rechallenge improves survival compared to standard of care (SOC) therapies. We hypothesize that cfDNA profiling will identify patients appropriate for panitumumab rechallenge, and that these molecularly selected patients will have improved survival compared to current SOC therapies. Methods: This is a randomized phase II, open label study designed to compare the overall survival (OS) of panitumumab rechallenge versus SOC (investigator choice TAS-102 or regorafenib). Secondary objectives include comparisons of progression free survival, objective response rate, clinical benefit rate, and quality of life as measured by the linear analogue self-assessment (LASA) questionnaire. Eligible patients have radiographically measurable KRAS, NRAS, and BRAF codon 600 wild-type mCRC based on tumor tissue testing, and must have experienced progression or intolerance to treatment with a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF Ab, and an anti-PD-1 Ab if the tumor has mismatch repair deficiency or is MSI-H. Progression after at least 4 months treatment with an anti-EGFR Ab is required. All patients must be enrolled in the COLOMATE cfDNA screening protocol (NCT03765736) and meet molecular eligibility based on Guardant360 cfDNA profiling (absence of amplification of ERBB2, KRAS, NRAS, and MET; absence of mutations of BRAF, EGFR, ERBB2, KRAS, NRAS, and MET [mutant allele frequency > 0.5%]). Greater than 90 days must have elapsed between the most recent treatment with an anti-EGFR Ab and cfDNA profiling. Dosing for all study drugs is according to clinical SOC. 120 patients will be randomized 1:1 to panitumumab rechallenge or SOC. With 83 OS events, this study will have 80% power to detect an improvement in median OS from 6.5 to 10 months (HR=0.65; 1-sided α= 0.15). This study began enrollment in 6/2020. Recruitment is ongoing at 16 sites in the Academic and Community Cancer Research United (ACCRU) network (ACCRU-GI-1623). Clinical trial information: NCT03992456.

Abstract Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC). Patients and Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples. Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses. Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

225 Background: ICIs induce durable responses in dMMR CRC patients. However, clinical and molecular biomarkers of response to ICIs have not been well-established. In this study, we investigated impact of specific MMR gene loss, BRAF V600E mutation and clinical characteristics of pts on clinical outcomes of ICIs. Methods: Pts were eligible if they had confirmed dMMR CRC by IHC or MSI-H by PCR and received ICIs between 01/01/2012 and 05/01/2019 at Winship Cancer Institute of Emory University, Mayo Clinic, Vanderbilt or Stanford University. Due to the functional dependency, the groups were categorized as protein loss of MLH1+PMS2 vs MSH2+MSH6. Log-rank test, Cox hazard model and Fisher’s exact test were used for survival outcomes, the best response and the distribution of variables among the subgroups. Results: A total of 66 pts with dMMR CRC were identified and BRAF status was available for 41 pts. ORRs in MLH1+PMS2 and MSH2+MSH6 groups were 72.9% and 56.5% respectively (P = 0.189). At 2 years, PFS rates were 55.6% and 78.2% for MLH1+PMS2 and MSH2+MSH6 groups respectively (P < 0.001). Pts with BRAF V600E mutations had significantly worse outcomes as compared to pts with wild-type BRAF (2-year PFS rate of 35.0% and 73.3% respectively; P < 0.001). Notably pts < 65 had better 2-year disease control rates when compared to > 65 (71.1% and 41.5% respectively; P < 0.001). We also observed worse 2-year PFS rates in pts with liver metastases (P = 0.014). CRC side and tumor volume did not impact 2-year PFS rates in our cohort. Conclusions: Our data suggest that pts with loss of function in MSH2+MSH6 may have better 2 year-PFS rates compared pts with MLH1+PMS2 even though ORR favored MLH1+PMS2 group suggesting that ORR may not reflect the durability of ICI response in dMMR CRC patients. Consistently, pts with BRAF V600E mutation which is associated with MLH1 promoter methylation had significantly worse 2-year PFS rates. Overall, our findings suggest that BRAFV600E mutation, the affected MMR proteins, pt age, and site of metastasis may impact durability of ICI response in dMMR CRC patients.