MRD Enrichment Is Credible, Clearance Alone Will Not Carry Approval

Natera Partners with Incyte for Phase II Colorectal Cancer Study

Natera, Inc. has announced a clinical collaboration agreement with Incyte for a new Phase II study in colorectal cancer (CRC). This interventional trial will evaluate Incyte’s investigational bispecific immunotherapy, INCA33890, in patients with stage 2/3 CRC who have completed surgery and adjuvant chemotherapy. Natera's Signatera will be integrated as both a primary and secondary endpoint, guiding treatment decisions by identifying high-risk, MRD-positive patients for enrollment. The collaboration leverages Natera's expertise in MRD-guided clinical trial strategy and aims to improve patient outcomes by enabling early identification and targeted intervention before radiographic progression.

• Natera and Incyte are collaborating on an interventional Phase II study to evaluate INCA33890, Incyte's investigational bispecific immunotherapy, in patients with stage 2/3 colorectal cancer. This partnership aims to combine Natera's precision medicine capabilities with Incyte's therapeutic development to address the critical unmet need of patients with minimal residual disease after standard treatment.
• Natera's Signatera, a cell-free DNA test, plays a central role in the study design, serving as both a primary and secondary endpoint. It will be used for longitudinal testing for up to 12 months following adjuvant chemotherapy to identify MRD-positive patients who are eligible for enrollment, thereby guiding treatment strategies and potentially altering disease progression before it becomes radiographically evident.
• The study specifically targets colorectal cancer patients who remain MRD-positive after surgery and adjuvant chemotherapy, a population known to have a significantly elevated risk of recurrence. By identifying these high-risk individuals early, the trial seeks to evaluate whether INCA33890, guided by Signatera, can improve outcomes through a novel treatment approach before radiographic progression occurs.

Addressing Unmet Needs in MRD-Positive Colorectal Cancer

Recent literature converges on molecularly defined refractory subsets and age-defined populations with disparate outcomes. Microsatellite stable disease with liver involvement, KRAS G12C and BRAF-mutant disease, molecular residual disease after resection, and young-onset and elderly groups emerge as key areas of unmet need.

• MSS/pMMR metastatic CRC with liver or peritoneal metastases resistant to immunotherapy: In 96 patients treated with regorafenib, nivolumab (REGONIVO) or regorafenib, ipilimumab, nivolumab (RIN), liver or peritoneal metastases led to poor outcomes, with 0 % ORR, and median PFS of 2.0 and 1.5 months respectively, versus lung-only metastases with an ORR of 56.3 % and a PFS of 14 months. Across 16 prospective trials comprising 1,713 patients, response rates to immunotherapy in patients with colorectal liver metastases (CRLM) varied from 0% to 23%, with reduced or null responses compared to patients without liver involvement. A retrospective study in MSS/pMMR CRLM refractory to ≥ 2 lines compared HAIC (oxaliplatin, 5-fluorouracil, leucovorin) combined with regorafenib and sintilimab versus regorafenib monotherapy, with median PFS 6.5 vs. 3.4 months and OS 14.1 vs. 8.1 months.

• KRAS G12C-mutated metastatic CRC: KRAS G12C mutations define a small subset accounting for approximately 3% to 4% of cases and remaining associated with substantial unmet need after standard chemotherapy, with modest monotherapy activity due to upstream EGFR dependency with adaptive MAPK pathway reactivation. Sotorasib plus panitumumab improved progression-free survival in the randomized phase 3 CodeBreaK 300 trial, whereas adagrasib plus cetuximab demonstrated activity in KRYSTAL-1 but did not improve progression-free or overall survival versus chemotherapy in second-line phase 3 KRYSTAL-10 despite higher objective response rate.

• BRAF-mutant MSS/pMMR disease as immunologically cold tumors: MSS/pMMR colorectal cancer is an immunologically "cold" tumor that is insensitive to immunotherapy, with low levels of tumor infiltrating lymphocytes, low tumor mutational burden, and high rate of WNT/β-catenin pathway mutations. BRAF mutant patients with microsatellite stability/DNA proficient mismatch repair (MSS/pMMR) subtype have poor response to chemotherapy, driving evaluation of targeted therapy combined with immune checkpoint blockade and novel immune-based combinations.

• Resected stage II-III CRC with molecular residual disease detected by ctDNA: After curative-intent resection, recurrence rates of 15-20% in stage II and 30-40% in stage III highlight limitations of pathological staging, with ctDNA as readout of molecular residual disease. The DYNAMIC trial showed ctDNA-guided management reduced adjuvant chemotherapy use from 27.9% to 15.3% with five-year recurrence-free survival 88% vs. 87%, GALAXY confirmed ctDNA prognostic value with disease-free survival hazard ratio of 11.99, DYNAMIC-III showed escalating intensity in ctDNA-positive stage III did not improve recurrence-free survival (HR 1.11), and ALTAIR showed trifluridine/tipiracil failed to significantly improve disease-free survival at molecular recurrence (HR 0.79).

• Young-onset CRC under 50 years and elderly frail patients: Young-onset rectal cancer (< 50 years) is increasing and often diagnosed at advanced stages, with rectum (45%) and left-sided (47.1%) cancers most common and higher stage (III and IV) on diagnosis. Elderly patients aged > 75 had worse disease-free survival (hazard ratio 3.04) after curative-intent surgery, and octogenarians with modified Frailty Index m-FI scores greater than or equal to 3 had 2-year survival rate of 72% versus 85% for scores less than or equal to 2, with higher postoperative complications and discharge to rehabilitation.

Evolving Colorectal Cancer Treatment with MRD Guidance

Neoadjuvant strategies have reshaped management of locally advanced colon and rectal cancer. Neoadjuvant chemotherapy has demonstrated tumor downstaging, improved resectability, and reduced recurrence rates in trials including FOxTROT (Fluoropyrimidine oxaliplatin and targeted receptor pre-operative therapy), OPTICAL (A phase III study to evaluate the 3-year disease-free survival in patients with locally advanced colon cancer receiving either perioperative or postoperative chemotherapy with FOLFOX or CAPOX regimens), and NeoCol (Neoadjuvant chemotherapy versus standard treatment in patients with locally advanced colon cancer). In PRODIGE 22, a randomized multicentre phase II trial in high-risk T3, T4 and/or N2 colon cancer, 3-year overall survival was 90.4% in both arms [hazard ratio (HR) = 0.85], with 3-year disease-free survival of 76.8% and 69.2% (HR=0.94), recurrence-free survival of 73% and 69.2% (HR = 0.86) and time to recurrence of 82% and 72% (HR = 0.67) in perioperative and control arms, respectively, and no benefit from adding cetuximab. In locally advanced rectal cancer treated with 6-8 cycles of oxaliplatin and fluoropyrimides based chemotherapy without radiotherapy, R0 resection was performed in 27 (100%) patients, complete pathologic response (ypT0N0) was confirmed in four (14.8%) patients, and overall and disease-free survival at five years was 85% and 84.7%, respectively. A prospective, multicentre, randomised, open-label trial (NCT07333053) is evaluating FOLFOX-based transarterial infusion chemotherapy at week 0 and week 4 plus FOLFOX-based intravenous chemotherapy at week 2 and week 6 versus FOLFOX-based intravenous chemotherapy every 2 weeks for 8 weeks in microsatellite stable or proficient mismatch repair unresectable colorectal cancer, with objective response rate as primary endpoint.

First-line and refractory metastatic colorectal cancer treatment has evolved through intensified chemotherapy, maintenance de-escalation, and molecularly targeted combinations. First-line FOLFOXIRI-B (fluorouracil, folinic acid, oxaliplatin, and irinotecan plus bevacizumab) was used in 25 patients (9%; 95% CI, 6%-12%) in 2021 compared with 142 (2%; 95% CI, 2%-3%) in 2015 to 2018, with 21 of 157 eligible patients (13.4%) treated during the study period. In GOIM 2802, bevacizumab plus FOLFOX-4 versus biweekly XELOX-2 showed objective response rate of 55.6% versus 48.3% (P = .43), progression-free survival of 10.0 versus 9.9 months (hazard ratio, 0.96; 95% confidence interval, 0.65-1.41; P = .84) and overall survival of 29.8 versus 25.0 months (hazard ratio, 1.21; 95% confidence interval, 0.77-1.92; P = .41). As second-line treatment after XELOX/FOLFOX failure, median progression-free survival was 104 and 112 days (3.5 and 3.7 months) with FOLFIRI and irinotecan, respectively [hazard ratio (HR) = 1.084, 95% confidence interval (CI) = 0.7911-1.485; p = 0.6094], with higher leucopenia (73.9% versus 55.4%), neutropenia (72.7% versus 56.6%), mucositis (40.9% versus 14.5%) and grade 3-4 neutropenia (47.7% versus 21.7%) with FOLFIRI. Trifluridine/tipiracil plus bevacizumab versus trifluridine/tipiracil showed disease control rate of 64% (6 studies; n = 289) versus 43% (10 studies; n = 2809), median progression-free survival of 4.2 (5 studies; n = 244) versus 2.6 (6 studies; n = 1781) months, and median overall survival of 9.8 (5 studies; n = 244) versus 8.1 (6 studies; n = 1814) months. Maintenance with fluoropyrimidine plus cetuximab versus bevacizumab after mFOLFOX6 induction showed disease control rates of 79% and 74%, median progression-free survival of maintenance therapy of 5.98 months and 4.83 months, and overall survival of 32.4 months and 25.6 months, respectively. For KRAS G12C-mutated disease, sotorasib alone showed objective response rate of 7.1 to 9.7%, disease control rates of 73.8 to 82.3% and median progression-free survival spanning 4-5.6 months, rising to 26.4% with panitumumab, while adagrasib with cetuximab led to 42% objective response rate and median progression-free survival of 6.9 months versus 19% with adagrasib alone, and divarasib monotherapy produced 36% objective response rate and 85.5% disease control rate with progression-free survival of 5.6 months, climbing to 62.5% and 8.1 months with cetuximab. In a randomized phase III trial, sotorasib combined with panitumumab prolonged progression-free survival versus triflurdin/tipiracil or regorafenib (5.6 months [4.2; 6.3] versus 2.2 months [1.9; 3.9]). Real-world BRAF-V600E cohorts reported median overall survival from metastatic diagnosis of 13.7 months (95% CI: 11.3-17.6) in Poland and median overall survival of 12.9 months in Canada.

Immunotherapy efficacy remains defined by mismatch repair and microsatellite instability status, with expanding neoadjuvant and combination applications. For deficient mismatch repair (dMMR) tumors, neoadjuvant immunotherapy exemplified by NICHE (Neoadjuvant immune checkpoint inhibition and novel IO combinations in early-stage colon cancer) has shown good pathologic response rates, and checkpoint inhibitors are first-choice palliative treatment in MSI-H/dMMR colorectal cancer. Cohort data showed response rate of 33% for pembrolizumab and 65% for nivolumab and ipilimumab, with 55 and 75% alive after 2 years, while first-line pembrolizumab versus chemotherapy showed progression-free survival of 16.5 vs. 8.2 months. In previously treated MSI-H/dMMR metastatic colorectal cancer, nivolumab 240 mg plus relatlimab 160 mg every 2 weeks in CheckMate 142 produced investigator-assessed objective response rate of 50% (95% CI 36% to 65%) and disease control rate of 70% (95% CI 55% to 82%), median progression-free survival of 27.5 (95% CI 5.3 to 43.7) months with 38% at 3 years, and median overall survival not reached (95% CI 17.2 months to not estimable) with 56% at 3 years. Dostarlimab 500 mg intravenously every 3 weeks for 9 cycles is under evaluation in AZUR-1 (NCT05723562) in untreated Stage II/III dMMR/MSI-H locally advanced rectal cancer enrolling approximately 150 patients, with primary endpoint of clinical complete response by independent central review at 12 months. In microsatellite stable/proficient mismatch repair disease, POCHI is evaluating pembrolizumab with Capox Bevacizumab as first-line treatment in 55 patients with high immune infiltrate defined by Immunoscore and TuLIS, with primary endpoint of progression-free survival at 10 months expected greater than 50%. In CheckMate 9X8, nivolumab plus 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab versus standard-of-care showed median progression-free survival by blinded independent central review of 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30), with higher objective response rate (60% vs 46%) and durable responses (median 12.9 vs 9.3 months). A meta-analysis of PD-1/PD-L1 inhibitors reported overall objective response rate of 0.16 (95%CI 0.06-0.31) and disease control rate of 0.50 (95%CI 0.35-0.65), with objective response rates of 0.40 (95% CI 0.30-0.51) in dMMR-MSI-H ≥ 5% versus 0.04 (95% CI 0.00-0.09) in dMMR-MSI-H < 5% subgroups.