RASolute 302: A Phase III Breakthrough in Broad RAS Targeting

Daraxonrasib is an orally administered, multiselective RAS(ON) inhibitor designed to target the active, GTP-bound state of multiple mutant and wild-type RAS proteins. The phase III RASolute 302 trial randomized 500 patients with metastatic RAS-mutant pancreatic ductal adenocarcinoma (PDAC) whose disease had progressed after one prior systemic therapy to receive either daraxonrasib or investigator's choice of chemotherapy.

Daraxonrasib significantly improved clinical outcomes compared with chemotherapy. Median overall survival was 13.2 months versus 6.7 months, corresponding to a 60% reduction in the risk of death. Median progression-free survival was 7.2 months compared with 3.6 months, while objective response rates were 31.6% and 11.2%, respectively. Grade 3 or higher adverse events occurred in 61.8% of patients receiving daraxonrasib and 69.6% of those receiving chemotherapy. The most common grade 3 or higher treatment-related adverse events associated with daraxonrasib were rash and stomatitis.[8]

These findings represent a major therapeutic advance for patients with metastatic RAS-mutant PDAC and are expected to redefine the standard of care in the second-line setting. Moreover, given the substantial improvement in survival outcomes, daraxonrasib is likely to be evaluated in earlier lines of therapy and in patients with localized disease.

Clinical takeaway: The RASolute 302 trial is practice-changing and establishes daraxonrasib as a new standard second-line treatment option for patients with metastatic RAS-mutant pancreatic ductal adenocarcinoma. Whether pan-RAS inhibitors or allele-specific KRAS inhibitors will achieve more durable and deeper responses remains an important unanswered question that will ultimately define our future therapeutic algorithms.

FOLFIRI as an alternative chemotherapy backbone for BRAF V600E targeting  

The phase III BREAKWATER trial established first-line encorafenib plus cetuximab in combination with chemotherapy for patients with BRAF V600E–mutant metastatic colorectal cancer by nearly doubling overall survival. The initial randomized cohort of the BREAKWATER trial evaluated encorafenib plus cetuximab with mFOLFOX6. Cohort 3 separately assessed whether FOLFIRI could serve as an alternative chemotherapy backbone. This question is clinically relevant because many patients are not ideal candidates for oxaliplatin because of baseline neuropathy, or prior oxaliplatin exposure during the adjuvant therapy.

Cohort 3 randomized 147 previously untreated patients to encorafenib, cetuximab, and FOLFIRI or FOLFIRI with or without bevacizumab. The objective response rate was 64.4% with encorafenib, cetuximab, and FOLFIRI compared with 39.2% with the control regimen. Median progression-free survival was 15.2 versus 8.3 months, corresponding to a 56% reduction in the risk of progression or death. Median overall survival was not reached in the experimental arm and was 20.3 months in the control arm. The 18-month overall survival rates were 72.0% and 54.5%, respectively. The safety profile was consistent with the known toxicities of the individual agents, with no new safety signals.[1] Although the result of study remains preliminary, similar efficacy results with reasonable safety profile potentially offers broader therapeutic approaches for this population to individualize the chemotherapy backbone for each patient based on their co-morbidities and preferences.

Clinical takeaway: Encorafenib plus cetuximab should be integrated with chemotherapy in the first-line treatment of BRAF V600E–mutant metastatic colorectal cancer. Pending the mature results, FOLFIRI appears to be ****a reasonable alternative to mFOLFOX6, particularly for patients with preexisting neuropathy or prior oxaliplatin exposure.

SWOG S2107: Adding nivolumab does not overcome immunotherapy resistance for BRAF V600E mutated CRC

BRAF V600E–mutant colorectal cancer has an unusual molecular phenotype. Although most of these tumors are microsatellite stable, some demonstrate immune and transcriptional features resembling immune hot tumors . Early single-center data suggested that combining BRAF and EGFR inhibition with PD-1 blockade might produce greater activity than BRAF and EGFR inhibition alone and lead to a randomized SWOG trial.

SWOG S2107 investigated patients with previously treated, MSS, BRAF V600E–mutant metastatic colorectal cancer who were BRAF inhibitor naive. Of 88 patients enrolled, 85 were eligible and evaluable and were assigned in a 2:1 ratio to encorafenib and cetuximab with or without nivolumab, respectively.

The trial did not meet its primary endpoint. Median progression-free survival was 5.8 versus and 6.3 months with and without nivolumab, respectively. Response rates were 35% and 32%, while median overall survival was 13.5 and 11.6 months suggesting no benefit with the addition anti-PD1. Grade 3–4 treatment-related adverse events were common in interventional arm with 54% events compared 36% in SOC arm.[2]

Clinical takeaway: Nivolumab did not demonstrate any meaningful clinically activity when added to encorafenib and cetuximab for patients with MSS, BRAF V600E–mutant metastatic colorectal cancer.  Further studies are warranted to better understand the biology of BRAF V600E mutated CRC. 

Adjuvant aspirin: The benefit is not univeral

Aspirin exerts antineoplastic effects in colorectal cancer through inhibition of cyclooxygenase-2 (COX-2), thereby reducing prostaglandin-mediated inflammation, cellular proliferation, and angiogenesis. In an observational study, Liao et al. found that aspirin use after diagnosis was associated with improved colorectal cancer–specific and overall survival among patients with PIK3CA-mutated tumors, but not those with wild-type PIK3CA, suggesting a potential molecularly defined therapeutic effect (Liao X, et al. N Engl J Med. 2012;367:1596–1606). Most recently, phase III ALASCCA trial demonstrated a significant reduction in recurrence among patients with localized colorectal cancer harboring PI3K-pathway alterations, including alterations in PIK3CA, PIK3R1, and PTEN[4].

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Most recently, the phase III EPISODE-III trial evaluated low-dose aspirin in all patients with stage III colorectal cancer, including MSI-high CRC following curative resection. A total of 882 patients were randomized to aspirin 100 mg daily or placebo for three years in addition to standard adjuvant chemotherapy.

At a median follow-up of four years, three-year disease-free survival was 78.8% with aspirin and 75.4% with placebo. The difference was not statistically significant. Three-year overall survival was 95.2% and 96.6%, respectively. Grade 3 or higher aspirin-related adverse events occurred in fewer than 1% of patients

Clinical takeaway: These findings suggest that aspirin benefit is biomarker dependent rather than universal. Adjuvant aspirin should not be prescribed routinely to all patients with resected stage III colorectal cancer rather only for patients with PI3K-pathway altered CRC after individualized assessment of bleeding and cardiovascular risks.

CIRCULATE: The role of ctDNA a predictive biomarker

Postoperative circulating tumor DNA is a powerful prognostic marker following colorectal cancer resection. CIRCULATE examined whether ctDNA could also identify patients who benefit from adjuvant chemotherapy rather than merely identifying recurrence risk.

Patients with resected stage II pMMR/MSS colon cancer underwent tumor-informed next-generation sequencing. Notably, those with detectable postoperative ctDNA were randomized 2:1 to capecitabine, with oxaliplatin permitted at the investigator’s discretion, or observation. Most patients with negative ctDNA were assigned to observation or off-study follow-up.

Among observed patients, three-year disease-free survival was 52% for those with positive ctDNA and 87% for those with negative ctDNA. Three-year overall survival was 88% and 98%, respectively.

The intention-to-treat analysis did not meet its primary endpoint: among ctDNA-positive patients, three-year disease-free survival was 61% with chemotherapy and 38% with observation. In the per-protocol analysis of 36 patients, chemotherapy reduced the three-year recurrence rate from 62% to 19% and increased three-year disease-free survival from 38% to 77%. The study closed early and was underpowered because ctDNA positivity was less common than anticipated.[5]

Clinical takeaway: Positive postoperative ctDNA in patients with pMMR/MSS stage II colon cancer identifies a very high-risk population and provides compelling evidence supporting the use of adjuvant chemotherapy. Importantly, patients with positive postoperative ctDNA should not be assigned to observation-only or other non-treatment arms, given their markedly elevated risk of recurrence. Future clinical trials should avoid observation-only strategies in this MRD positive population, and instead prioritize evaluation of novel therapeutic interventions aimed at improving outcomes.

HERIZON-GEA-01: Zanidatamab as a Novel HER2-Targeted Therapy

HER2-positive gastroesophageal adenocarcinoma has traditionally been treated with trastuzumab in combination with chemotherapy, with the addition of PD-1 blockade in selected patients. The phase III HERIZON-GEA-01 trial evaluated whether more comprehensive HER2 inhibition with zanidatamab could further improve clinical outcomes.

Zanidatamab is a biparatopic bispecific antibody that simultaneously binds two distinct, nonoverlapping HER2 epitopes, resulting in enhanced receptor internalization, antibody-dependent cellular cytotoxicity, and more complete HER2 pathway inhibition.

In this phase III trial, 914 patients with previously untreated HER2-positive advanced gastroesophageal adenocarcinoma were randomized to receive zanidatamab plus chemotherapy and tislelizumab, zanidatamab plus chemotherapy, or trastuzumab plus chemotherapy.

Median progression-free survival was 12.4 months with both zanidatamab-containing regimens (zanidatamab plus chemotherapy with or without tislelizumab), compared with 8.1 months for trastuzumab plus chemotherapy. Median overall survival was significantly longer with zanidatamab, chemotherapy, and tislelizumab than with trastuzumab plus chemotherapy (26.4 vs 19.2 months). At the interim analysis, median overall survival with zanidatamab plus chemotherapy alone was 24.4 months versus 19.2 months with trastuzumab plus chemotherapy; however, this difference had not yet reached statistical significance. Diarrhea was the most common grade 3 or higher adverse event. [6]

Clinical takeaway: HERIZON-GEA-01 demonstrates that zanidatamab-based therapy significantly improves progression-free survival compared with trastuzumab-based treatment. The combination of zanidatamab, chemotherapy, and PD-1 blockade has the potential to establish a new first-line standard of care for patients with HER2-positive advanced gastroesophageal adenocarcinoma, pending confirmation from more mature overall survival analyses.

References

  1. Kopetz S, Tabernero J, Lonardi S, et al. A randomised study of encorafenib, cetuximab, and FOLFIRI versus FOLFIRI with or without bevacizumab in BRAF V600E–mutant colorectal cancer: BREAKWATER Cohort 3. Ann Oncol. Published online May 31, 2026. doi:10.1016/j.annonc.2026.04.017.

  2. Morris VK II, Colby S, Kopetz S, et al. SWOG S2107: Randomized phase II trial of encorafenib and cetuximab with or without nivolumab for patients with previously treated MSS, BRAF V600E metastatic colorectal cancer. J Clin Oncol. 2026;44(suppl 16):3504. doi:10.1200/JCO.2026.44.16_suppl.3504.

  3. Takashima A, Hirano Y, Shiozawa M, et al. Adjuvant aspirin for stage III colorectal cancer after curative resection: Primary analysis of the randomized, double-blind, placebo-controlled phase III EPISODE-III trial. _J Clin Oncol._2026;44(suppl 17). doi:10.1200/JCO.2026.44.17_suppl.LBA3508.

  4. Martling A, Myrberg IH, Nilbert M, et al. Low-dose aspirin for PI3K-altered localized colorectal cancer. N Engl J Med. 2025;393:1051–1064. doi:10.1056/NEJMoa2504650.

  5. Folprecht G, Stasik S, Reinacher-Schick A, et al. Chemotherapy for patients with circulating tumour DNA–positive stage II colon cancer: CIRCULATE, an AIO/ABCSG trial. Ann Oncol. Published online May 31, 2026. doi:10.1016/j.annonc.2026.05.001.

  6. Shitara K, Elimova E, Liu T, et al. Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. N Engl J Med. 2026;394:2002–2014. doi:10.1056/NEJMoa2517729.

  7. Shitara K, Shoji H, Fazio N, et al. First-line zolbetuximab plus mFOLFOX6 and nivolumab in unresectable CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: A phase 2 trial. Nat Med. 2026;32:2182–2190. doi:10.1038/s41591-026-04306-9.

  8. O’Reilly EM, Wainberg ZA, Hendifar AE, et al. Daraxonrasib or chemotherapy in previously treated metastatic pancreatic cancer. N Engl J Med. Published online May 31, 2026. doi:10.1056/NEJMoa2605555.