BACKGROUND:Current therapies offer limited benefit for patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC). Aberrant activation of the RAS pathway is the key driver of PDAC, with oncogenic RAS mutations present in more than 90% of cases. Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS. METHODS:In this phase 3, international, open-label, randomized trial, we randomly assigned patients with previously treated mPDAC to receive daraxonrasib or chemotherapy of the investigator's choice. The dual primary end points were overall survival and progression-free survival in the subpopulation of patients with RAS G12 mutations (the RAS G12 population). Key secondary end points included overall survival and progression-free survival in the overall population (which included patients with RAS G12, G13, or Q61 mutations or with no RAS mutation identified) and objective response and patient-reported quality of life in the RAS G12 and overall populations. Safety was also assessed. RESULTS:A total of 500 patients, including 91.8% with RAS G12 mutations, were randomly assigned to receive daraxonrasib (248 patients) or chemotherapy (252 patients). The median overall survival in the RAS G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survival in the overall population was 13.2 months and 6.7 months, respectively; the hazard ratio was 0.40 in both populations (P<0.001). The median progression-free survival in the RAS G12 population was 7.3 months with daraxonrasib and 3.5 months with chemotherapy, and that in the overall population was 7.2 months and 3.6 months, respectively; the hazard ratios were 0.45 and 0.49, respectively (P<0.001 for both comparisons). Adverse events that occurred after the start of treatment were reported in all the patients in the daraxonrasib group and in 97.7% of those in the chemotherapy group; the incidence of adverse events of grade 3 or higher was 61.8% and 69.6%, respectively. Treatment-related adverse events that led to treatment discontinuation occurred in 1.2% of the patients in the daraxonrasib group and in 11.2% of those in the chemotherapy group. CONCLUSIONS:Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy. (Funded by Revolution Medicines; RASolute 302 ClinicalTrials.gov number, NCT06625320.).

BACKGROUND:RAS mutations, as a group, are the most common oncogenic drivers of non-small-cell lung cancer (NSCLC), and they occur in approximately 30% of patients. Whether daraxonrasib (RMC-6236) - an oral RAS(ON) multiselective, tri-complex inhibitor of guanosine triphosphate-bound mutant and wild-type RAS protein isoforms - is safe and effective in patients with RAS-mutant NSCLC is unknown. METHODS:In this phase 1-2, multicenter, dose-escalation and dose-expansion study of daraxonrasib, we enrolled patients with previously treated advanced RAS-mutant NSCLC and administered daraxonrasib in doses of 10 to 400 mg orally once daily in 21-day cycles. The primary end point was safety. Secondary end points included investigator-assessed objective response (complete or partial response) and the duration of response, with response assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS:As of the data-cutoff date of July 21, 2025, a total of 136 patients with NSCLC who had been enrolled and treated with daraxonrasib at doses of 300 mg or less had been evaluated for safety and efficacy. Adverse events of any grade occurring with a dose of 300 mg or less, regardless of attribution, were reported in 99% of the patients, with rash, diarrhea, nausea, vomiting, and mucositis or stomatitis occurring in at least 30% of patients. Adverse events of grade 3 or higher were reported in 54% of the patients, with pneumonia (in 10%), diarrhea (in 9%), rash (in 8%), and anemia (in 5%) occurring in at least 5% of patients; four grade 5 adverse events occurred. The percentage of patients who had an objective response was 31% with daraxonrasib at a dose of 120 mg or less, 34% at doses of 160 to 220 mg, and 37% at a dose of 300 mg. CONCLUSIONS:Among patients with previously treated metastatic RAS-mutant NSCLC receiving daraxonrasib at a dose of 300 mg or less daily, 54% had adverse events of grade 3 or higher, and antitumor activity was reported in more than 30%. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

Immune checkpoint inhibitors (ICIs) have limited activity in mismatch repair proficient or microsatellite stable (MMRp/MSS) colorectal cancer (CRC). KRAS mutations, present in approximately 40% of these cancers, can generate neoantigens that are targets for therapeutic vaccines. In this single-arm, phase I study (NCT04117087), we evaluated mKRAS-VAX, a pooled mutant KRAS (mKRAS) peptide vaccine targeting six KRAS mutations with nivolumab and ipilimumab in 13 patients with pretreated metastatic MMRp/MSS CRC. Both primary endpoints of safety and immunogenicity (within 17 weeks post-vaccination) were met. Secondary endpoints included treatment efficacy defined by RECIST v1.1 criteria. All adverse events attributed to mKRAS-VAX were grade 1 or 2, and the addition of mKRAS-VAX did not increase the frequency of severe immune-related adverse events beyond the expected profile of dual ICIs alone. mKRAS-VAX elicited an increase in tumor-specific mKRAS-reactive T-cells in 8/12 biomarker-evaluable patients (75%) by direct ex vivo IFNγ ELISpot and in 12 patients (100%) following in vitro expansion. Our findings support further development of mKRAS vaccines with ICIs for advanced MMRp/MSS CRC.

Abstract Background Cholangiocarcinoma (CCA) is a global health problem with a rising incidence, accounting for approximately 10% of all primary liver cancers worldwide. Surgical resection remains the only potentially curative treatment; however, the majority of patients present with advanced-stage disease, thereby limiting curative options. As a result, there is a substantial unmet need for the development of effective systemic therapies. Therapeutic strategies are increasingly focused on targeted approaches guided by next-generation sequencing. KRAS mutations are reported in approximately 20% of CCA cases, with KRAS G12D representing the most prevalent variant, accounting for roughly 40% of KRAS-mutant tumors. Here, we describe an ongoing Phase 1/2 study (NCT07020221) to assess the safety and efficacy of VS-7375, a highly selective oral, non-covalent, small molecule KRAS G12D (ON/OFF) inhibitor, in patients with advanced KRAS G12D-mutated solid tumors, including cholangiocarcinoma. Methods Patient enrollment is currently ongoing in Part B3, in which the preliminary anticancer activity of VS-7375 (600 mg or 900 mg QD) is being assessed in patients with solid tumors, including cholangiocarcinoma. Eligible patients must have locally advanced unresectable or metastatic solid tumor harboring a KRAS G12D mutation. Key inclusion criteria include measurable disease according to RECIST vl.1, 1 or 2 prior lines of standard systemic therapy, ECOG performance status of 0 or 1, and adequate organ and cardiac function. Efficacy of the regimen will be evaluated through confirmed ORR, PFS rate, unconfirmed PR and CR rates, OCR, DOR, and PFS per RECIST vl.1.

Abstract Background TOPAZ-1 demonstrated durvalumab + gemcitabine and cisplatin (GemCis) superiority over GemCis in first-line treatment of advanced biliary tract cancers. Real-world data from US patients and patients excluded from TOPAZ-1 (patients with autoimmune conditions [AICs] who did not receive immunotherapy) are lacking. We report real-world data for patients with cholangiocarcinoma treated with durvalumab + GemCis. Methods This retrospective, observational study enrolled adult patients diagnosed with cholangiocarcinoma in the US from the International Cholangiocarcinoma Patient Registry (ICPR) treated with first-line durvalumab + GemCis between 2021–2023. De-identified medical records from ICPR were obtained directly from consenting patients/caregivers. Patient demographics and tumor characteristics (primary objective; assessed at initial diagnosis), comorbidities, second-line treatment modalities, median real-world overall survival (mrwOS), and median real-world time to next treatment (mrwTTNT; initiation of first-line treatment and last activity in the database or death) are reported. Results Seventy patients received first-line durvalumab + GemCis: 13 (18.6%) had AIC(s) and 57 (81.4%) did not. Patient demographics, clinical characteristics, and comorbidities are shown (Table). Median (quartile 1–3) time from diagnosis to start of first-line treatment was 1.0 (0.7–1.7) months; median follow-up from first dose of first-line treatment was 7.0 (3.7–12.1) months. The mrwOS (95% CI) was 15.5 (15.1–not evaluable [NE]) months. mrwTTNT (95% CI) was 10.8 (10.4–15.7) months overall and was 20.8 (10.4–NE) months in patients who died without receiving subsequent treatment (censored at date of last activity). Among patients with AIC(s), <5 received second-line therapy (all received chemotherapy alone). Among patients with no AICs, 15 received second-line treatment; 11 (73.3%) received targeted therapy alone and <5 received chemotherapy alone. Conclusions This dataset demonstrates patients with AIC(s) are treated with durvalumab + GemCis in clinical practice. The mrwOS for durvalumab + GemCis in this patient population is consistent with TOPAZ-1 and global real-world studies.

BACKGROUND:Eligibility criteria for clinical trials are crucial for maintaining safety and study integrity. However, overly restrictive criteria can result in unrepresentative trial populations, leading to gaps in understanding real-world treatment efficacy. Addressing potentially modifiable exclusions (PMEs) could enhance trial accessibility and participation without compromising safety. METHODS:The authors retrospectively analyzed screen-failed patients with biliary tract cancer or pancreatic cancer between August 2019 and November 2024 at The University of Texas MD Anderson Cancer Center. Screen-failed patients were those who provided informed consent but did not participate for any reason. Clinical data were obtained from screening logs and electronic health records. PMEs were identified and validated by two independent medical oncologists. RESULTS:Of 585 screen-failed patients from 18 trials, 509 were analyzed (367 with pancreatic cancer and 142 with biliary tract cancer) after excluding 76 because of incomplete data. Leading causes of screen failure were declined participation (19%), comorbidities (12%), suboptimal organ function (11%), absence of a biomarker (10%), and insufficient biospecimens (7%). Reasons for declining included preference for standard care (23%), travel (22%), and competing trials (5%). The authors identified 69 patients (13.6%) who had PMEs (primarily borderline laboratory abnormalities), including liver function (23%), kidney function (20%), platelet count (12%), hemoglobin (7%), and white blood cell count (6%) abnormalities. Other PMEs included previous or concurrent malignancies (9%) and viral hepatitis (4%). PMEs were evenly distributed across trials. CONCLUSIONS:Rigid eligibility criteria exclude stable patients who might benefit from investigational treatments. Easing criteria related to incidental or asymptomatic laboratory abnormalities could broaden trial accessibility and improve enrollment in populations that are more representative of real-world use.

BACKGROUND:Current therapies for patients with pancreatic ductal adenocarcinoma (PDAC) provide modest benefit. Activating RAS mutations occur in more than 90% of PDAC tumors. Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate-bound mutant and wild-type RAS. METHODS:In this phase 1-2 study, we evaluated daraxonrasib in patients with advanced solid tumors with activating RAS mutations. Patients received 10 to 400 mg of daraxonrasib orally once daily; 300 mg was selected as the phase 3 dose. The primary end point was safety. Pharmacokinetics and antitumor activity were secondary end points. This report focuses on the 168 study patients with previously treated RAS-mutated PDAC. RESULTS:Among the 168 patients with PDAC who received daraxonrasib at a dose of 300 mg or less, treatment-related adverse events of any grade were reported in 96%; such events of grade 3 or higher were reported in 30%. Treatment-related adverse events that occurred in at least 10% of the patients included rash, diarrhea, nausea, stomatitis or mucositis, vomiting, and fatigue. In a subgroup of 26 patients with RAS G12 mutations who were treated with second-line daraxonrasib at a dose of 300 mg, an objective response to therapy was reported in 35% (95% confidence interval [CI], 17 to 56). The median duration of response was 8.2 months (95% CI, 3.8 to not evaluable), with median values of 8.5 months for progression-free survival and 13.1 months for overall survival. Among the 38 patients with RAS G12, G13, or Q61 mutations, 29% (95% CI, 15 to 46) had an objective response. The median duration of response was 8.2 months (95% CI, 3.8 to 8.8), with median values of 8.1 months for progression-free survival and 15.6 months for overall survival. CONCLUSIONS:Daraxonrasib was associated with treatment-related adverse events of grade 3 or higher in one third of patients with previously treated RAS-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

In this phase I study, we test a pooled synthetic long peptide vaccine targeting the six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab in resected pancreatic adenocarcinoma. Co-primary endpoints include safety and maximal percent change of IFNγ-producing mutant KRAS T cell responses in the blood within 17 weeks. Secondary endpoints include disease-free survival, overall survival, and maximal percent change of IFNγ-producing mutant KRAS T cell responses at any time after vaccination. Vaccine-related adverse events are grade 1-2. 11/12 and 10/12 patients generate a significant increase in average T cell response to 6 mutant KRAS antigens and tumor-specific response, respectively. Immunophenotyping demonstrate Th1 CD4 central memory and effector memory T cells, and CD8 effector memory T cells at a lower frequency. The vaccine also generates cross-reactive T cells that recognize more than one mutant KRAS antigen. These findings support the safety and diverse anti-tumor immunity of mutant KRAS vaccines (NCT04117087).

PURPOSE:Pancreatic adenosquamous carcinoma (ASQ) is a rare variant with poorly defined clinical and molecular features compared to conventional pancreatic ductal adenocarcinoma (PDAC). This study aimed to characterize the clinical outcomes, genomic landscape, and spatial transcriptomic architecture of ASQ. EXPERIMENTAL DESIGN:We retrospectively evaluated clinicopathologic features, treatment patterns, and survival of ASQ patients treated at Johns Hopkins from 2013-2023 (n=178). Genomic landscapes of ASQ (n=244) versus PDAC (n=29,021) were compared using the FoundationCore database. Surgically resected ASQ tumors (n=11 from 8 patients) were analyzed using Visium spatial transcriptomics with a comparator PDAC dataset (n=4). RESULTS:ASQ patients had poor outcomes in both resected and advanced disease. FoundationCore analysis revealed similar KRAS mutation frequency, higher MTAP loss, and enrichment of low-frequency immune biomarkers (MSI-high, PD-L1+, TMB ³10 muts/Mb) in ASQ compared with PDAC. Spatial transcriptomics revealed broadly similar immune cell proportions across subtypes, with higher regulatory T-cell abundance observed in ASQ in the context of sparse detection in PDAC. Differences in spatial co-localization patterns of immune populations were observed between ASQ and PDAC, while distance analyses within ASQ showed immune infiltrates closest to squamous regions and farthest from glandular regions. Furthermore, ASQ showed increased squamous/basal lineage expression compared with PDAC, with intratumoral squamous regions enriched for epithelial-mesenchymal transition, apical junction, inflammatory, and stress response pathways relative to the glandular niche. CONCLUSIONS:Despite shared genomic drivers with PDAC, ASQ exhibits transcriptionally distinct features with spatially organized tumor and immune heterogeneity, supporting the need for subtype-specific therapeutic strategies.

Abstract Background & Objectives Based on the TOPAZ-I study, durvalumab combined with gemcitabine and cisplatin (GemCis) is now supported as a standard of care treatment for cholangiocarcinoma. Patients with extrahepatic cholangiocarcinoma (eCCA) often have underlying autoimmune conditions (AICs) which could restrict immunotherapy use. Treatment patterns in patients with eCCA with AICs and non-autoimmune conditions (NAICs) are reported. Method This retrospective observational analysis of adult patients diagnosed with eCCA in the United States enrolled in the International Cholangiocarcinoma Patient Registry between 2019 and 2023, focused on those treated with durvalumab. The registry contains de-identified data from medical records obtained directly from consenting patients and caregivers. Patients were followed from index date (date of eCCA diagnosis) until the last activity in the database or death. Demographics, clinical characteristics, biomarkers, treatment patterns, and adverse events (AEs) are reported. Results Overall, 135 patients with eCCA were enrolled: 24 (17.8%) had 2:1 AICs and 111 (82.2%) had NAICs. Baseline demographics were comparable between groups: the median (quartile [Q]l-Q3) age at diagnosis was 63.0 (55.0-70.0) years, the mean number of comorbidities in the overall population was 10.1, and 50.4% of patients were female. PD-Ll positivity was noted in 12.6% of patients and HER2 positivity in 10.4%. Of 91 patients with eCCA who received first-line therapy, 34 (37.4%) received GemCis alone, 27 (29.7%) chemotherapy alone (non-GemCis +/- nab-paclitaxel), 9 (9.9%) GemCis plus nab-paclitaxel, 7 (7.7%) durvalumab plus GemCis, 7 (7.7%) durvalumab monotherapy or in combination, and 7 (7.7%) other regimens. Treatment patterns by autoimmune comorbidity status are also reported (Table). Overall, 129 patients (95.6%) had ≥1 AE; fatigue was the most common (71.1%). Conclusion More patients with eCCA received a first-line durvalumab-based regimen post-March 2022 vs the full study period. The use of durvalumab as first-line treatment in this subgroup may suggest that AICs do not restrict its use.

BACKGROUND:Systemic chemotherapeutics have limited efficacy in many advanced solid tumours. This study evaluated the safety and tolerability of INT230-6, a unique intratumoural (IT) formulation of cisplatin, vinblastine, and 8-((2-hydroxybenzoyl)amino)octanoate (SHAO), an amphiphilic cell-penetration enhancer. METHODS:In this single-arm phase 1/2 trial (NCT03058289), adults with advanced or metastatic disease who progressed on a median of three prior therapies received multiple doses of IT INT230-6 monotherapy once every 28 days or biweekly for five treatments with maintenance dosing every 9 weeks. INT230-6 dose was based on tumour diameter or volume and escalated across five cohorts. A fixed-dose cohort received up to 175 mL. FINDINGS:No dose-limiting toxicities were reported among 64 enrolled patients; seven (10·9%) discontinued treatment due to adverse events (AEs). Overall, 52/64 (81·3%) patients had treatment-related AEs (TRAEs), including grade ≥3 TRAEs (7/64 [10·9%]) and serious TRAEs (3/64 [4·7%]). INT230-6 achieved a disease control rate (DCR) of 75% (48/64 patients) and median overall survival (mOS) of 11·9 months (95% confidence interval [CI]: 6·3-19·4). In an exploratory analysis, patients dosed at ≥40% of total tumour burden vs <40% had improved DCR (40/48 [83·3%] vs 8/16 [50%]) and mOS (18·7 months [95% CI: 11·5-23·5] vs 3·1 months [95% CI: 1·6-5·9]). Fifteen patients survived ≥21 months; eight were alive at study end. INT230-6 induced a qualitative decrease in proliferating cancer cells in injected tumours and a qualitative increase in activated T-cells infiltrating the tumour microenvironment. Ten patients had abscopal responses. INTERPRETATION:IT INT230-6 was well tolerated and manifested promising treatment benefits. FUNDING:Intensity Therapeutics, Inc.

Receiver operating curve demonstrating relationship between tumor mutational burden and clinical benefit

Representativeness of study participants

Supplementary Table 7. Summary of All Adverse Events Attributed to Nivolumab and/or Relatlimab.

Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Immune checkpoint inhibitors (ICIs) have minimal activity in the ∼95% of metastatic CRC that are MMRp/MSS, largely due to significantly lower expression of neoantigens. Combining neoantigen vaccines targeting mutant KRAS (mKRAS), an oncogenic driver found in ∼40% of CRC, with ICIs, may sensitize metastatic mKRAS MMRp/MSS CRC to immunotherapy. This is a first-in-human Phase 1 trial (NCT 04117087) of mKRAS-VAX - a pooled synthetic long peptide (SLP) vaccine targeting the six most common KRAS mutations (G12D, G13D, G12V, G12C, G12A, G12R) - in combination with ipilimumab/nivolumab (ipi/nivo) in patients with heavily pretreated MMRp/MSS CRC (progression on 2 or more lines of chemotherapy). Key inclusion criteria included tumor expression of a KRAS mutation included in mKRAS-VAX and prior 5-fluorouracil, oxaliplatin, and irinotecan exposure. In the priming phase, patients received 4 weekly doses of mKRAS-VAX as well as ipilimumab (1mg/kg every 6 weeks for 2 doses) and nivolumab (3mg/kg every 3 weeks for 4 doses). In the boost phase, patients received mKRAS-VAX every 8 weeks and nivolumab (480mg every 4 weeks) up to 1 year total. Primary endpoints are safety and mKRAS-specific T cell response. Secondary endpoints are overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). At the time of data cutoff (December 13, 2024), 12 patients have been treated. Most adverse events were grade 1 (61.2%) or grade 2 (29.6%). 31.6% of AEs were immune-related including three that were grade 3 (2 adrenal insufficiency, 1 arthralgia). There was one grade 4 adverse event (sepsis), which was not treatment related. 8/12 (75%) patients achieved a mKRAS-specific T cell response to their tumor specific KRAS mutation as assessed by serial IFNγ ELISpot, with a median 9-fold increase from baseline. There was one RECIST partial response (8.3%) and 2/7 (29%) patients with active liver metastases had tumor shrinkage, a phenotype which is increasingly recognized as refractory to immunotherapy in MMRp/MSS CRC. The disease control rate (DCR) was 41.7% (5/12) with a median PFS was 3.7 months and median OS of 24.9 months. mKRAS-VAX and ipi/nivo is well-tolerated and induced mKRAS-specific T-cell responses. Moreover, this strategy resulted in meaningful clinical responses in chemorefractory metastatic mKRAS MMRp/MSS CRC with OS that was provocative. Ongoing studies of the T cell repertoire in blood and tumor tissue will be used to identify biomarkers that predict response to mKRAS-targeted immunotherapy. A Phase 1b clinical trial (NCT06411691) investigating mKRAS-VAX with ICIs balstilimab and botensilimab in advanced MMRp/MSS CRC and pancreatic ductal adenocarcinoma is underway. Hejia Henry Wang, Amanda Huff, Saurav Haldar, Maureen Berg, Christopher Thoburn, Katherine Bever, Michael Pishvaian, Valerie Lee, Dung Le, Eric Christenson, Marina Baretti, Jennifer Durham, Amy Thomas, Mark Yarchoan, Daniel Laheru, Julie Nauroth, Jiayun Lu, Hao Wang, Elizabeth M. Jaffee, Nilofer Azad, Neeha Zaidi. Mutant KRAS peptide vaccine combined with ipilimumab/nivolumab in advanced mismatch repair proficient/microsatellite stable (MMRp/MSS) colorectal cancer: Preliminary analysis from a phase I study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT264.

Supplementary Table S2. Splicing antigenicity differences between samples with mutated and samples without mutated splicing factor genes. The splicing antigenicity differences between samples with mutated and non-mutated splicing factors for all 119 chosen splicing factor genes and for each TCGA cancer subtype.

Summary of evidence evaluating potential predictive biomarkers of response to immune checkpoint blockade in patients with MSI-H non-colorectal cancer tumors