Keun-Wook Lee

Purpose: Pemetrexed, a standard antifolate chemotherapy for non‐squamous non‐small cell lung cancer (NSCLC), is often limited by acquired resistance. We investigated whether SRC kinase mediates pemetrexed resistance and whether SRC inhibition can suppress survival signaling in pemetrexed‐resistant NSCLC cells. Methods: Pemetrexed‐resistant cell lines (PC9 R, NCI‐H460 R, and NCI‐H3122 R) were generated through chronic pemetrexed exposure. Protein phosphorylation profiling and Western blotting identified key signaling alterations. SRC was abrogated using transient and doxycycline‐inducible CRISPR/Cas9 systems, and reciprocal siRNA knockdown of SRC and thymidylate synthase (TS) was performed. Three SRC inhibitors—dasatinib, bosutinib, and saracatinib—were assessed using cell viability, colony formation, apoptosis, and cell cycle assays. Results: All pemetrexed‐resistant cell lines demonstrated elevated phosphorylated SRC (p‐SRC Y416) and enhanced downstream signaling. SRC knockout reduced p‐SRC Y416, p‐STAT3, and p‐FAK, while increasing markers of DNA damage (γ‐H2AX) and apoptosis (cleaved caspase‐3), impairing cell viability and clonogenicity. SRC knockdown reduced TS expression in two resistant models, whereas TS knockdown did not suppress p‐SRC Y416. Among SRC inhibitors, dasatinib showed the most potent, dose‐dependent suppression of SRC signaling. Dasatinib also induced G0/G1 arrest, DNA damage, and apoptosis, thereby reducing colony formation. Conclusion: SRC activation is a critical mechanism of acquired pemetrexed resistance in NSCLC and may contribute to resistance through TS‐associated survival signaling. SRC inhibition, particularly with dasatinib, disrupts pro‐survival pathways and promotes DNA damage‐mediated cell death in pemetrexed‐resistant cells. These findings support further investigation of SRC inhibitors, alone or with pemetrexed, as a biomarker‐guided therapeutic strategy for SRC‐activated pemetrexed‐resistant NSCLC.

Background Ceralasertib, an ATR inhibitor, is known to exacerbate replication stress induced by the PARP inhibitor (PARPi) olaparib, with the combination having the potential to overcome PARPi resistance in the clinic. This modular Phase 1 study evaluated the combination in advanced solid tumours, including breast cancer. Methods Dose escalation of ceralasertib alone (Part A1) or with olaparib (Part A2) in patients with all solid tumours was followed by expansion in PARPi-naïve patients with BRCA1/2 m HER2-negative breast cancer (Part B3) or BRCA1/2 wt triple-negative breast cancer (Part B4). Results Overall, 142 patients were treated. No dose-limiting toxicities occurred in Part A1. Based on haematological safety in Part A2, the combination recommended Phase 2 dose was ceralasertib 160 mg once-daily, days 1–7, plus olaparib 300 mg twice-daily continuously (28-day cycles). In Parts B3 and B4, 36/37 (97.3%) and 24/25 (96.0%) patients had treatment-emergent adverse events (grade ≥3: 16/37 [43.2%], 9/25 [36.0%]; leading to discontinuation: 2/37 [5.4%], 1/25 [4.0%]), and 7 (18.9%) and 3 (12.0%) required ceralasertib dose reductions. Objective response rates were: Part A1, 0%; Part A2, 16.4% (n = 10/61); Part B3, 37.8% (n = 14/37); and Part B4, 0%. Conclusion In PARPi-naïve patients with BRCA1/2 m HER2-negative breast cancer, ceralasertib-olaparib had generally manageable safety and demonstrated preliminary antitumour activity. Trial registration number NCT02264678.

Evorpacept blocks the CD47–signal regulatory protein α interaction, enhancing antibody-dependent cellular phagocytosis. In the phase 2 portion of ASPEN-06 (a multicenter, open-label, randomized phase 2/3 study), 127 patients with pretreated, human epidermal growth factor receptor 2 (HER2)-overexpressing, advanced gastric/gastroesophageal junction cancer were randomized to evorpacept plus trastuzumab, ramucirumab and paclitaxel (evo + TRP; n = 63; fresh HER2⁺ biopsy, n = 22) or TRP alone (n = 64; fresh HER2⁺ biopsy, n = 26). The primary end point was investigator-assessed objective response rate (ORR). The primary analysis of ORR was designed to evaluate an ORR exceeding the historical 30% benchmark (ramucirumab/paclitaxel) (80% power for intent to treat (ITT) and 50% power for the ITT subpopulation (HER2 overexpression based on a post-trastuzumab ‘fresh’ biopsy)) and an improvement of ≥8.0% and ≥9.7% versus TRP in the ITT and ITT subpopulations, respectively. Key secondary end points included ORR by blinded independent central review, duration of response and progression-free survival by investigator or blinded independent central review, overall survival and safety. Post hoc biomarker analyses, including the assessment of the association of treatment efficacy with retained HER2 status (defined by HER2 positivity on fresh tumor biopsy or amplification in circulating tumor DNA analysis) and CD47 expression in tumor samples, were conducted. The investigator-assessed ORRs were 40.3% (evo + TRP) versus 26.6% (TRP) in the ITT population and 54.8% versus 23.1% in the fresh biopsy HER2⁺ subgroup. ORR differences (13.7% and 31.7%) exceeded the prespecified thresholds in both the ITT population and fresh biopsy HER2⁺ subgroup, meeting one of the two primary objectives; however, compared to the historical benchmark (30%), ORRs in the ITT population (40.3%; P = 0.0949, one-sided) and fresh biopsy HER2⁺ subgroup (54.8%; P = 0.030, one-sided) did not meet the prespecified statistical criterion (one-sided α = 0.025). While hematologic toxicities were more common with evo + TRP, overall safety was similar. In summary, evo + TRP showed encouraging efficacy with manageable safety in advanced gastric/gastroesophageal junction cancer. ClinicalTrials.gov identifier: NCT05002127.

Purpose: DeFianCe was a randomized phase II study evaluating sirexatamab, a Dickkopf-related protein 1 (DKK1)–neutralizing antibody, plus chemotherapy and bevacizumab as second-line therapy for metastatic colorectal cancer (mCRC). Patients and Methods: Patients with mCRC and progression, during or after 1 prior systemic therapy line, were randomized 1:1 to investigator-choice folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) or folinic acid, 5-fluorouracil, and oxaliplatin (mFOLFOX6) plus bevacizumab, with or without intravenous sirexatamab. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and safety. Baseline plasma DKK1 was a prespecified candidate biomarker. Results: In part B, 188 patients were randomized. The median PFS was 9.2 months with sirexatamab versus 8.3 months with control [hazard ratio (HR), 0.84; 95% confidence interval (CI), 0.58–1.21; one-sided P = 0.1712]; the primary endpoint was not met. The median OS was not reached in either arm (HR, 0.83; 95% CI, 0.46–1.48; one-sided P = 0.2632), and the ORR was 35.1% versus 26.6% (one-sided P = 0.1009). The final analysis included 119 investigator-assessed PFS events versus 145 planned events. Safety was generally comparable between arms. In exploratory baseline plasma DKK1 analyses, greater treatment benefit was observed in patients with DKK1 above the median for PFS (HR, 0.61; 95% CI, 0.37–1), OS (HR, 0.42; 95% CI, 0.19–0.91), and ORR (38% vs. 23.7%). Conclusions: Sirexatamab plus chemotherapy and bevacizumab did not improve PFS in the intent-to-treat population but was generally well tolerated. However, the consistent association between higher baseline plasma DKK1 and greater sirexatamab benefit suggests that DKK1-directed therapy may require biomarker-selected evaluation rather than all-comer development in mCRC.

Inclusion and exclusion criteria

Representativeness of study participants

Purpose:Targeting the adenosine pathway may enhance the efficacy of chemo/immunotherapy regimens in patients with heavily pretreated advanced metastatic colorectal cancer (mCRC), for whom treatment options are limited.Patients and Methods:The phase II ARC-9 study, Cohort B (NCT04660812), evaluated the efficacy and safety of etrumadenant (A2a and A2b receptor antagonist), zimberelimab (anti–PD-1 mAb), FOLFOX, and bevacizumab (EZFB) versus regorafenib in patients with third-line mCRC who previously progressed on oxaliplatin- and irinotecan-containing regimens.Results:From September 21, 2021, to September 12, 2022, 112 patients were randomized 2:1 to EZFB (n = 75) or regorafenib (n = 37). As of November 13, 2023, the median survival follow-up was 20.4 months. The primary endpoint of progression-free survival (PFS) was improved with EZFB (6.2 months) versus regorafenib [2.1 months; hazard ratio (HR), 0.27; 95% confidence interval (CI), 0.17–0.43; nominal P < 0.0001], as was the secondary endpoint of overall survival (OS; EZFB, 19.7 months; regorafenib, 9.5 months; HR, 0.37; 95% CI, 0.22–0.63; nominal P = 0.0003). The confirmed overall response rate was 17% (90% CI, 10.6%–26.1%) with EZFB and 3% (90% CI, 0.1%–12.2%) with regorafenib. Treatment-emergent adverse events (TEAE), grade ≥3 TEAEs, and TEAEs leading to discontinuation of all study treatments were reported in 99%, 82%, and 5% of the EZFB arm and in 87%, 49%, and 17% of the regorafenib arm, respectively.Conclusions:EZFB significantly improved survival outcomes compared with regorafenib in patients with mCRC as a third-line treatment, with a manageable safety profile. Further investigation is warranted, given the clinically meaningful improvements in PFS and OS.

PFS subgroups analysis. 1L, first-line therapy; BOR, best overall response; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; EZFB, etrumadenant and zimberelimab with mFOLFOX-6 and bevacizumab; HR, hazard ratio; mFOLFOX-6, modified FOLFOX-6; MSI, microsatellite instability; MSI-L, MSI low; MSS, microsatellite stable; NGS, next-generation sequencing; PCR, polymerase chain reaction; PD, progressive disease; PFS, progression-free survival; PR, partial response; rego, regorafenib; SD, stable disease. aDisease progression occurred >2 months after the last prior oxaliplatin dose in the metastatic setting (n = 11), or inclusion was approved by the medical monitor (n = 1)

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