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The intracranial objective response rate (ORR) in RANO-BM–evaluable patients (n = 16) was 31.3% (n = 5), which included 1 intracranial complete response. Notably, 2 of 5 intracranial responders also had leptomeningeal disease at baseline, and 4 of the 5 did not receive prior CNS radiotherapy. The intracranial disease control rate (DCR) was 68.8%, and the median intracranial duration of response (DOR) was 8.1 months (95% CI, 3.1-not evaluable).

The systemic ORR in RECIST 1.1–evaluable patients (n = 29) was 27.6% (n = 8) and the DCR was 58.6%. The median DOR was 7.6 months (95% CI, 2.07-9.07).

“Zipalertinib demonstrated clinically meaningful intracranial antitumor activity…in patients with NSCLC harboring EGFR exon 20 insertions or other uncommon single or compound uncommon mutations,” Helena A. Yu, MD, attending physician at Memorial Sloan Kettering Cancer Center in New York, New York, stated in the presentation. “The intracranial response rate was similar to the systemic response rate in the reported population,” Yu added.

What Led to Zipalertinib’s Evaluation in the REZILENT2 Trial?

Poor prognosis is associated with the presence of CNS metastases in patients with EGFR-mutant NSCLC, reflecting a clinical need for more effective treatment options.

Zipalertinib is an oral, highly selective, irreversible EGFR TKI that has proven active in advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in the phase 1/2 REZILIENT1 trial (NCT04036682), including in patients with CNS metastases.²

To be eligible for enrollment in the subsequent REZILIENT2 trial, patients had to be at least 18 years of age and have received a diagnosis of locally advanced or metastatic NSCLC with documented exon 20 insertions or other uncommon single or compound non–EGFR exon 20 insertion mutations. Measurable disease per RECIST 1.1/CNS per RANO-BM criteria was also required, as was an ECOG performance status of 0 or 1.

Patients with active brain metastases had to be newly diagnosed and/or have progressing brain lesions without CNS targeted therapy and/or leptomeningeal disease. There was no limit on the number of prior therapies patients could have received in the advanced or metastatic setting.

Patients received 100 mg of oral zipalertinib twice daily until progressive disease or other discontinuation criteria were met. A total of 32 patients were enrolled, 16 of whom were evaluable by RANO-BM.

The data cutoff was February 17, 2025, and the study remains ongoing.

The primary end point was ORR per RECIST 1.1 criteria. Secondary end points included intracranial ORR, intracranial DOR, intracranial DCR per RANO-BM, and safety.

What Were the Baseline Characteristics of the Study Population?

Within the RANO-BM–evaluable population (n = 16), 62.5% had not received prior CNS radiotherapy. Among all enrolled patients (n = 32), 68.8% did not receive any prior CNS radiotherapy.

In the former population, the median age was 63.0 years (range, 23-75). Most patients were female (56%), White (63%), and had an ECOG performance status of 1 (63.0%). Almost one-fifth (19%) of patients had leptomeningeal disease. Most patients also had EGFR exon 20 insertion mutations (56%) as opposed to other EGFR mutations (44%). The median number of prior lines of systemic therapy was 2 (range, 0-4); 56% had received prior EGFR TKI therapy and 6% received prior amivantamab-vmjw (Rybrevant).

Within the total population, the median age was 62.5 years (range, 23-83). Most patients were female (56%), White (50%), and had an ECOG performance status of 1 (72.0%). Almost one-fifth (19%) of patients had leptomeningeal disease. Most patients also had EGFR exon 20 insertion mutations (66%) as opposed to other EGFR mutations (41%). The median number of prior lines of systemic therapy was 2 (range, 0-4); 44% had received prior EGFR TKI therapy and 6% received prior amivantamab-vmjw (Rybrevant).

How Safe Was the Agent?

Yu also noted that the safety profile of zipalertinib at the given dose of 100 mg twice daily was consistent with that from prior data. Yu emphasized the low incidence of EGFR-related grade 3 or greater toxicity, noting that there was no grade 3 or greater diarrhea. Moreover, 2 cases of fatal interstitial lung disease occurred.

Treatment-related adverse effects (TRAEs) that occurred in at least 15% of patients included paronychia (grade 1, 6.3%; grade 2, 15.6%; grade ≥3, 3.1%), dermatitis aceniform (grade 1, 9.4%; grade 2, 9.4%; grade ≥3, 3.1%), stomatitis (grade 1, 15.6%; grade 2, 6.3%; grade ≥3, 0%), anemia (grade 1, 9.4%; grade 2, 0%; grade ≥3, 9.4%), dry skin (grade 1, 6.3%; grade 2, 9.4%; grade ≥3, 0%), and rash (grade 1, 6.3%; grade 2, 6.3%; grade ≥3, 3.1%).

Dose interruptions due to TRAEs occurred in 15.6% of patients.

“The study is ongoing and full results from cohort C of the REZILENT2 trial will be forthcoming in a future presentation,” Yu concluded.

Disclosures: Yu reported consulting or advisory roles for AstraZeneca, Daiichi Sankyo, Blueprint Medicines, Janssen, C4 Therapeutics, Cullinan Oncology, Black Diamond Therapeutics, Taiho Oncology, AbbVie, Novocure, Takeda, Bristol Myers Squibb/Roche, Orion Clinical; research funding from AstraZeneca (Inst), Astellas Pharma (Inst), Lilly (Inst), Novartis (Inst), Pfizer (Inst), Daiichi Sankyo (Inst), Cullinan Oncology (Inst), Janssen Oncology (Inst), Erasca, Inc (Inst), Blueprint Medicines (Inst), Black Diamond Therapeutics (Inst), and Systimmune (Inst); and other relationship with Astellas Pharma.

References

1. Yu HA, Ohashi K, Ariyasu R, et al. Activity of zipalertinib against active central nervous system (CNS) metastases in patients with non-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion (ex20ins)/other uncommon mutations. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 1847MO.
2. Piotrowska Z, Passaro A, Nguyen D, et al. Zipalertinib in patients with Epidermal Growth Factor Receptor exon 20 insertion-positive non-small cell lung cancer previously treated with platinum-based chemotherapy with or without amivantamab. J Clin Oncol. 2025;43(21):2387-2397. doi:10.1200/JCO-25-00763

Disitamab vedotin plus toripalimab-tpzi (Loqtorzi) demonstrated a statistically significant improvement in survival compared with standard-of-care chemotherapy as a frontline treatment for patients with HER2-expressing locally advanced or metastatic urothelial carcinoma, according to results from the phase 3 RC48-C016 trial (NCT05302284) shared at the 2025 ESMO Congress.¹ Results were simultaneously published in the New England Journal of Medicine.²

With a median survival follow-up of 18.2 months and a data cutoff date of March 31, 2025, the median progression-free survival (PFS) per blinded independent review committee (BIRC) was 13.1 months (95% CI, 11.1-16.7) with the disitamab vedotin treatment compared with 6.5 months (95% CI, 5.7-7.4) with chemotherapy, representing a 64% reduction in the risk of progression or death (HR, 0.36; 95% CI, 0.28-0.46; P <.0001). The 12- and 18-month PFS rates with disitamab vedotin were 54.5% and 38.4%, respectively, vs 16.2% and 7.5% with chemotherapy.

The median overall survival (OS) was 31.5 months (95% CI, 21.7-not evaluable) in the disitamab vedotin arm compared with 16.9 months (95% CI, 14.6-21.7) in the chemotherapy arm, correlating with a 46% reduction in the risk of death (HR, 0.54; 95% CI, 0.41-0.73; P <.0001). The 12-, 18-, and 24-month OS rates in the disitamab vedotin arm were 79.5%, 64.6%, and 52.8%; in the chemotherapy arm, these rates were 62.5%, 48.1%, and 39.4%.

The PFS and OS benefits were consistent across all prespecified subgroups.

In the disitamab vedotin arm, the overall response rate (ORR) per BIRC was 76.1% (95% CI, 70.3%-81.3%), with complete responses (CRs) in 4.5% and partial responses (PRs) in 71.6% of patients; in the chemotherapy arm, the ORR was 50.2% (95% CI, 43.7%-56.7%), with CRs in 1.2% and PRs in 49.0%. The investigator-assessed ORR with disitamab vedotin was 71.6% (95% CI, 65.5%-77.2%), with CRs in 4.1% and PRs in 67.5% of patients compared with a 49.8% ORR (95% CI, 43.3%-56.3%) with chemotherapy, comprising of CRs in 3.3% and PRs in 46.5% of patients.

The median duration of response per BIRC was 14.6 months (95% CI, 11.3-18.7) with the disitamab vedotin combination compared with 5.6 months (95% CI, 5.3-5.8) with chemotherapy. In the disitamab vedotin arm, the 6-, 12-, and 18-month DOR rates were 78.9%, 58.5%, and 42.4%; in the chemotherapy arm, these rates were 37.2%, 19.0%, and 8.7%.

“The phase 3 RC48-C016 study demonstrated for the first time superiority of an anti-HER2 antibody-drug conjugate plus an anti-PD1 inhibitor in a biomarker-selected patient population with [locally advanced and metastatic urothelial cancer],” lead study author Jun Guo, of the Key Laboratory of Carcinogenesis and Translational Research in the Department of Melanoma and Sarcoma at Peking University Cancer Hospital and Institute in Beijing, China, said in the presentation. “Disitamab vedotin plus toripalimab offers a valuable new treatment option and represents a new standard of care for the [first-line] treatment of patients with HER2-expressing [locally advanced or metastatic urothelial cancer].”

The open-label RC48-CO16 trial randomly assigned 484 patients 1:1 to receive either disitamab vedotin plus toripalimab (n = 243) or gemcitabine plus cisplatin/carboplatin (n = 241). Treatment consisted of 2.0 mg/kg of intravenous disitamab vedotin and 3.0 mg/kg of toripalimab every 2 weeks, or gemcitabine at 1000 mg/m² on day 1 and day 8 and cisplatin at 70 mg/m² on day 1 or carboplatin at area under curve 4.5 on day 1 every 3 weeks. There was no maximum number of cycles set for the disitamab vedotin treatment, and the maximum number of chemotherapy cycles was 6.

Eligible patients in the trial had no prior systemic treatment for unresectable locally advanced or metastatic urothelial cancer and central lab-confirmed HER2 immunohistochemistry of 1+, 2+, or 3+; additionally, patients were eligible for cisplatin or carboplatin, had measurable disease per RECIST v1.1, and had an ECOG performance status of 0 or 1.

The primary end points were PFS per BIRC and OS. Secondary end points included PFS by investigators, ORR, DCR, DOR, safety, and quality of life.

Subsequent systemic anticancer treatment was received by 27.2% of patients on the disitamab vedotin arm and 64.7% of the chemotherapy arm; this comprised anti–HER2-containing therapy in 2.1% and 40.2%, respectively, PD-1/PD-L1 inhibitor therapy in 10.7% and 50.2%, and both in 0.8% and 31.1%.

Regarding safety, treatment-emergent adverse events (TEAEs) occurred in 100% of patients across both arms, and treatment-related AEs (TRAEs) occurred in 98.8% of patients on the disitamab vedotin arm and 100% of those on the chemotherapy arm. Grade 3 or higher TRAEs occurred in 55.1% and 86.9% of patients, respectively; grade 3, 4, and 5 TRAEs were observed in 44.0%, 9.9%, and 1.2% of those on the experimental arm vs 41.9%, 43.7%, and 1.4% of the chemotherapy arm. TRAEs led to treatment discontinuation in 12.3% vs 10.4%, respectively.

Any-grade and grade 3 or higher immune-related AEs occurred in 46.9% and 18.9% of the disitamab vedotin arm.

Disclosures: Guo noted having advisory board/consultant roles for MSD, Roche, Pfizer, Bayer, Novartis, Simcere, RemeGen, Shanghai Junshi Bioscience, and Oriengene.

References

1. Sheng X, Zeng G, Zhang C, et al. Disitamab vedotin (DV) plus toripalimab (T) versus chemotherapy (C) in first-line (1L) locally advanced or metastatic urothelial carcinoma (la/mUC) with HER2-expression. Presented at the 2025 European Society of Medical Oncology Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA7.
2. Sheng X, Zeng G, Zhang C, et al. Disitamab vedotin plus toripalimab in HER2-expressing advanced urothelial cancer. N Engl J Med. Published online October 19, 2025. doi:10.1056/NEJMoa2511648

Michiel van der Heijden, MD, PhD, medical oncologist at the Netherlands Cancer Institute in Amsterdam, presented the findings at the 2025 European Society for Medical Oncology Congress in Berlin, Germany.

At last year’s ESMO Congress in Barcelona, Spain, Thomas B. Powles, MBBS, MRCP, MD, presented findings from NIAGARA. The patient population consisted of adults with cisplatin-eligible MIBC (cT2-T4aN0/1M0), urothelial cancer or urothelial cancer with divergent differentiation or histologic subtypes, evaluated and confirmed for radical cystectomy, and with creatine clearance of 40 mL/min or lower. Patient were randomly assigned 1:1 to either the durvalumab arm or the comparator arm. Patients in the durvalumab arm received neoadjuvant durvalumab, 1500 mg intravenously every 3 weeks and gemcitabine plus cisplatin for 4 cycles followed by radical cystectomy and 8 cycles of adjuvant durvalumab. Patients in the comparator arm received 4 cycles of gemcitabine plus cisplatin for 4 cycles followed by radical cystectomy. The 2 primary end points were event-free survival (EFS) and pathological complete response. Regarding EFS, there was a significant reduction in risk (HR=0.68, 95% CI, 0.56-0.82). Median follow-up was 42.3 months (range 0.03-61.3 months).^2,3

Data from NIAGARA supported the FDA’s approval of neoadjuvant durvalumab in combination with gemcitabine and cisplatin, followed by adjuvant durvalumab monotherapy following radical cystectomy, for adult patients with muscle invasive bladder cancer.⁴

At ESMO 2025, van der Heijden presented HRQOL outcomes from the NIAGARA study. In NIAGARA, the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and EQ-5D-5L were assessed via electronic device at baseline and every 4 weeks until disease progression. van der Heijden explained that the EORTC QLQ-C30 measures global health scale (GHS)/QoL as well as functional and symptom subscales. GHS/QoL and Physical, Fatigue, and Pain were included in NIAGARA as prespecified priority subscales, with a 10-point change in score compared with baseline being deemed clinically meaningful.

The EQ-5D-5L visual analogue scale is constructed for patients to rate their current overall health; for NIAGARA, the investigators reported visual analogue scale change from baseline.

A total of 439 (82.4%) of patients in the durvalumab arm completed the baseline EORTC QLQ-C30 assessment vs 450 (84.9%) patients in the comparator arm. In addition, 416 (78.0%) patients in the durvalumab arm completed the baseline and at least 1 postbaseline assessment vs 410 (77.4%) of patients in the comparator arm. The compliance rate range from baseline to adjuvant week 29 was 50.9%-82.4% in the durvalumab arm vs 44.3%-84.9% in the comparator arm.

For the EQ-5D-5L, 417 (78.2%) patients completed the baseline assessment vs 430 (81.1%) patients in the comparator arm. Further, 391 (73.4%) patients in the durvalumab arm completed the baseline and at least 1 postbaseline assessment vs 380 (71.7%) patients in the comparator arm. The compliance rate range from baseline to adjuvant week 29 was 49.9%-78.2% in the durvalumab arm vs 43.2%-81.1% in the comparator arm.

For GHS/QoL, van der Heijden reported that that the difference between arms for overall mean change from baseline (CFB) was 1.6 (95% CI, –0.44 to 3.69), and with the Physical Functioning subscale, the difference between arms for overall CFB was 1.2 (95% CI, –0.80 to 3.17). For the Fatigue subscale, the difference between arms for overall CFB was –0.9 (95% CI, –3.25 to 1.52), and for the Pain subscale, the difference between arms for overall CFB was –2.1 (95% CI, –4.44 to 0.16).

The EQ-5D-5L visual analogue scale “also did not show any difference between the treatment arms,” according to van der Heijden.

“Overall, the addition of perioperative durvalumab to neoadjuvant chemotherapy significantly improved event-free survival and overall survival without adversely affecting patient-reported outcomes,” van der Heijden said in his concluding remarks.

References

1. van der Heijden M, Powles TB, Galsky MD, et al. Health-related quality of life (HRQOL) outcomes from the NIAGARA trial of perioperative durvalumab (D) plus neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC). Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract 3069MO.
2. Powles TB, van der Heijden MS, Galsky MD, et al. A randomized phase III trial of neoadjuvant durvalumab plus chemotherapy followed by radical cystectomy and adjuvant durvalumab in muscle-invasive bladder cancer (NIAGARA). Presented at: 2024 European Society for Medical Oncology Annual Congress. September 13-17, 2024. Barcelona, Spain. Abstract LBA5.
3. Powles T, Catto JWF, Galsky MD, et al. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. Published online September 15, 2024. Accessed October 17, 2025. https://www.nejm.org/doi/abs/10.1056/NEJMoa2408154
4. FDA approves durvalumab for muscle invasive bladder cancer. News release. US Food & Drug Administration. Published online March 28, 2025. Accessed October 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-muscle-invasive-bladder-cancer
5. IMFINZI (durvalumab) approved in the US as first and only perioperative immunotherapy for patients with muscle-invasive bladder cancer. News release. AstraZeneca. Published online March 31, 2025. Accessed October 17, 2025. https://www.astrazeneca-us.com/media/press-releases/2025/IMFINZI-durvalumab-approved-in-the-US-as-first-and-only-perioperative-immunotherapy-for-patients-with-muscle-invasive-bladder-cancer.html