Combination effect of inavolisib and FGFR inhibitors in FGFR2-expressing cell lines

FGFR2 controls HER3 to induce p85β binding and signaling in FGFR2 high-expressing cell lines

3004 Background: Delta-like ligand 3 (DLL3) is highly expressed in neuroendocrine carcinomas (NEC). Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager that targets DLL3-positive (DLL3+) tumors. NCT04429087 is an ongoing, Phase (Ph) I dose-escalation trial of obrixtamig in patients (pts) with DLL3+ pulmonary and extrapulmonary NEC (epNEC), who had failed to respond to standard treatment (Tx). This analysis examined the efficacy and safety of obrixtamig in pts with epNEC with high vs low DLL3 expression. Methods: Obrixtamig was given IV in 4 dose-escalation regimens (R): RA (fixed dose q3w); RB1 (fixed dose qw); RB2 (step-up dose, then qw) and RB3 (step-up dose, then qw for 3 weeks, then q3w), until disease progression or unacceptable toxicity. Efficacy was assessed through objective response rate (ORR) and disease control rate (DCR) using RECIST v1.1. Results are reported for pts who received obrixtamig RB2 or RB3, categorized as having high vs low DLL3, using a threshold of ≥50% of tumor cells stained with an investigational antibody for DLL3 (SP347, Roche Diagnostics). Results: As of June 21, 2024, 60 pts with epNEC were included (gastroenteropancreatic [GEP]: 45.0%, genitourinary [GU]: 30.0%, other/unknown primary site: 25.0%); 30 each DLL3-high and DLL3-low. Mean age: 63.9 years in DLL3-high; 59.1 in DLL3-low pts. Baseline characteristics were well-balanced across DLL3 groups. All pts had received prior systemic therapy; 30.0% of DLL3-high and 50.0% of DLL3-low pts had received > 2 lines of prior Tx. Efficacy data are shown in the Table. After obrixtamig Tx, pts with high DLL3 expression had greater ORR, DCR, and duration of response (DoR) than DLL3-low pts. Responses were seen most frequently amongst pts with DLL3-high GEP (50.0%) or GU (60.0%) epNECs. Seven DLL3-high pts are still receiving Tx. Most treatment-related AEs (TRAEs) were mild to moderate for both groups (Table). Conclusions: Analyses from this ongoing Ph I study show greater obrixtamig efficacy in patients with epNEC with high DLL3 expression compared with low DLL3 expression, with a manageable safety profile that is comparable across both groups. The ORR of 40.0% and median DoR of 7.9 months in heavily pretreated epNEC tumors with DLL3 high expression are encouraging, and support further development of obrixtamig for this subgroup. Clinical trial information: NCT04429087 . Efficacy/safety parameter DLL3-high (n=30) DLL3-low (n=30) ORR, % (95% CI) 40.0 (24.6–57.7) 3.3 (0.6–16.7) DCR, % (95% CI) 66.7 (48.8–80.8) 26.7 (14.2–44.4) Median DoR (95% CI), months 7.9 (6.2–NC) 2.8 (NC–NC) TRAEs, all G/G ≥3, (%) 100.0/23.3 90.0/20.0 Cytokine release syndrome, all G/G ≥3, (%) 70.0/3.3 60.0/3.3 Neurotoxicity, including immune effector cell-associated neurotoxicity syndrome*, all G/G ≥3, (%) 16.7/6.7 10.0/3.3 *Evaluated with a customised MedDRA query. CI, confidence interval; NC, not calculable.

Proposed mechanistic model of FGFR2-mediated inavolisib sensitivity

PURPOSE:PIK3CA mutations frequently drive solid tumors, particularly hormone receptor-positive breast cancer. Inavolisib, an ATP-competitive p110α inhibitor, also promotes the degradation of mutated p110α. PI3K inhibitors have generally shown modest single-agent activity and have safety concerns. PATIENTS AND METHODS:A first-in-human phase 1 study (NCT03006172) evaluated oral inavolisib in patients with PIK3CA-mutated solid tumors to determine the maximum tolerated dose and safety. Correlative analyses included ctDNA. Preclinical studies in cell lines and xenografts elucidated the role of FGFR2. RESULTS:The maximum tolerated dose was 9 mg daily, with a manageable safety profile (e.g., hyperglycemia and diarrhea). Inavolisib showed linear pharmacokinetics, consistent pharmacodynamic modulation, and antitumor activity in hormone receptor-positive PIK3CA-mutated breast cancer (26% objective response rate and 45% clinical benefit rate). FGFR2 hotspot mutations in ctDNA were strongly associated with clinical benefit. Preclinically, oncogenic FGFR2 signaling enhanced inavolisib sensitivity by engaging HER3, RAS, and p85β, that facilitated mutated p110α degradation, surpassing nondegrading inhibitors. Combination therapy with FGFR2 inhibitors showed synergy and delayed resistance. CONCLUSIONS:These findings highlight a novel cooperativity between FGFR2 and p110α that boosts the effectiveness of inavolisib. The data support advancing precision oncology beyond single biomarkers to complex algorithms utilizing co-occurring alterations, suggesting that combining inavolisib with FGFR2 inhibitors may offer enhanced and more durable responses in PIK3CA/FGFR2-altered tumors.

Representativeness of study participants

Evaluation of the anti-tumor activity of FGFR2 inhibitor in combination with inavolisib in MFM223x2.2 xenograft model

Effects of FGFR1/2/3/4 knockdown on inavolisib sensitivity

2642 Background: Specific DLL3 expression on the surface of epNEC tumor cells makes it a promising therapeutic target, but there is a lack of prospective data on DLL3 expression patterns in pts with epNEC. Obrixtamig (BI 764532) is a DLL3/CD3 IgG-like T-cell engager. The first-in-human phase I trial (NCT04429087) showed obrixtamig activity in pts with DLL3-positive epNEC, especially pts with DLL3-high tumors (Capdevila et al, ASCO 2025, #3004). We report updated DLL3 expression data and pt/tumor characteristics in pts with epNEC from NCT04429087. Methods: DLL3 IHC was performed with an investigational DLL3 antibody (SP347) at the Roche CDx CAP/CLIA Laboratory. DLL3 expression was categorized as: negative (absent or weak tumor cell [TC] membrane/cytoplasm staining), positive (moderate-to-strong staining in any TCs), high (≥50% moderate-to-strong TC staining), or low (<50% moderate-to-strong TC staining). Results: As of Sept 4, 2025, 282 of 365 screened pts with epNEC were DLL3-evaluable, of whom 235 (83.3%) had DLL3-positive tumors (DLL3-high: n=120 [42.6%], DLL3-low: n=115 [40.8%]); 47 (16.7%) were DLL3-negative. In the DLL3-positive treated set (n=93), 51 pts (54.8%) had DLL3-high and 42 (45.2%) had DLL3-low tumors. The prevalence of DLL3-high tumors in male/female pts was 47.5%/68.8%, and prevalence in pts with liver/brain metastases was 57.1%/70.0%. DLL3-high prevalence by primary tumor site, GI/GU/cancer of unknown primary site (CUP), was 44.9%/67.7%/60.0%. Pt characteristics in obrixtamig-treated DLL3-high and -low epNEC subgroups are in Table 1. Conclusions: In the largest prospectively screened cohort of pts with epNEC, high (83.3%) prevalence of DLL3 expression was seen, underscoring DLL3 as a promising target for clinical development of DLL3-targeted therapies such as obrixtamig. Obrixtamig safety and efficacy in pts with DLL3-positive epNEC are being assessed in several ongoing trials, including DAREON-5 (NCT05882058), with the data expected to inform and support Phase III development. Clinical trial information: NCT04429087 . DLL3-high (n=51) DLL3-low (n=42) Male / female, n (%) 29 (56.9) / 22 (43.1) 32 (76.2) / 10 (23.8) Primary tumor site: GI / GU / CUP, n (%) 22 (43.1) / 21 (41.2) / 6 (11.8) 27 (64.3) / 10 (23.8) / 4 (9.5) Lactate dehydrogenase ≤ULN / >ULN, n (%) 22 (43.1) / 29 (56.9) 16 (38.1) / 26 (61.9) Prior lines of therapy: 1 / 2 / 3 / >3 12 (23.5) / 17 (33.3) / 9 (17.6) / 13 (25.5) 11 (26.2) / 12 (28.6) / 10 (23.8) / 9 (21.4) Median duration of prior anticancer treatment, weeks (range) 22 (5–349) 22 (8–148) Prior radiotherapy / surgery / anti PD-(L)1, n (%) 22 (43.1) / 28 (54.9) / 14 (27.5) 11 (26.2) / 24 (57.1) / 9 (21.4) Liver / brain metastases, n (%) 40 (78.4) / 7 (13.7) 30 (71.4) / 3 (7.1) Median sum of diameters of target lesions, mm (IQR) 87.5 (64.0–123.0) 117.3 (66.2–176.0)

Effects of inavolisib and FGFR2 inhibition on downstream signaling in FGFR2-high and FGFR2-low expressing cell lines

Study NCT03006172 Arm A participants whose liquid biopsies harbored an FGFR2 mutation

BACKGROUND:This first-in-human clinical study explored lomvastomig, an immunoglobulin G1-based Fc-silenced bispecific antibody that simultaneously blocks the immune checkpoint receptors programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain-3. METHODS:Lomvastomig was characterized in cell cultures and preclinically in cancer mouse models. The phase 1, open-label, multicenter clinical study of lomvastomig included a dose-escalation part in patients with advanced and/or metastatic solid tumors and an expansion part with four tumor-specific cohorts, which enrolled checkpoint inhibitor (CPI)-experienced patients with melanoma and non-small-cell lung cancer (NSCLC) and CPI-naïve patients with SCLC and esophageal squamous cell carcinoma (ESCC). Primary and secondary objectives included safety/tolerability, maximum tolerated dose (MTD)/recommended dose for expansion (RDE), pharmacokinetics, drug receptor occupancy, and antitumor activity. RESULTS:39 and 95 patients were enrolled in the dose-escalation and expansion parts, respectively. Lomvastomig was well tolerated up to the highest tested dose of 2,100 mg every 2 weeks (Q2W). One dose-limiting toxicity was reported at 1,200 mg (grade 3 troponin T increase). No MTD was reached, and 2,100 mg Q2W was established as the RDE. Linear pharmacokinetics across the studied dose range suggested target saturation. Peripheral blood drug receptor occupancy on CD3+ and CD8+ was saturated at >90% throughout treatment for doses ≥70 mg. Objective responses were observed at 2,100 mg lomvastomig during dose-escalation (21%; n=19), and in the CPI-experienced melanoma (8%, n=38) and CPI-naïve ESCC (20%, n=15) expansion cohorts. CONCLUSIONS:Lomvastomig had a tolerable and manageable safety profile at 2,100 mg Q2W. Clinical activity was limited in CPI-experienced patients with melanoma and NSCLC, while an encouraging signal was observed in CPI-naïve patients with ESCC. TRIAL REGISTRATION NUMBER:NCT03708328 (registration date: 2018-10-09).

Abstract 5T4, a Type I transmembrane glycoprotein, has limited expression in normal adult tissues but is over expressed in a broad spectrum of solid tumors. It modulates the CXCR4 and WNT signaling pathways contributing to epithelial to mesenchymal transition and correlates with poorer clinical outcomes among a range of cancers, such as NSCLC, CRC and ovarian. JK06 is a tetravalent, biparatopic DAR2 MMAE ADC targeting 5T4, providing picomolar affinity & enhanced internalization to compensate for generally lower 5T4 expression levels and poor intrinsic internalization kinetics. Patients with advanced relapsed/refractory solid tumors, unselected for 5T4 expression, receive intravenous JK06 monotherapy once every 3 weeks. Dose escalation has been completed, and the study is currently enrolling multiple tumor-specific cohort expansions with randomization across two dose levels to identify RP2D in NSCLC and breast cancer. Fresh and archival tumor biopsies are collected for retrospective correlation of 5T4 expression to efficacy and safety. Responses are assessed every 9 weeks per RECIST v1.1. Exploratory evaluations of changes in quality of life after JK06 treatment are included in cohort expansions. To date, sixty-nine (69) refractory metastatic solid tumor patients (n = 38 in dose escalation; n = 31 in cohort expansions) have been treated, median age of 61.5 years and > 74% of treated patients have had ≥ 3 prior lines of therapy. Treatment has been well-tolerated with predominantly low-grade treatment-related adverse events (TRAEs) (Gr 1 & 2), such as fatigue (30%), alopecia (16%), decreased appetite (10%), dry eye (10%) and peripheral sensory neuropathy (PSN) (10%). At the target doses being considered for optimization, four patients (out of 62 treated patients) have sustained JK06-related Gr 3 adverse events (AEs): fatigue, malaise, keratitis and PSN, that resolved, with one able to continue treatment with dose reduction; no Gr 4 JK06-related AEs have been observed to date. Three patients underwent dose reductions, and three additional patients were discontinued due to TRAEs. One patient sustained Gr 5 treatment-related pneumonitis at a higher dose that is not being evaluated in cohort expansion. Among 13 response-evaluable NSCLC patients in dose escalation, a 38% ORR has been observed, with 1 confirmed complete response (cCR) and 4 confirmed partial responses (cPR) (one with CNS response), with the longest continuing therapy for 51 weeks. One of six evaluable breast cancer patients (17% ORR) achieved a cPR and remained on treatment for > 27 weeks. To date, JK06 demonstrates promising clinical activity among refractory NSCLC and breast cancer at multiple dose levels while being well tolerated without significant drug-related toxicities. Updated dose escalation data and initial expansion cohort data will be presented. Citation Format: Omar Saavedra, Fabricio Racca, Valentina Boni, Emiliano Calvo, Brant Delafontaine, Sylvie Rottey, Bernd Dekeyser, Hans Prenen, Maria deMiguel, Valentina Gambardella, Lionel d'Hondt, Vladimir Galvao, Judit W. Johnson, Jonathan P. McNally, Jennifer Lindelien, Alice Drumheller, Jijun Dong, Samuel P. Murphy, Shalabh Singhal, Naimish Pandya, Nuria Kotecki. A phase 1b / 2 study of JK06, a 5T4-targeted antibody drug conjugate, in patients with unresectable locally advanced or metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT250.

2587 Background: Sunekafusp alpha (ANV600) is a novel PD-1-targeted, IL- 2Rβ/γ agonist, which binds, without blocking, a unique epitope distinct from pembrolizumab, or other PD-1 checkpoint inhibitors. Methods: In this phase 1 study, safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of increasing doses of ANV600 administered intravenously in two different dosing regimen were investigated in patients with advanced solid tumors as monotherapy and in combination with pembrolizumab. A Bayesian Optimal Interval design guided the dose escalation to determine the MTD and RP2D. Results: 63 patients were treated: 44 in monotherapy at 10 to 150 μg/kg ANV600 and 19 in combination therapy at 30 to 90 μg/kg ANV600. The median (range) number of previous lines of treatment was 4 (1-16) in monotherapy and 4 (2-10) in combination therapy. In mono- and combination therapy 27 (61%) and 9 (47%) patients were previously treated with a checkpoint inhibitor (CPI). ANV600 was generally well tolerated. Most common treatment related adverse events were pyrexia, transient and self-limiting transaminase elevations, and low-grade (≤G2) cytokine release syndrome. No treatment-related death was reported. The recommended phase 2 dose of ANV600 was determined to be 90 μg/kg Q1W as starting dose for 4 weeks followed by 150 µg/kg Q2W as maintenance dose. Selective targeting of PD-1-expressing cells was demonstrated, with preferential induction of proliferation of PD-1⁺ CD8⁺ T cells compared to PD-1⁻ CD8⁺ T cells. In the monotherapy setting, 12 patients (32%) experienced target lesion shrinkage; 4 of these (33%) were CPI treatment-naïve. Disease control was observed in 16 patients (42%). Clinical benefit was in general long lasting. A complete response was confirmed in 1 patient with bronchial adenocarcinoma, starting at 6 months after initiation of monotherapy treatment and still ongoing after 9 months of treatment. The patient was previously progressing under 1 st line anti-PD-L1 therapy and 2 nd line chemotherapy with carboplatin and paclitaxel. Similarly, in the combination therapy setting, 4 patients (24%) experienced target lesion shrinkage; 2 of these (50%) were CPI treatment-naïve. Disease control was observed in 10 patients (59%). Conclusions: ANV600 as monotherapy and in combination with pembrolizumab showed a favorable safety profile. Highly promising efficacy signals with one ongoing complete response, several long-lasting partial responses and stable diseases were reported in CPI-naïve and CPI pre-treated patients, including CPI-resistant tumors. Clinical trial information: NCT06470763 .

Abstract Background: Brain metastasis (BM) is prevalent in extensive-stage small-cell lung cancer (ES-SCLC) and also a common cause for treatment failure. BM remains as an unmet need with limited treatment options available such as palliative radiotherapy. ZL-1310 is a novel antibody-drug conjugate (ADC) that employs the TMALIN® (Tumor Microenvironment Activable LINker-payload) platform, an anti-DLL3 monoclonal antibody linked to a topoisomerase I inhibitor payload via a protease-cleavable linker. ZL-1310 has demonstrated encouraging systemic efficacy in heavily pre-treated ES-SCLC. We report the initial intracranial efficacy of ZL-1310 from a phase 1 study. Methods: This multi-country Phase 1 study (NCT06179069) enrolled adults with ES-SCLC who have progressed following ≥1 platinum-based chemotherapy. Those with stable or asymptomatic BM are eligible (including those with no prior brain radiotherapy). ZL-1310 is given intravenously every 3 weeks until disease progression or unacceptable toxicity. Systemic efficacy was assessed by investigators using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Intracranial efficacy was assessed by blinded independent radiologists using Modified Criteria for Radiographic Response Assessment in NeuroOncology (mRANO). Results: As of 1 Aug 2025, 104 pts received ZL-1310 across 6 dose levels (0.8-2.8 mg/kg). The median age was 65 years (range: 36, 80); 42.3% of pts were female, and 28.8% were Asian. Fifty-four (51.9%) had 1 prior line and the remaining 50 (48.1%) had 2 or more lines of prior therapies. A total of 94 (90.4%) received a prior anti-PDL1, 13 (12.5%) had prior lurbinectedin, and 10 (9.6%) had prior DLL3-targeted therapy. Brain metastases were present in 33 (31.7%) pts (including 11 pts with untreated BM) at baseline. Independently reviewed intracranial efficacy results were available for 24 pts, including 15 pretreated with radiation and 9 untreated. Confirmed intracranial response was 58.3% (14/24, 95% CI: 36.6, 77.9%), including 5 CR and 9 PR. The intracranial response rate in pts without prior brain radiation was 66.7% (6/9) and 53.3% (8/15) in pts with prior brain radiation. Intracranial disease control rate was 95.8% (23/24). The median time to onset of intracranial response was 5.6 weeks (min 5.1, max 8.7 weeks). Of the 33 pts with BM and systemic efficacy evaluable, confirmed ORR was 61%, including 1 confirmed CR. Grade ≥3 treatment-related adverse events were reported for 22/104 (21.2%) pts overall and 5/39 (12.8%) pts in the 1.6 mg/kg dose level; those reported in ≥2 pts at the 1.6 mg/kg dose level included anemia and neutropenia (2 pts each). Independent mRANO evaluation is ongoing and updated data will be provided. Conclusions: ZL-1310 is well tolerated and demonstrated encouraging systemic efficacy in heavily pretreated ES-SCLC with BM. The preliminary independent assessment also showed ZL-1310 has high intracranial efficacy including in patients with untreated BM. Citation Format: Pedro Rocha, Manish Patel, Yi-Long Wu, Jun Zhao, Grace Dy, María Eugenia Olmedo García, Qiming Wang, Valentina Gambardella, Oscar Juan-Vidal, Afshin Dowlati, David Vicente Baz, Alexander Spira, Anne C. Chiang, Yingying Du, Martin Gutierrez, Xiaorong Dong, Jie Hu, Mariam Alexander, Haiyong Wang, Wenxiu Yao, Liza Villaruz, Zhen Wang, Pingkuan Zhang, Renke Zhou, Xiao Wang, Luis Paz-Ares. Intracranial activity of ZL-1310, a DLL3-targeted ADC, in patients with previously treated extensive-stage small cell lung cancer and baseline brain metastasis: Analysis of a phase 1 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT193.

3038 Background: 5T4, a Type I transmembrane glycoprotein, is over expressed in a broad spectrum of solid tumors. It modulates the CXCR4 & WNT signaling pathways contributing to epithelial to mesenchymal transition contributing to metastatic progression & correlates with poor clinical outcomes among a range of cancers, such as NSCLC, CRC & ovarian. JK06 is a tetravalent, biparatopic DAR2 MMAE ADC targeting 5T4, providing picomolar affinity & enhanced internalization to compensate for generally lower 5T4 expression levels & poor intrinsic internalization kinetics. Methods: Pts with advanced relapsed/refractory solid tumors, unselected for 5T4 expression, receive IV JK06 monotherapy once every 3 wks. Dose escalation has been completed, and the study is currently enrolling multiple tumor-specific cohort expansions with randomization across two doses of JK06 to identify an RP2D in NSCLC & breast cancer. Fresh & archival tumor biopsies are being collected for retrospective correlation of 5T4 expression to efficacy & safety. Responses are assessed every 9 wks per RECIST v1.1. Exploratory evaluations of changes in quality of life after JK06 treatment are included in cohort expansions. Results: To date, 80 refractory metastatic solid tumor pts (n = 39 in dose esc; n = 41 in cohort expansions) have been treated, median age of 60 yrs, >70% treated with ≥ 3 prior lines of therapy, including >75% of treated pts with prior taxane exposure. Treatment has been well-tolerated with predominantly low-grade treatment-related adverse events (TRAEs) (Gr 1 & 2), such as fatigue (35%), alopecia (18%), decreased appetite (18%), dry eye (10%) & peripheral sensory neuropathy (PSN) (9%). Among 70 pts have sustained JK06-related Gr 3 adverse events (AEs): fatigue, malaise, gait disturbance, keratitis, vomiting, corneal ulcer, & PSN, that resolved, with two continuing treatment with dose reduction; no Gr 4 JK06-related AEs have been observed to date. Four pts underwent dose reductions, and five additional pts were discontinued due to TRAEs. Among 19 response-evaluable NSCLC pts to date, a 32% ORR has been observed, with 1 confirmed complete response (cCR), 4 confirmed partial responses (cPR) (one with CNS response) & 1 with unconfirmed partial responses (uPR), with the longest continuing therapy for 51 wks. Responses have been observed in adenomatous, squamous & EGFR mutant NSCLC pts. One of seven evaluable breast cancer pts (14% ORR) achieved a cPR and remained on treatment for >27 wks. Conclusions: To date, JK06 demonstrates promising emerging clinical activity in refractory NSCLC & breast cancer at multiple dose levels while being well tolerated without significant drug-related toxicities. Updated safety & clinical activity data from both dose escalation & expansion cohorts, including the initial assessment of dose randomization, will be presented. Clinical trial information: NCT06667960 .