Leap Therapeutics Reports Initial Clinical Data from Part B of the DeFianCe Study and Part C of the DisTinGuish Study
Leap Therapeutics (LPTX) has reported initial data from two clinical studies. In the DeFianCe study Part B, sirexatamab combination therapy showed a 35% objective response rate in second-line colorectal cancer patients, compared to 23% in the control arm. The drug demonstrated particularly strong results in patients with high DKK1 levels, achieving a 48% response rate in the upper quartile.
Key subgroups showed promising results: 51% response rate in anti-VEGF therapy-naive patients, 54% response rate in prior anti-EGFR therapy patients, and 43% response rate in RAS wildtype tumors. The company plans to proceed with Phase 3 registrational studies in second-line colorectal cancer.
However, in the DisTinGuish Part C study for gastric cancer, despite showing activity in biomarker populations, the results did not generate sufficient signals to advance to Phase 3 trials in gastric cancer.
Leap Therapeutics (LPTX) ha riportato dati iniziali da due studi clinici. Nel secondo studio DeFianCe Parte B, la terapia combinata con sirexatamab ha mostrato un 35% di tasso di risposta obiettiva nei pazienti con cancro colorettale in seconda linea, rispetto al 23% nel gruppo di controllo. Il farmaco ha dimostrato risultati particolarmente forti nei pazienti con alti livelli di DKK1, raggiungendo un 48% di tasso di risposta nel quartile superiore.
I gruppi chiave hanno mostrato risultati promettenti: 51% di tasso di risposta nei pazienti naive alla terapia anti-VEGF, 54% di tasso di risposta nei pazienti con precedenti terapie anti-EGFR, e 43% di tasso di risposta nei tumori con wildtype RAS. L'azienda ha in programma di procedere con studi registrativi di Fase 3 per il cancro colorettale in seconda linea.
Tuttavia, nello studio DisTinGuish Parte C per il cancro gastrico, nonostante abbia mostrato attività in popolazioni con biomarcatori, i risultati non hanno generato segnali sufficienti per procedere verso le sperimentazioni di Fase 3 nel cancro gastrico.
Leap Therapeutics (LPTX) ha reportado datos iniciales de dos estudios clínicos. En el estudio DeFianCe Parte B, la terapia combinada con sirexatamab mostró una tasa de respuesta objetiva del 35% en pacientes con cáncer colorrectal en segunda línea, en comparación con el 23% en el grupo de control. El fármaco demostró resultados particularmente fuertes en pacientes con altos niveles de DKK1, alcanzando una tasa de respuesta del 48% en el cuartil superior.
Los subgrupos clave mostraron resultados prometedores: tasa de respuesta del 51% en pacientes naive a la terapia anti-VEGF, tasa de respuesta del 54% en pacientes que recibieron terapia anti-EGFR previamente, y tasa de respuesta del 43% en tumores con tipo silvestre RAS. La compañía planea avanzar con estudios registrativos de Fase 3 en cáncer colorrectal en segunda línea.
Sin embargo, en el estudio DisTinGuish Parte C para el cáncer gástrico, a pesar de mostrar actividad en poblaciones biomarcadoras, los resultados no generaron señales suficientes para avanzar a ensayos de Fase 3 en cáncer gástrico.
Leap Therapeutics (LPTX)는 두 개의 임상 연구에서 초기 데이터를 보고했습니다. DeFianCe 연구의 B 부분에서, sirexatamab 결합 요법은 2차 결장암 환자에서 35%의 객관적 반응률을 보였으며, 대조군에서는 23%였습니다. 이 약물은 DKK1 수치가 높은 환자들에서 특히 강력한 결과를 보여주었으며, 상위 사분면에서 48%의 반응률을 달성했습니다.
핵심 하위 그룹에서도 유망한 결과가 나타났습니다: VEGF 억제제 요법에 나이가 없는 환자에서 51%의 반응률, 이전의 EGFR 억제제 요법을 받은 환자에서 54%의 반응률, 그리고 RAS 야생형 종양에서 43%의 반응률이 나타났습니다. 이 회사는 2차 결장암에 대한 3상 등록 연구를 진행할 계획입니다.
하지만 위암을 위한 DisTinGuish C 부분 연구에서는 바이오마커 집단에서 활성을 보였음에도 불구하고, 위암에 대한 3상 시험으로 진행할 충분한 신호를 생성하지 못했습니다.
Leap Therapeutics (LPTX) a rapporté des données initiales de deux études cliniques. Dans l'étude DeFianCe Partie B, la thérapie combinée avec le sirexatamab a montré un taux de réponse objective de 35% chez les patients atteints de cancer colorectal en deuxième ligne, contre 23% dans le bras de contrôle. Le médicament a montré des résultats particulièrement forts chez les patients ayant des niveaux élevés de DKK1, atteignant un taux de réponse de 48% dans le quartile supérieur.
Les sous-groupes clés ont montré des résultats prometteurs : taux de réponse de 51% chez les patients naïfs vis-à-vis de la thérapie anti-VEGF, taux de réponse de 54% chez les patients ayant déjà reçu une thérapie anti-EGFR, et taux de réponse de 43% chez les tumeurs de type sauvage RAS. L'entreprise prévoit de poursuivre avec des études d'enregistrement de Phase 3 dans le cancer colorectal en deuxième ligne.
Cependant, dans l'étude DisTinGuish Partie C pour le cancer de l'estomac, malgré une activité observée dans des populations biomarqueurs, les résultats n'ont pas généré de signaux suffisants pour avancer vers des essais de Phase 3 dans le cancer de l'estomac.
Leap Therapeutics (LPTX) hat erste Daten aus zwei klinischen Studien veröffentlicht. In der DeFianCe-Studie Teil B zeigte die Kombinationstherapie mit sirexatamab eine 35%ige objektive Ansprechrate bei Patienten mit kolorektalem Krebs in der zweiten Linie, im Vergleich zu 23% in der Kontrollgruppe. Das Medikament erzielte besonders starke Ergebnisse bei Patienten mit hohen DKK1-Leveln, mit einer Antwortquote von 48% im obersten Quartil.
Wichtige Untergruppen zeigten vielversprechende Ergebnisse: eine 51%ige Ansprechrate bei Patienten, die naive gegenüber Antibody-VEGF-Therapien sind, eine 54%ige Ansprechrate bei Patienten nach vorheriger Antibody-EGFR-Therapie und eine 43%ige Ansprechrate bei RAS Wildtyp-Tumoren. Das Unternehmen plant, mit Phase-3-Registrierungsstudien bei kolorektalem Krebs in der zweiten Linie fortzufahren.
Im Gegensatz dazu zeigte die DisTinGuish-Studie Teil C für Magenkrebs trotz der Aktivität in Biomarker-Populationen keine ausreichenden Signale, um in Phase-3-Studien für Magenkrebs voranzuschreiten.
- 35% objective response rate in colorectal cancer vs 23% in control arm
- 48% response rate in patients with high DKK1 levels vs 11% in control
- Strong subgroup performance: 51% in anti-VEGF naive, 54% in prior anti-EGFR therapy
- Favorable safety profile with no additive toxicity
- Advancing to Phase 3 registrational trials for colorectal cancer
- DisTinGuish Part C study failed to meet primary endpoints in gastric cancer
- Discontinuation of gastric cancer program advancement to Phase 3
- High level of discordance between investigator assessment and BICR in gastric cancer study
Insights
The latest data from Leap Therapeutics' DeFianCe study represents a significant advancement in second-line colorectal cancer treatment. The 35% objective response rate with sirexatamab combination therapy, compared to 23% in the control arm, demonstrates meaningful clinical benefit. What's particularly compelling is the biomarker-driven approach, with DKK1-high patients showing an impressive 48% ORR in the upper quartile.
The subgroup analyses reveal several potential paths to market:
- Anti-VEGF naïve patients: 51% ORR vs 29% control
- Prior anti-EGFR therapy: 54% ORR vs 27% control
- RAS wildtype tumors: 43% ORR vs 32% control
The DKK1 biomarker strategy is particularly noteworthy as it could enable a precision medicine approach, potentially leading to higher approval chances and better reimbursement prospects. The safety profile, showing no additive toxicity to standard of care, is important for positioning in the second-line setting.
However, the negative outcome in the DisTinGuish gastric cancer study, despite some biomarker-positive signals, suggests a strategic pivot is necessary. This actually strengthens the company's position by allowing focused resource allocation to the more promising CRC program.
The imminent Phase 3 program in CRC represents a critical value inflection point. The multiple potential patient populations identified provide strategic optionality for the registration pathway, though the biomarker-selected approach may offer the most compelling risk-adjusted opportunity.
ORR benefit with sirexatamab observed across multiple potential Phase
Preparations will begin for a registrational Phase 3 study in second-line CRC patients
DisTinGuish Part C study in gastric cancer demonstrates activity in biomarker populations, but not the signal necessary to advance into Phase 3
Leap to host a conference call to present clinical data today, January 28, 2025, at 8:00 a.m. ET
Key Findings from Part B of the DeFianCe study:
"Data from Part B of the DeFianCe study closely mirror the findings from Part A, and together they demonstrate the potential of sirexatamab to provide a compelling treatment option for second-line CRC patients who do not benefit from current standard of care," said Cynthia Sirard, M.D., Chief Medical Officer of Leap. "Along with consistently achieving higher response rates than the control arm, the data also point to a favorable safety profile. While not yet fully mature, we are encouraged by the progression-free survival data thus far across key subgroups in the study. We look forward to reporting additional data from Part B as it matures over the coming months and beginning our planning for Phase 3 registrational studies."
"The patient population in second-line CRC is heterogeneous, and there is a true unmet need for new treatment options that are safe and effective. The latest findings from DeFianCe Part B are highly encouraging, as sirexatamab combination therapy is outperforming bevacizumab and chemotherapy alone in ORR in the intent-to-treat analysis and across key subgroups of interest," said Zev Wainberg, M.D., Professor of Medicine and Co-Director of the GI Oncology Program at UCLA. "Initial results also show increased response rates in patients with high
The DeFianCe study (NCT05480306) is a Phase 2, open-label, global study of sirexatamab in combination with bevacizumab and chemotherapy in patients with advanced microsatellite stable (MSS) CRC who have received one prior systemic therapy for advanced disease. Part B of the study is a 188 patient randomized controlled trial, with the primary objective being progression-free survival (PFS) in patients with left-sided cancers and in all patients. Key secondary and exploratory objectives include objective response rate (ORR), duration of response, and overall survival across tumor, treatment, and biomarker subgroups.
- Across the intent-to-treat (ITT) population with second-line MSS CRC (n=188):
- Patients treated with sirexatamab plus bevacizumab and chemotherapy (Experimental Arm, n=94) had ORR of
35% and disease control rate (DCR) of86% , compared to an ORR of23% and DCR of84% in patients treated with bevacizumab and chemotherapy alone (Control Arm, n=94)
- Patients treated with sirexatamab plus bevacizumab and chemotherapy (Experimental Arm, n=94) had ORR of
- Across the population with left-sided primary tumors (n=144):
- Patients treated in the Experimental Arm (n=71) had an ORR of
38% , compared to an ORR of25% in the Control Arm (n=73)
- Patients treated in the Experimental Arm (n=71) had an ORR of
- Plasma
DKK1 highly correlated with clinical activity:- Patients in the Experimental Arm with
DKK1 levels above the median (n=49) had an ORR of39% , compared to22% ORR in the Control Arm (n=36) - Patients in the upper-quartile of
DKK1 levels in the Experimental Arm (n=25) had an ORR of48% , compared to11% ORR in the Control arm (n=18)
- Patients in the Experimental Arm with
- Key patient subgroups demonstrated higher ORR in the Experimental Arm:
- No prior anti-VEGF therapy: Patients in the Experimental Arm (n=49) had an ORR of
51% , compared to29% ORR in the Control Arm (n=45) - Prior anti-EGFR therapy: Patients in the Experimental Arm (n=28) had an ORR of
54% , compared to27% ORR in the Control Arm (n=22) - RAS wildtype (RAS-wt) tumors: Patients in the Experimental Arm (n=35) had an ORR of
43% , compared to32% ORR in the Control Arm (n=25)
- No prior anti-VEGF therapy: Patients in the Experimental Arm (n=49) had an ORR of
- With only 3 months follow-up on the final patients enrolled and mean duration on study of approximately 6 months, PFS is not yet mature. Eighty-two patients are still on study, 46 in the Experimental Arm and 36 in the Control Arm. Early separation in the Kaplan-Meier PFS curves is being seen in many of the key patient subgroups, including
DKK1 biomarker, anti-VEGF-naïve, anti-EGFR-experienced, and RAS-wt patients. Leap expects to report additional data as it matures in 2025. - Sirexatamab plus bevacizumab and chemotherapy was well-tolerated, without additive toxicity to the standard of care.
The strong signal in CRC from the DeFianCe study supports Leap moving forward to plan a registrational Phase 3 clinical trial to evaluate sirexatamab plus bevacizumab and chemotherapy in second-line MSS CRC patients with high unmet need, subject to regulatory discussions. Potential Phase 3 patient populations include:
Key Findings from Part C of the DisTinGuish study:
Leap also reported data from Part C of the DisTinGuish study evaluating sirexatamab in combination with tislelizumab, BeiGene's anti-PD-1 antibody, and chemotherapy in first-line patients with advanced GEJ and gastric cancer. While demonstrating activity in biomarker populations, the study did not generate a clear positive signal and will be negative on the primary PFS endpoints when the study completes, resulting in the decision not to move forward with Phase 3 studies in gastric cancer.
"Sirexatamab plus tislelizumab and chemotherapy demonstrated improved confirmed response rates compared to the control arm in the ITT,
Part C of the DisTinGuish study (NCT0436380) is a Phase 2, randomized, open-label, multicenter study of sirexatamab in combination with tislelizumab and chemotherapy in first-line patients with advanced GEJ and gastric cancer. Part C enrolled 170 first-line, HER2-negative patients. Patients were randomized 1:1 to evaluate sirexatamab in combination with tislelizumab and chemotherapy, compared to tislelizumab and chemotherapy alone. The primary objective is PFS by IA in all patients and in
- Across the ITT population (n=170), patients treated with sirexatamab plus tislelizumab and chemotherapy (Experimental Arm, n=85) had a confirmed ORR of
52% by both IA and BICR, while patients treated with tislelizumab and chemotherapy alone (Control Arm, n=85) had a confirmed ORR of56% by IA and42% by BICR. - Based on BICR:
- Patients in the Experimental Arm with
DKK1 -high tumors (n=22) had a confirmed ORR of59% , compared to36% in the Control Arm (n=22) - Patients in the Experimental Arm with PD-L1-negative tumors (n=18) had a confirmed ORR of
44% , compared to32% in the Control Arm (n=19)
- Patients in the Experimental Arm with
- In the ITT population, preliminary median PFS in the Experimental Arm was 9.72 months by BICR and 7.66 months by IA compared to 11.99 months by BICR and 10.41 months by IA in the Control Arm. The median PFS for tislelizumab plus chemotherapy in the Phase 3 Rationale-305 study was 6.9 months (
95% CI: 5.7, 7.2). - In the
DKK1 -high population, preliminary median PFS in the Experimental Arm was 7.72 months by BICR and 7.43 months by IA compared to 7.79 months by BICR and 11.14 months by IA in the Control Arm. The hazard ratio for PFS by BICR was 0.68, representing a trend in favor of the Experimental Arm in the overall time to event analysis. - Sirexatamab plus tislelizumab and chemotherapy was well tolerated, without additive toxicity to the standard of care.
Conference Call:
Leap's management team will host a conference call today, January 28, 2025 at 8:00 a.m. Eastern Time to further discuss the data. The conference call will be broadcast live in listen-only mode and can be accessed via the webcast URL: https://edge.media-server.com/mmc/p/t93pn2ke. A replay of the event will be available for a limited time on the Investors page of the Company's website at https://investors.leaptx.com/.
About Leap Therapeutics
Leap Therapeutics (Nasdaq: LPTX) is focused on developing targeted and immuno-oncology therapeutics. Leap's most advanced clinical candidate, sirexatamab (DKN-01), is a humanized monoclonal antibody targeting the Dickkopf-1 (
FORWARD-LOOKING STATEMENTS
This press release contains forward-looking statements within the meaning of the federal securities laws. Such statements are based upon current plans, estimates and expectations of the management of Leap that are subject to various risks and uncertainties that could cause actual results to differ materially from such statements. The inclusion of forward-looking statements should not be regarded as a representation that such plans, estimates and expectations will be achieved. Words such as "anticipate," "expect," "project," "intend," "believe," "may," "will," "should," "plan," "could," "continue," "target," "contemplate," "estimate," "forecast," "guidance," "predict," "possible," "potential," "pursue," "likely," and words and terms of similar substance used in connection with any discussion of future plans, actions or events identify forward-looking statements.
All statements, other than historical facts, including statements regarding the potential safety, efficacy, and regulatory and clinical progress of Leap's product candidates; the anticipated timing for initiation or completion of clinical trials and release of clinical trial data and the expectations surrounding the outcomes thereof; Leap's future clinical or preclinical product development plans for any of Leap's product candidates; Leap's estimations of projected cash runway; and any assumptions underlying any of the foregoing, are forward-looking statements. Important factors that could cause actual results to differ materially from Leap's plans, estimates or expectations could include, but are not limited to: (i) the results of Leap's clinical trials and pre-clinical studies, including whether the final data from Part B of the DeFianCe study or Part C of the DisTinGuish study are the same as the initial data reported, (ii) Leap's ability to successfully finance or enter into new strategic partnerships for sirexatamab or any of its other programs; (iii) any regulatory feedback that Leap may receive from
CONTACT:
Douglas E. Onsi
President & Chief Executive Officer
Leap Therapeutics, Inc.
617-714-0360
donsi@leaptx.com
Matthew DeYoung
Investor Relations
Argot Partners
212-600-1902
leap@argotpartners.com
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FAQ
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