▎WuXiEdited by Kant Content Team

MSD recently announced interim positive results from the dose optimization portion of its ongoing IDeate-Lung01 Phase 2 clinical trial. The analysis shows that its jointly developed product with Daiichi SankyoPotential "first-in-class", B7-H3-targeted antibody-drug conjugate (ADC) ifinatamab deruxtecan (I-DXd) in previously treated extensive-stage small cell lung cancer (ES-SCLC) patients,Disease Control Rate (DCR) as high as 90.5%,The objective response rate (ORR) reached 54.8%.Detailed data were presented at the 2024 World Conference on Lung Cancer (WCLC24). The related Phase 3 clinical trial, IDeate-Lung02, has been initiated, and the first patient was dosed last month.

In 2022, more than 2.48 million cases of lung cancer were diagnosed globally. Small cell lung cancer (SCLC) is the second most common type of lung cancer, accounting for approximately 15% of all cases. Among patients with SCLC, 70% are in the extensive-stage, meaning the cancer has spread to one or both lungs and/or other parts of the body. Extensive-stage SCLC (ES-SCLC) is an aggressive and difficult-to-treat cancer with limited treatment options, and the five-year survival rate for patients is only 3%. While conventional first-line treatments for advanced SCLC may help extend life for some patients, current standard second-line therapies offer limited clinical benefits, creating an urgent need for new treatment approaches. According to statistics,Approximately 65% of SCLC tumors exhibit moderate to high levels of B7-H3 protein expression, which is associated with disease progression and poor prognosis.

IDeate-Lung01 is a global, multicenter, randomized, open-label Phase 2 trial consisting of two parts, designed to evaluate the safety and efficacy of ifinatamab deruxtecan in patients with ES-SCLC. In the first part of the trial (dose optimization), enrolled patients had previously received at least one line of platinum-based chemotherapy and up to three lines of treatment. In the second part of the trial (expansion), patients had previously received at least two lines of systemic therapy. In the first part of the trial, patients were randomized 1:1 to receive ifinatamab deruxtecan at doses of either 8 mg/kg or 12 mg/kg. In the second part of the trial, patients received treatment at the recommended expansion dose (12 mg/kg). The primary endpoint of the trial was the overall response rate (ORR) assessed by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), disease control rate (DCR), time to response, and overall safety. Intracranial ORR assessed by BICR was an exploratory endpoint.

BICRThe evaluation results show,The confirmed ORR for ES-SCLC patients treated with 12 mg/kg (n=42) and 8 mg/kg (n=46) ifinatamab deruxtecan were 54.8% (95% CI: 38.7-70.2) and 26.1% (95% CI: 14.3-41.1), respectively.12 mg/kgGroup with23Patients achieved partial remission (PR）；8 mg/kgGroup with1Example of Complete Remission (CR) and11ExamplePR。12 mg/kgAnd8 mg/kgMedian of the dose groupDoRRespectively4.2Months (95% CI：3.5-7.0) and7.9Months (95% CI：4.1-NE），DCR was 90.5% (95% CI: 77.4-97.3) and 80.4% (95% CI: 66.1-90.6), respectively.12 mg/kgThe median treatment duration in the dose group was4.7Months (Range:0.03-15.2），8 mg/kgThe median treatment duration in the dose group was3.5Months (Range:0.03–13.9）。

The median PFS for the 12 mg/kg and 8 mg/kg groups were 5.5 months (95% CI: 4.2-6.7) and 4.2 months (95% CI: 2.8-5.6), respectively, and the median OS were 11.8 months (95% CI: 8.9-15.3) and 9.4 months (95% CI: 7.8-15.9), respectively.The 12 mg/kg dose was selected as the dose for the dose expansion portion of the trial. As of the data cutoff on April 25, 2024, the median follow-up time for the 12 mg/kg group was 15.3 months (95% CI: 13.6-16.2), and the median follow-up time for the 8 mg/kg group was 14.6 months (95% CI: 13.4-16.5).

▲Summary of IDeate-Lung01 Trial Results (Image Source: Reference [1])

“In this patient population, we expect the progression-free survival to be very short, close to two months, rather than four months."Daiichi Sankyo Global R&D HeadKen TakeshitaDr. accepted by industry mediaEndpoints Newssaid in an interview.

In the subgroup of patients with brain lesions at baseline, the BICR-assessed intracranial ORR was 50.0% (95% CI: 18.7-81.3) for those receiving 12 mg/kg (n=10) and 66.7% (95% CI: 22.3-95.7) for those receiving 8 mg/kg (n=6).In these patients, 2 cases of intracranial CR were observed in each group. In the 12 mg/kg and 8 mg/kg groups, 3 and 2 cases of intracranial PR were observed, respectively, along with 5 and 2 cases of stable disease (SD).

The safety observed in the IDeate-Lung01 trial was consistent with previous trial results, with no new safety signals identified.

Ifinatamab deruxtecan is a potential "first-in-class" B7-H3-targeted ADC., designed using Daiichi Sankyo's proprietary DXd ADC technology, consists of a humanized B7-H3-targeting IgG1 monoclonal antibody. This antibody is linked via a cleavable tetrapeptide-based linker to multiple topoisomerase I inhibitor payloads. Ifinatamab deruxtecan was granted Orphan Drug Designation by the U.S. FDA in April 2023 and by the European Commission in February 2024 for the treatment of SCLC.

Ifinatamab deruxtecan is currently in the evaluation phase of a global development program, which includes multiple clinical trials:

• IDeate-Lung01：A Phase 2 trial evaluating the efficacy of this therapy as a monotherapy in previously treated ES-SCLC patients;

• IDeate-Lung02：A Phase 3 trial comparing the efficacy and safety of this therapy with investigator's choice of chemotherapy in patients with recurrent SCLC;

• IDeate-Lung03：A Phase 1b/2 trial evaluating the therapy in combination with the PD-L1-targeted antibody Tecentriq (atezolizumab), and whether in combination with carboplatin, as a first-line induction or maintenance therapy for patients with ES-SCLC;

• IDeate-PanTumor01: A phase 1/2 "first-in-human" trial for patients with advanced solid malignant tumors;

• IDeate-PanTumor02：A Phase 2 Trial for Patients with Recurrent or Metastatic Solid Tumors.

Image Source: 123RF

Apart from MSD，GSKAlso showcased at the World Lung Cancer Conference.B7-H3TargetedADCTherapyHS-20093（GSK5764227) inES-SCLCData in patients.GSKLast year from Hansoh Pharma (Hansoh Pharma) Obtain the rights to this therapy.According to the abstract,The ORR for patients receiving 8.0 mg/kg dose was 61.3%, and this figure was 50% in the 10 mg/kg dose group.Median of patients in the lower dose groupOSFor9.8months, while the median overall survival for the higher dose has not yet been reached.HS-20093Currently underway in China3Phase Trial, Examining the Therapy Compared to Chemotherapy for RecurrentSCLCThe Role of Patients.The two companies plan to expand the clinical development program to the United States, the European Union, and other countries and regions.

References:

[1] Ifinatamab Deruxtecan Continues to Demonstrate Promising Objective Response Rates in Patients with Extensive-Stage Small Cell Lung Cancer in IDeate-Lung01 Phase 2 Trial. Retrieved September 9, 2024 from https://www.merck.com/news/ifinatamab-deruxtecan-continues-to-demonstrate-promising-objective-response-rates-in-patients-with-extensive-stage-small-cell-lung-cancer-in-ideate-lung01-phase-2-trial/

[2] OA04Antibody Drug Conjugates in SCLC. Retrieved September 9, 2024 from https://cattendee.abstractsonline.com/meeting/20598/Session/139

[3] Merck, Daiichi Sankyo detail Phase 2 ADC results in small cell lung cancer, bispecific combo strategy. Retrieved September 9, 2024 from https://endpts.com/merck-daiichi-detail-phase-2-adc-results-in-small-cell-lung-cancer-bispecific-combo-strategy/

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