Ifinatamab Deruxtecan Shows Improved Clinical Activity at Higher Dose in ES-SCLC

Ifinatamab deruxtecan (I-DXd) demonstrated encouraging and improved efficacy in heavily pretreated patients with extensive-stage small cell lung cancer (ES-SCLC), particularly with a 12-mg/kg dose vs an 8-mg/kg dose, according to an interim analysis from the phase 2 IDeate-Lung01 trial (NCT05280470) that were presented at the 2024 IASLC World Conference on Lung Cancer.¹

At a median follow-up of 14.6 months (range, 0.6-17.0) in the 8-mg/kg arm (n = 46) and 15.3 months (range, 0.8-20.3) for the 12-mg/kg dose (n = 42), the confirmed overall response rate (ORR) via blinded independent central review (BICR) was 26.1% (95% CI, 14.3%-41.1%) vs 54.8% (95% CI, 38.7%-70.2%), respectively. In the 8-mg/kg arm, the ORR included 1 complete response (CR; 2.2%) and 11 partial responses (PRs; 23.9%). In the 12-mg/kg arm, the 54.8% ORR consisted of all PRs.

However, the median duration of response (DOR) was 7.9 months (95% CI, 4.1-not reached [NR]) and 4.2 months (95% CI, 3.5-7.0) in the 8-mg/kg and 12-mg/kg arms, respectively. The disease control rate (DCR) was 80.4% (95% CI, 66.1-90.6) and 90.5% (95% CI, 77.4-97.3) in the 8-mg/kg and 12-mg/kg arms, respectively.

“Disease control rates were excellent, actually, on both arms,” Charles M. Rudin, MD, PhD, a thoracic medical oncologist and deputy director at Memorial Sloan Kettering Cancer Center in New York, said during an oral presentation of results. “I'll point to the 12-mg/kg dose with a disease control rate of 90%—really impressive, I think, in the context of recurrent, metastatic, small cell lung cancer.”

In the phase 2 trial, patients with ES-SCLC (n = 88) were randomly assigned to receive either 8 mg/kg of I-DXd intravenously (n = 46) or 12 mg/kg (n = 42). Patients enrolled in the trial had ES-SCLC and previously received 1 to 3 lines of therapy, including platinum-based chemotherapy, had an ECOG performance status of 0 or 1, and at least 1 measurable lesion per RECIST 1.1. Patients with asymptomatic brain metastases that were untreated or previously untreated were permitted to enroll.

The primary end point was ORR by BICR; secondary end points were DOR and progression-free survival (PFS), both by BICR and investigator assessment; overall survival (OS); DCR; time-to-treatment response by BICR and investigator; ORR by investigator; and safety. The data cutoff date was April 25, 2024. Treatment was ongoing in 4 patients in each arm.

The median age was 64 years (range, 34-85), 71.6% of patients were male, and most patients had an ECOG performance status of 1 (78.4%). Forty-two percent of patients had brain metastasis at baseline. Half of patients had 2 prior lines of systemic therapy, and slightly more than half had a chemotherapy-free interval of less than 90 days. Patients received either lurbinectedin (Zepzelca; 15.9%), irinotecan or topotecan (35.2%), tarlatamab (6.8%), or amrubicin (6.8%) as their select prior anticancer therapy.

Results showed that the confirmed ORR via BICR per RECIST 1.1 criteria for systemic response was 26.3% (95% CI, 9.1-51.2) and 61.1% (95% CI, 35.7-82.7) in the 8-mg/kg (n=19) and 12-mg/kg (n = 18) arms, respectively, for patients with brain metastases at baseline. The 26.3% ORR comprised a 5.3% CR rate and a 21.1% PR rate; the stable disease (SD), progressive disease (PD), and not evaluable (NE) rates were 57.9%, 10.5%, and 5.3%, respectively. The 61.1% ORR in the 12-mg/kg arm consisted fully of PRs; the SD, PD, and NE rates were 27.8%, 11.1%, and 0%, respectively.

Among patients with brain target lesions at baseline in the 8-mg/kg (n = 6) and 12-mg/kg arms (n = 10), the confirmed ORR for systemic response was 16.7% (95% CI, 0.4-64.1) and 60.0% (26.2%-87.8%) for a systemic response. The 16.7% ORR consisted of 1 CR; the SD, PD, and NE rates were 50.0%, 33.3%, and 0%, respectively. The 60.0% ORR in the 12-mg/kg arm consisted of all PRs; the SD, PD, and NE rates were 30.0%, 10.0%, and 0%, respectively.

Also in those with brain target lesions, the intracranial confirmed ORR was 66.7% (95% CI, 22.3-95.7) vs 50.0% (95% CI, 18.7-81.3) in the same respective arms. The 66.7% ORR had a 33.3% CR rate and a 33.3% PR rate; the SD rate was also 33.3%. The 50.0% ORR consisted of a 20.0% CR rate and a 30.0% PR rate; 5 patients (50.0%) had SD.

Additional findings showed that the median PFS was 4.2 months (95% CI, 2.8-5.6) compared with 5.5 months (95% CI, 4.2-6.7) in the 8-mg/kg vs 12-mg/kg arms, respectively. The median OS was 9.4 months (95% CI, 7.8-15.9) and 11.8 months (95% CI, 8.9-15.3), respectively.

Regarding safety in the ES-SCLC patient population, I-DXd was generally well tolerated at both doses. The median treatment duration was 3.5 months (range, 0.03-13.9) and 4.7 months (range, 0.03-15.2) among patients in the 8-mg/kg and 12-mg/kg arms. The median number of treatment cycles were 6.0 (range, 1.0-21.0) and 7.5 (range, 1.0-23.0) in the respective arms.

“We have a fair bit of experience with antibody-group conjugates with the deruxtecan payload at this point, and I don't think there were any great surprises here,” Rudin said during the presentation.

Treatment discontinuations in patients from the 8-mg/kg arm were due to grade 3 pneumonia (n = 1), grade 2 pneumonitis (n = 1), and grade 4 pulmonary embolism (n = 1). In the 12-mg/kg arm, discontinuations were due to grade 1 and grade 3 pneumonia (n =1; n= 1), grade 2 pneumonitis (n = 1), grade 2 ILD (n = 1), grade 3 pneumocystis jirovecii pneumonia (n = 1), grade 4 radiation pneumonitis (n = 1), and grade 5 septic shock (n =1).

The most common any-grade adverse effects in 10% or less of the patient population receiving 8 mg/kg and 12 mg/kg of I-DXd included nausea (28.3%; 50.0%), decreased appetite (17.4%; 42.9%), anemia (13.0%; 35.7%), decreased neutrophil count/neutropenia (10.9%; 33.3%), decreased white blood cell count (4.3%; 21.4%), asthenia (13.0%; 21.4%), infusion-related reactions (6.5%; 14.3%), diarrhea (10.9%; 14.3%), fatigue (13.0%; 14.3%), and vomiting (15.2%; 7.1%).

“Treatment-related adverse events associated with grade 3 and above were similar, a little bit higher treatment-emergent adverse events associated with drug discontinuation on the 12-mg/kg dose cohort, perhaps related to longer duration of treatment,” Rudin said. “We can see that the primary adverse effect is really focusing on GI toxicity and hematologic toxicity, again, not unexpected.”

Reference

Rudin C, Ahn, M, Johnson, M, et al. Ifinatamab deruxtecan (I-DXd) in extensive-stage small cell lung cancer (ES-SCLC): interim analysis of IDeate-Lung01. Presented at: 2024 IASLC World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA04.03.