Ifinatamab Deruxtecan Effective in ES-SCLC

The antibody-drug conjugate ifinatamab deruxtecan (I-DXd) is effective in extensive-stage small cell lung cancer (ES-SCLC), with a higher dose of the drug almost doubling the response rate over a lower dose, suggests the phase 2 Ideate-lung01 study.

The research, presented at the IASLC World Conference on Lung Cancer (WCLC) 2024 on September 8, also indicated that the drug is equally effective in patients with brain metastases, with responses seen within brain target lesions.

“I-DXd demonstrated promising efficacy in patients with heavily pretreated ES-SCLC,” said study presenter Charles M. Rudin, MD, PhD, Hassenfeld professor and chief, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York City, noting that the 12-mg/kg dose used in the study “had improved efficacy” over the 8-mg/kg comparator.

Rudin reported that, with the safety profile of the drug “generally manageable,” the 12-mg/kg dose has been selected for further clinical development, including in the ongoing IDeate-Lung02 phase 3 study involving patients with relapsed SCLC following only one prior line of therapy.

I-DXd targets B7-H3 (or CD276), which is part of the B7 family that includes immune checkpoint proteins such as programmed death ligand 1 (PD-L1). It can have co-stimulatory or co-inhibitory T-cell functions and is commonly expressed across multiple malignancies. The protein B7-H3 has been shown to be upregulated in 65% of SCLC samples.

The ongoing phase 1/2 IDeate-Pantumor01 study indicated that I-DXd has robust and durable efficacy in the subset of patients with heavily treated SCLC, with a confirmed objective response rate (ORR) of 52.4% and a median duration of response of 5.9 months and manageable toxicity.

Study Methods and Results

The current phase 2 study involved patients with recurrent, metastatic ES-SCLC who had received at least one prior line of platinum-based chemotherapy and up to three prior lines of systemic therapy. The patients included in this study also had radiologically documented progressive disease while receiving or after their most recent prior systemic therapy.

The participants, who were required to be aged at least 18 years and have an Eastern Cooperative Oncology Group performance status of 0-1, could have asymptomatic brain metastases, whether untreated or previously treated.

They were randomized to either 8 mg/kg or 12 mg/kg I-DXd every 3 weeks. “It’s really a pick the winner design to help to define a subsequent dose for phase 3 testing,” Rubin said.

Patients were subsequently eligible to enter a second extended enrollment phase, but the data from that are not yet mature.

For the dose-optimization phase, 46 patients were assigned to I-DXd 8 mg/kg, while 42 received the 12-mg/kg dose. Patients in the lower-dose arm were more likely to be female and to have a performance status of 0.

Half of the patients had received two prior lines of therapy, while just over half had chemotherapy-refractory SCLC, meaning they had progressive disease within 90 days of completing first-line induction chemotherapy.

Just over three quarters of the patients had received a prior anti-PD-L1 therapy.

The median treatment duration was 3.5 months and 4.7 months with the 8-mg/kg and 12-mg/kg doses, respectively. The median follow-up for those receiving the 8-mg/kg dose was 14.6 months vs 15.3 months for those receiving the higher dose.

The ORR by blinded independent central review was 26.1% with the 8-m/kg dose of I-DXd, rising to 54.8% with the 12-mg/kg dose. Both doses were associated with rapid responses, at a median time to response of 1.4 months in both arms.

Rudin pointed out that, “although some of these responses are transient, certainly there is a patient population here that is experiencing a really durable benefit on this antibody-drug conjugate, with prolonged responses now lasting over a year on treatment.”

The median progression-free survival was similar between the two study doses, at 4.2 months with I-DXd 8 mg/kg and 5.5 months with the 12-mg/kg dose. The median overall survival was 9.4 months and 11.8 months, respectively.

“I think these are reasonably impressive numbers given the patient population,” Rudin said.

He also showed that the ORR was similar in patients with brain metastases at baseline and that the drug was associated with intracranial responses in patients with brain target lesions at baseline, seen in 66.7% of those given the lower dose and 50.0% of those receiving the higher dose of I-DXd.

“Importantly for the management of patients with brain metastases, none of these patients had primary progression in the brain,” suggesting that “this relatively large molecule does appear to have CNS activity,” Rudin noted.

Finally, Rudin turned to the safety results, which showed that grade ≥ 3 treatment-emergent adverse events (TEAEs) were observed in 43.5% of lower-dose patients and 50.0% of higher-dose patients, with 6.5% and 16.7% of such events, respectively, linked to drug discontinuation.

The most common treatment-related TEAEs were nausea, decreased appetite, and anemia, which occurred more frequently in patients given I-DXd 12 mg/kg than those given the 8-mg/kg dose.

Interstitial lung disease/pneumonitis, a notable adverse event among patients treated with a topoisomerase I inhibitor as part of an antibody-drug conjugate, was seen in 8.7% of lower-dose patients and 11.9% of those assigned to the higher dose. There was one death linked to this adverse event in the lower-dose group.

I-DXd Shows ‘Impressive’ ORR

Anjali Rohatgi, MD, PhD, Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, commented that, currently, the options for relapsed SCLC, such as topotecan, irinotecan, and platinum rechallenge, offer objective response rates of approximately 20% and overall survival of around 6 months in patients with chemotherapy-resistant disease.

“There are additional options listed in NCCN guidelines, also with dismal response rates and overall survival,” she added.

Rohatgi, who was not involved in the study, continued that a few different aspects of antibody-drug conjugates make them promising for treating lung cancer.

These include that they deliver cytotoxic chemotherapy directly to cancer cells, have familiar adverse event profiles, and have multiple mechanisms of action. Plus, there is evidence of these drugs demonstrating intracranial activity, and doctors can give them in the outpatient setting, she said.

Rohatgi described the ORR seen with I-DXd as “impressive” and highlighted the intracranial activity of the drug.

She pointed out that “we don’t know too much about extent of disease or duration of response, but we will find this out next week,” when further data are presented at ESMO 2024.

The study was sponsored by Daiichi Sankyo, Inc. In October 2023, Daiichi Sankyo entered into a global development and commercialization collaboration agreement with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey.

Rudin declared relationships with AbbVie Amgen, AstraZeneca, D2G, Daiichi Sankyo, Epizyme, Genentech/Roche, Ipsen, Jazz, Kowa, Lilly, Merck, Syros, Auron, Bridge Medicines, DISCO, Earli, and Harpoon Therapeutics.

Rohatgi declared relationships with Apollomics, AbbVie, Gilead, Calithera Biosciences [ended], Moderna, and AstraZeneca.