Significant Survival Boost With Novel ADCs in Relapsed Small-Cell Lung Cancer

Two investigational anti-B7-H3 antibody-drug conjugates (ADCs) significantly improved survival outcomes in patients with relapsed small-cell lung cancer (SCLC), according to a pair of Chinese trials.

In the TAISHAN-302 study, patients treated with tambotatug pelitecan (Tam-Peli) had a median overall survival (OS) of 13.3 months versus 9.4 months among those treated with the standard chemotherapy topotecan, reducing the risk of death by 54% (HR 0.46, 95% CI 0.35-0.62, P<0.0001). The median follow-up was 9.2 months, reported Li Zhang, MD of the Sun Yat-sen University Cancer Center in Guangdong, at the World Conference on Lung Cancer (WCLC) in Seoul, South Korea. Trial results were published simultaneously in the New England Journal of Medicine.

In the ARTEMIS-008 study with a median follow-up of 12.2 months, patients treated with risvutatug rezetecan (Ris-Rez) had a median OS of 18.5 months versus 10.3 months with topotecan, translating into the same 54% reduced risk of death (HR 0.46, 95% CI 0.35-0.62, P<0.0001), reported Jie Wang, MD, of Peking Union Medical College in Beijing.

Treatment with both drugs also resulted in significant improvements in median progression-free survival (PFS) compared with topotecan:

• Tam-Peli: PFS 7.4 months vs 2.8 months (HR 0.29, 95% CI 0.23-0.37, P<0.001)
• Ris-Rez: PFS 7.2 months vs 3.0 months (HR 0.33, 95% CI 0.25-0.42)

Objective response rates also were substantially improved at 59.1% with Tam-Peli versus 9.7% with topotecan, and 58.3% with Ris-Rez versus 12.6% with topotecan.

Both Tam-Peli and Ris-Rez will be “great options for our patients,” said WCLC invited discussant Anne Chiang, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut.

Chiang noted that the FDA has granted priority review to another B7-H3-directed ADC — ifinatamab deruxtecan — for adult patients with extensive-stage SCLC who have experienced disease progression on or after platinum-based chemotherapy. A Prescription Drug User Fee Act action-date is set for October, “so our landscape is changing in real-time,” she said.

“In my opinion, there is a new standard emerging,” Chiang added. She predicted that within the next 2 to 5 years, ADCs will become the new second-line treatment for relapsed SCLC, “and may even replace chemotherapy” in the front-line setting.

TAISHAN-302

Zhang noted that treatment options for relapsed SCLC have been limited. While topotecan is standard second-line therapy, it comes with a modest survival benefit and substantial hematologic side effects.

The phase III open-label study randomized 451 patients to Tam-Peli and topotecan. Patients receiving Tam-Peli were treated with 2.0 mg/kg IV on day 1 of each 3-week cycle, with a maximum dose of 200 mg, with treatment continuing until disease progression or unacceptable toxicity.

Median patient age was 62. Patients who had never smoked accounted for 28.0% in the Tam-Peli group and 30.1% in the topotecan group.

Across the two groups, 96.2% had systemic disease, and 34.4% had a history or presence of brain metastases at baseline. A total of 393 patients (87.1%) had received previous anti-PD-L1 or anti-PD-1 therapy, and 48.8% had platinum-resistant disease.

At the data-cutoff date, the median duration of treatment was 7.2 months in the Tam-Peli group and 2.3 months in the topotecan group. In addition, 71 patients (31.6%) in the Tam-Peli group and eight patients (3.5%) in the topotecan group were still receiving the assigned treatment.

For safety, adverse events (AEs) of grade ≥3 occurred in 55.4% and 77.9% of the two groups, respectively, and serious AEs occurred in 38.8% and 43.3%.

Dose reductions due to an AE occurred in 28.1% of patients in the Tam-Peli group and 37.3% in the topotecan group, with permanent discontinuation due to an AE occurring in 7.1% and 3.7%, respectively. Zhang’s group wrote that “dose intensity was preserved with tambotatug pelitecan, with fewer reductions in the dose of tambotatug pelitecan than in the dose of topotecan over a substantially longer treatment period.”

Interstitial lung disease (ILD) or pneumonitis occurred in 4.9% on Tam-Peli and 1.4% on topotecan.

ARTEMIS-008

The multicenter, open-label phase III study randomized 461 patients to receive Ris-Rez 8.0 mg/kg every 3 weeks or topotecan 1.2 mg/m² on days 1 through 5 every 3 weeks.

Median patients age was 61.5 in the Ris-Rez group and 63 in the topotecan group. Patients who had never smoked accounted for 31% of the study population, and more than 80% had previously received PD-L1 inhibitors.

Median exposure duration was 6.9 months for Ris-Rez and 28 months for topotecan.

Wang reported grade ≥3 treatment-related AEs (TRAEs) occurred less frequently with Ris-Rez than with topotecan, at 60.9% versus 78.2%, while serious TRAEs occurred in 34.3% and 37.5%, respectively.

The most common grade ≥3 AEs were hematologic toxicities, including decreased neutrophil count, decreased white blood cell count, anemia, decreased lymphocyte count, and decreased platelet count.

AEs leading to dose reductions occurred in 20.4% of patients in the Ris-Rez group and 38.0% in the topotecan group, while those leading to treatment discontinuation occurred in 9.1% and 4.2%, respectively.

The incidence of ILD was 11.7% with Ris-Rez versus 1.9% with topotecan.