New Data From 2023 ESMO Congress Further Define the Evolving Role of ADCs in NSCLC

Nicolas Girard, MD, PhD

With a plethora of data coming out of the 2023 European Society for Medical Oncology (ESMO) Congress, findings from multiple clinical trials examining antibody-drug conjugates (ADCs) in non–small cell lung cancer (NSCLC) demonstrated encouraging antitumor activity and manageable safety profiles, including results from the phase 3 TROPION-Lung01 study (NCT04656652), which evaluated datopotamab deruxtecan (Dato-DXd; DS-1062a) vs docetaxel in pretreated patients with advanced or metastatic disease.¹

“In the setting of lung cancer, we have multiple agents under development and multiple targets [such as] Trop-2, MET, and ERBB3. We have a panel of opportunities with these new drugs [and] the efficacy of docetaxel is limited, so anything that will improve the outcomes of patients is [important] to consider,” Nicolas Girard, MD, PhD, professor of respiratory medicine at University of Versailles Saint Quentinen Yvelines as well as the head of the Curie-Montsouris Thorax Institute at the Institut Curie in Paris, France, said in an interview with OncologyLive®.

Patients treated with Dato-DXd (n = 299) experienced a median progression-free survival (PFS) of 4.4 months (95% CI, 4.2-5.6) vs 3.7 months in the docetaxel arm (n=305), conferring a 25% reduction in the risk of progression or death (HR, 0.75; 95% CI, 0.62-0.91; P = .004). However, additional data revealed that patients with squamous histology did not experience the same PFS benefit when treated with the Trop-2–directed ADC vs docetaxel (HR, 1.38; 95% CI, 0.94-2.02). Patients with nonsquamous histology achieved a median PFS of 5.6 months (95% CI, 4.4-7.0) in the Dato-DXd arm (n = 229) vs 3.7 months (95% CI, 2.9-4.2) in the docetaxel arm (n = 232; HR, 0.63; 95% CI, 0.51-0.78).¹

Additionally, most patient subgroups that were examined experienced a PFS benefit with Dato- DXd compared with docetaxel, including those with actionable genomic alterations (HR, 0.38) and brain metastases at baseline (HR, 0.64).

“We need to have an understanding of which patients are the best [to receive] Dato-DXd in the second-line setting, but there is a lot of thought going [into] the first-line setting [in terms of] integrating agents in combination with immune checkpoint inhibitors and platinum chemotherapy,” Girard explained. “Data from TROPION-Lung01 [demonstrated] an incremental benefit in terms of PFS, [but] we probably need to wait a little bit more to understand whether there is an overall survival benefit.”

Examining Actionable Genomic Alterations

In another clinical trial, Dato-DXd demonstrated efficacy for all patients with NSCLC, including those with EGFR mutations and those with ALK rear- rangements who were heavily pretreated in the phase 2 TROPION-Lung05 study (NCT04484142).²

“In EGFR-positive disease the use of Dato-DXd [resulted in] a median objective response rate [ORR] of approximately 50%,” Antonio Passaro, MD, PhD, a thoracic oncologist at the European Institute of Oncology in Milan, Italy, said in an interview with OncologyLive. He noted that the response rate is “very interesting, and a future clinical trial [is needed] to corroborate and confirm [these findings].”

Among patients who received Dato-DXd, the ORRs were 35.8% (95% CI, 27.8%-44.4%) in the overall population of patients with NSCLC (n = 137), 43.6% (95% CI, 32.4%-55.3%) for those with EGFR mutations (n = 78), and 23.5% (95% CI, 10.7%-41.2%) for those with ALK rearrangements (n = 34); the median duration of response was 7.0 months in each group. Additionally, the median PFS was 5.4 months (95% CI, 4.7-7.0), 5.8 months (95% CI, 5.4-8.3), and 4.3 months (95% CI, 2.6-6.9) in eac group, respectively.²

“Safety [data] showed a specific kind of toxicity, [such as] stomatitis, mucositis, or ocular toxicity, but it’s very interesting—not all patients showed this kind of toxicity,” Passaro said.

Grade 3 or higher adverse effects of special interest included oral mucositis/ stomatitis (11%), ocular surface toxicity (2%), and adjudicated drug-related interstitial lung disease (1%).

“There are different toxicity profiles, and how do we sequence a drug like Dato-DXd if it’s available with chemotherapy?” Stephen V. Liu, MD, who is an associate professor of medicine, director of thoracic oncology, and director of developmental therapeutics at the Lombardi Comprehensive Cancer Center of Georgetown University in Washington, DC, explained in an nterview with OncologyLive. “Other ADCs, such as the HER3-[directed] ADC patritumab deruxtecan [HER3-DXd], have shown a lot of activity and a different safety profile. It’s good to have more options. We’re still learning how to optimally sequence [these options].”

Additional ASC Data May Inform Care

Patients with NSCLC with brain metastases may also experience benefit from treatment with ADCs. Systemic responses to treatment with fam-trastuzumab deruxtecan-nxki (Enhertu) were similar among patients with brain metastases and without, according to pooled analyses from the phase 2 DESTINY-Lung01 (NCT03505710) and DESTINY-Lung02 (NCT04644237) trials.³

Data from DESTINY-Lung02 revealed that patients with brain metastases who received trastuzumab deruxtecan 5.4 mg/kg every 3 weeks (n=14) achieved an intracranial confirmed ORR (IC-cORR) of 50.0% (95% CI, 23.0%-77.0%) comprised of 3 complete responses and 4 partial responses (PRs). Additionally, 6 patients experienced stable disease (SD) and 1 patient experienced disease progression (PD). Pooled data from DESTINY-Lung01 and DESTINY-Lung02 showed that patients with brain metastases treated with trastuzumab deruxtecan 6.4 mg/kg every 3 weeks (n=30) experienced an IC-cORR of 30.0% (95% CI, 14.7%-49.4%); all responses were PRs, 13 patients had SD, 4 had PD, and data were missing or not estimable for 4 patients.

Further, 86% of patients with measurable brain metastases who received the 5.4 mg/kg dose of trastuzumab deruxtecan and 78% of those in the pooled 6.4 mg/kg dosing group experienced a reduction in brain lesion size from baseline.³

“We generally thought that large molecules like monoclonal antibodies [and] ADCs don’t cross the blood-brain barrier and won’t have much activity in the brain. That’s [led to] a lot of combinations with small molecules and concern for the need of radiation, but as we’re learning from our breast cancer colleagues, these drugs do have activity in the brain. Probably not the molecule itself, maybe the payload...but there is activity in the brain.”

References

1. Ahn MJ, Lisberg A, Paz-Ares L, et al. Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): results of the randomized phase 3 study TROPION-Lung01. Ann Oncol. 2023;34(suppl 2):S1305-S1306. doi:10.1016/j.annonc.2023.10.061
2. Paz-Ares L, Ahn MJ, Lisberg AE, et al. TROPION-Lung05: datopotamab deruxtecan (Dato-DXd) in previously treated non-small cell lung cancer (NSCLC) with actionable genomic alterations (AGAs). Ann Oncol. 2023;34(suppl 2):S755-S756. doi:10.1016/j.annonc.2023.09.2348
3. Li BT, Planchard D, Goto K, et al. Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2 (ERBB2)-mutant (HER2m) metastatic non–small cell lung cancer (NSCLC) with and without brain metastases (BMs): pooled analyses from DESTINY-Lung01 and DESTINY-Lung02. Ann Oncol. 2023;34(suppl 2):S762-S763. doi:10.1016/j.annonc.2023.09.2354