Increasingly Targeted ADCs Drive NSCLC Treatment Innovations

Shirish M, Gadgeel, MD

As the wave of antibody-drug conjugates (ADCs) continues to make its way onto the non–small cell lung cancer (NSCLC) scene, crucial next steps for improving the efficacy of these agents will include continuing to develop their targeted potential and moving them into the earlier-stage setting, according to Shirish M. Gadgeel, MD.

“It is possible that these different categories of ADCs may translate into different efficacies in NSCLC,” Gadgeel said in an episode of OncLive^® Insights.

During the program, Gadgeel highlighted key treatment advances achieved with ADCs in NSCLC, including recent developments with sacituzumab govitecan-hziy (Trodelvy), the power of patritumab deruxtecan (HER3-DXd) in patients with EGFR-mutant disease, and where the future of ADCs in NSCLC is headed.

Gadgeel is the division head for Hematology/Oncology and the associate director of Patient Experience and Clinical Care at Henry Ford Cancer in Detroit, Michigan.

Sacituzumab Govitecan Evokes Favorable Outcomes in NSCLC

Gadgeel began by highlighting findings from the phase 2 EVOKE-02 trial (NCT05186974), which evaluated frontline sacituzumab govitecan plus pembrolizumab (Keytruda) in patients with metastatic NSCLC (mNSCLC).1 Cohort A of the trial (n = 29) investigated the combination in patients with a PD-L1 tumor proportion score (TPS) of at least 50%, whereas cohort B (n = 32) tested the combination in patients with a PD-L1 TPS of less than 50%. The combination elicited respective overall response rates (ORRs) of 69% and 44% in patients with PD-L1–high and –low disease.

“The combination was reasonably well tolerated, though there were toxicities observed with sacituzumab govitecan that are known with this drug in terms of fatigue, diarrhea, and cytopenias,” Gadgeel noted. “In that context, there was no added toxicity seen with [sacituzumab govitecan] when combined with pembrolizumab, particularly immune-related adverse effects [AEs] and pneumonitis,” Gadgeel added.

He highlighted that sacituzumab govitecan is already FDA approved for patients with pretreated advanced or metastatic bladder cancer2 and pretreated hormone receptor–positive, HER2-negative breast cancer.³

On the heels of the EVOKE-02 data, the ongoing phase 3 EVOKE-03 trial (NCT05609968) is assessing pembrolizumab plus sacituzumab govitecan vs pembrolizumab monotherapy in patients with PD-L1–high mNSCLC.⁴

HER3-DXd Leaves a Lasting Impression on Brain Metastases

Gadgeel shifted his focus to the evaluation of the HER3-directed ADC HER3-DXd, which was evaluated in patients with EGFR-mutated NSCLC in the phase 2 HERTHENA-Lung 01 trial (NCT04619004). This trial enrolled 225 patients with EGFR-mutated NSCLC who had previously received treatment with agents such as EGFR TKIs.5 In the overall population, HER3-DXd elicited an ORR of 29.8% (95% CI, 23.9%-36.2%) and a median progression-free survival of 5.5 months (95% CI, 5.1-5.9).

Additionally, the agent produced intracranial confirmed ORRs of 20.0% (95% CI, 12.5%-29.5%) in all patients with baseline brain metastases (n = 95) and 33.3% (95% CI, 17.3%-52.8%) in those whose baseline brain metastases had not been irradiated (n = 30).⁶

Gadgeel emphasized that a biologics license application seeking the approval of HER3-DXd for the treatment of patients with locally advanced or metastatic EGFR-mutant NSCLC was granted priority review by the FDA in 2023.⁷ 

“The toxicities observed with [HER3-DXd] included gastrointestinal toxicities, nausea, vomiting, diarrhea, fatigue, and cytopenias, very similar to the toxicities observed with fam-trastuzumab deruxtecan-nxki [T-DXd; Enhertu], a drug that is utilized in breast cancer as well as in HER2 mutation–positive NSCLC,” Gadgeel explained. “The ADCs are associated with toxicities, though in general they’re better tolerated than many of the cytotoxic chemotherapy drugs that we utilize. Nonetheless, one needs to be aware of certain unique AEs, such as pneumonitis, that can be observed with these drugs.”

Gadgeel highlighted that in general, the rate of ADC-associated pneumonitis does not increase with the addition of checkpoint inhibitors, although he cautions that the data in this area are limited. He also applauds the efficiency of the mechanism of action of ADCs, particularly regarding their activity in the central nervous system (CNS). In HERTHENA-Lung 01, HER3-DXd elicited a CNS disease control rate (DCR) of 80.0% (95% CI, 70.5%-87.5%) among all patients with CNS metastases and a CNS DCR of 76.6% (95% CI, 57.7%-90.1%) in those whose baseline brain metastases had not been irradiated The median CNS duration of response was 9.2 months (95% CI, 8.1-11.1) and 8.4 months (95% CI, 5.8-9.2), respectively.6 Furthermore, findings from the phase 2 DESTINY-Lung02 trial (NCT04644237) of T-DXd in patients with HER2-mutant NSCLC with baseline brain metastases (n = 14) demonstrated that treatment with 5.4 mg/kg of the ADC produced a confirmed intracranial ORR of 50% (95% CI, 23.0%-77.0%).⁸

“Though the numbers of patients with brain metastases were relatively limited in these trials, I think this is a very encouraging aspect of these drugs, and it appears, at least as of now, that the efficacy of these ADCs against brain metastases may be superior to standard cytotoxic chemotherapy,” Gadgeel emphasized.

The Momentum of Recent Successes Launches the Future of ADCs

“Over the past year, there’s clearly been a change in the treatment paradigm,” Gadgeel continued. He explained that immunotherapy and targeted therapy are being increasingly evaluated in earlier stages of NSCLC, where they induce greater benefits than those historically observed in patients with advanced-stage disease.

Gadgeel went on to emphasize the importance of the emergence of ADCs in the NSCLC treatment armamentarium, explaining the 3 categories under which these agents fall. One category encompasses ADCs that have shown benefit in unselected NSCLC populations. For example, TROP2-directed ADCs, such as sacituzumab govitecan, have a specific target, but are under evaluation in all-comers with NSCLC. The second category comprises HER2-directed ADCs, such as T-DXd, that are used in patients with HER2-positive disease. The third category constitutes HER3-directed ADCs, such as HER3-DXd, which, although under investigation in several subsets of patients with NSCLC, as well as in patients with estrogen receptor–positive breast cancer, has so far elicited favorable responses in patients with EGFR-mutated NSCLC.

Although ADCs are currently used for patients with NSCLC in the second-line setting, Gadgeel noted that ongoing research is evaluating these agents in the frontline setting, and that, akin to targeted therapy and immunotherapy, ADCs may also soon make their way into the early-stage NSCLC setting.

“[2023] has been exciting. It has consolidated the knowledge that we have gained about immunotherapy and targeted therapy over the past many years with greater emphasis on their use in earlier stages of lung cancer. Now, we have a newer tool, a group of drugs that are ADCs, that may give us another way of treating [patients with] NSCLC and providing even greater benefit,” Gadgeel concluded.

References

1. Gilead’s phase 2 EVOKE-02 study of Trodelvy (sacituzumab govitecan-hziy) in combination with KEYTRUDA (pembrolizumab) demonstrates promising clinical activity in first-line metastatic non-small cell lung cancer. News release. Gilead Sciences, Inc. September 10, 2023. Accessed April 5, 2024. https://www.gilead.com/news-and-press/press-room/press-releases/2023/9/gileads-phase-2-evoke02-study-of-trodelvy-sacituzumab-govitecanhziy-in-combination-with-keytruda-pembrolizumab-demonstrates-promising-clinica
2. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. FDA. April 13, 2021. Accessed April 5, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sacituzumab-govitecan-advanced-urothelial-cancer
3. US FDA approves Trodelvy in pre-treated HR+/HER2- metastatic breast cancer. News release. Gilead Sciences. February 3, 2023. Accessed April 5, 2024. https://www.gilead.com/news-and-press/press-room
4. Study of pembrolizumab (MK-3475) monotherapy versus sacituzumab govitecan in combination with pembrolizumab for participants with metastatic non-small cell lung cancer (NSCLC) with programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% (MK-3475-D46). ClinicalTrials.gov. Updated April 5, 2024. Accessed April 5, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05609968
5. Yu HA, Goto Y, Hayashi H, et al. HERTHENA-Lung01, a phase II trial of patritumab deruxtecan (HER3-DXd) in epidermal growth factor receptor–mutated non–small-cell lung cancer after epidermal growth factor receptor tyrosine kinase inhibitor therapy and platinum-based chemotherapy. J Clin Oncol. 2023;41(35):5363-5375. doi:10.1200/JCO.23.01476
6. Johnson ML, Jänne PA, Goto Y, et al. Intracranial efficacy of HER3-DXd in patients with previously treated advanced EGFR-mutated NSCLC: results from HERTHENA-Lung01. Ann Oncol. 2023;34(suppl 2):S760-S761. doi:10.1016/j.annonc.2023.09.2353
7. Patritumab deruxtecan granted priority review in the U.S. for certain patients with previously treated locally advanced or metastatic EGFR-mutated non-small cell lung cancer. News release. Daiichi Sankyo and Merck. December 22, 2023. Accessed April 5, 2024. https://www.businesswire.com/news/home/20231221780782/en
8. 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