For advanced non-small cell lung cancer (NSCLC), treatment strategies typically include platinum-based doublet chemotherapy, immunotherapy, and targeted therapy, with specific methods determined by molecular biomarker testing. Current unmet medical needs for advanced NSCLC patients include a lack of new treatment options following the failure of immunotherapy combinations, resistance to targeted therapies, and strategies to improve efficacy.

Antibody-drug conjugates (ADCs) are an emerging drug class designed to deliver potent payloads directly to cancer cells, protecting normal tissue cells, reducing adverse events (AEs), and enhancing quality of life. Many recently developed ADCs are currently being investigated for use in NSCLC, with safety profiles varying across different agents. Potential strategies to optimize ADC safety include dose-capping, fractionated administration, and setting limits on treatment duration.

Limiting the Number of Treatment Cycles

“Limiting the number of treatment cycles” is a strategy historically explored in chemotherapy to balance efficacy and toxicity. Multiple studies have demonstrated that adding more chemotherapy cycles does not necessarily improve response rates, survival outcomes, or quality of life.

Researchers conducted a time-to-event analysis in patients receiving polatuzumab vedotin (an anti-CD79b antibody-drug conjugate containing the potent payload monomethyl auristatin E) to explore this strategy. The analysis revealed that limiting treatment to a maximum of 6–8 cycles significantly reduced the incidence of grade 2 or higher peripheral neuropathy, the primary limiting adverse event reported.

Additionally, “time-to-response” can offer insights into defining the optimal number of ADC treatment cycles. Such studies will help confirm whether limiting the number of treatment cycles can effectively reduce toxicity while preserving efficacy.

ADC in Combination with Immunotherapy/Targeted Therapy

Moreover, “combining ADCs with immunotherapy or targeted therapies” is an approach under investigation to enhance efficacy and address or prevent resistance in patients. Importantly, some trials are examining these combinations as first-line treatments for NSCLC. Table 2 presents ongoing trials combining ADCs with immunotherapy or targeted therapies.

For patients receiving ADC in combination with immunotherapy/targeted therapy, continuing maintenance immunotherapy or targeted therapy after an adequate number of ADC cycles may be a promising option, as illustrated below.

Conclusion

In summary, the use of ADCs is expanding significantly, offering potential treatment options for patients who have failed immunotherapy/targeted therapy and even as first-line treatment for NSCLC patients. However, the use of ADCs has introduced new types of drug-related toxicities, necessitating methods to mitigate toxicity. Strategies such as “limiting the number of ADC doses and combining ADC with maintenance therapy” are worth exploring to improve patients’ quality of life.

Reference

1.Hendriks LE, Kerr KM, Menis J, et al; ESMO Guidelines Committee. Non-oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023;34(4):358-376.

2.Hendriks LE, Kerr KM, Menis J, et al; ESMO Guidelines Committee. Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.Ann Oncol. 2023;34(4):339-357.

3.Meyer M, Fitzgerald B, Paz-Ares L, et al. New promises and challenges in the treatment of advanced non-small-cell lung cancer.Lancet. 2024;404(10454):803-822.

4.Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy.Signal Transduct Target Ther. 2022;7(1):93.

5.Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody-drug conjugates for cancer therapy.Nat Rev Clin Oncol. 2021;18(6):327-344.

6.Goto K, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small-cell lung cancer: primary results from the randomized, phase II DESTINY-Lung02 trial.J Clin Oncol. 2023;41(31):4852-4863.

7.Paz-Ares LG, Juan-Vidal O, Mountzios GS, et al. Sacituzumab govitecan versus docetaxel for previously treated advanced or metastatic non-small-cell lung cancer: the randomized, open-label phase III EVOKE-01 study.J Clin Oncol. 2024;42(24):2860-2872.

8.Ahn M, Lisberg A, Paz-Ares L, et al. LBA12 Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small-cell lung cancer (NSCLC): results of the randomized phase III study TROPION-Lung01.Ann Oncol. 2023;34:S1305-S1306.

9.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 and platinum-based chemotherapy.J Clin Oncol. 2023;41(35):5363-5375.

10.Camidge DR, Bar J, Horinouchi H, et al. Telisotuzumab vedotin monotherapy in patients with previously treated c-Met protein-overexpressing advanced nonsquamous EGFR-wildtype non-small cell lung cancer in the phase II LUMINOSITY trial.J Clin Oncol. 2024;42(25):3000-3011.

11.Tarantino P, Ricciuti B, Pradhan SM, Tolaney SM. Optimizing the safety of antibody-drug conjugates for patients with solid tumours.Nat Rev Clin Oncol. 2023;20(8):558-576.

12.Socinski MA, Morris DE, Masters GA, Lilenbaum R; American College of Chest Physicians. Chemotherapeutic management of stage IV non-small cell lung cancer.Chest. 2003;123(suppl 1 ):226S-243S.

13.Smith IE, O’Brien ME, Talbot DC, et al. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin.J Clin Oncol. 2001;19(5):1336-1343.

14.Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer.J Clin Oncol. 2002;20(5):1335-1343.

15.Park JO, Kim SW, Ahn JS, et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer.J Clin Oncol. 2007;25(33):5233-5239.

16.Rossi A, Chiodini P, Sun JM, et al. Six versus fewer planned cycles of first-line platinum-based chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data.Lancet Oncol. 2014;15(11):1254-1262.

17.Lu D, Gillespie WR, Girish S, et al. Time-to-event analysis of polatuzumab vedotin-induced peripheral neuropathy to assist in the comparison of clinical dosing regimens.CPT Pharmacometrics Syst Pharmacol. 2017;6(6):401-408.

18.Iwata TN, Ishii C, Ishida S, Ogitani Y, Wada T, Agatsuma T. A HER2-targeting antibody–drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model.Mol Cancer Ther. 2018;17(7):1494-1503.

19.Haratani K, Yonesaka K, Takamura S, et al. U3-1402 sensitizes HER3-expressing tumors to PD-1 blockade by immune activation.J Clin Invest. 2020;130(1):374-388.

20.Goto Y, Su W, Levy B, et al. TROPION-Lung02: Datopotamab deruxtecan (Dato-DXd) plus pembrolizumab (pembro) with or without platinum chemotherapy (Pt-CT) in advanced non-small cell lung cancer (aNSCLC).J Clin Oncol. 2023;41:16s (suppl; abstr 9004).

21.<jrn>Comer F, Mazor Y, Hurt E, et al. AZD9592: an EGFR-cMET bispecific antibody-drug conjugate (ADC) targeting oncogenic drivers in non-small-cell lung cancer (NSCLC) and beyond.Cancer Res. 2023;83:7s (suppl; abstr 5736).