The optimum balance between efficacy and toxicity with different doses of trastuzumab deruxtecan in HER2 mutated non-small cell lung cancer in DESTINY-Lung02 trial

Human epidermal growth factor receptor 2 (HER2 or ERBB2) mutations are present in 1.6–4% of non-small cell lung cancer (NSCLC) (1). It is more frequent in patients with NSCLC who are never smokers, women, and with adenocarcinoma histology (2). Most of the HER2 mutations (>90%) are represented by in-frame insertions in exon 20 of the tyrosine kinase domain (ex20ins) (2). Importantly, HER2 mutation is a distinct entity not associated with HER2 gene amplification in NSCLC (2). There have been efforts at targeting HER2 mutations with pan-HER, as well as selective, small molecules tyrosine kinase inhibitors (TKIs). However, these TKIs achieved sub-optimal outcomes and were associated with significant toxicity (3-5).

Antibody-drug conjugates (ADCs) are a novel class of therapeutics that combine cytotoxic molecules and targeted antibodies via a linker. ADCs have been evaluated in patients with metastatic NSCLC (Table 1). Ado-trastuzumab emtansine (TDM1) showed limited efficacy in HER2-overexpressing (HER2-OE) or mutant NSCLC (10). Trastuzumab deruxtecan (T-DXd) is an ADC comprising of an anti-HER2 monoclonal antibody (trastuzumab) and a topoisomerase I inhibitor payload (deruxtecan) coupled by a tetrapeptide-based linker (11). T-DXd is approved by the US Food and Drug Administration (FDA) for HER2-positive metastatic breast and gastric cancer based on DESTINY-Breast01 (dose 5.4 mg/kg) and DESTINY-Gastric01 trials (dose 6.4 mg/kg), respectively (12,13).

Although the initial hope was that ADCs would be ‘targeted’ and have a much wider therapeutic window, it has been understood that even though the efficacy may be better than conventional cytotoxic drugs and monoclonal antibodies, the potent cytotoxic payload confers a relatively narrow therapeutic index and toxicities, which can lead to treatment interruption, discontinuation, and rarely mortality. Hence, there are ongoing efforts for toxicity mitigation and optimal dose-finding strategies.

The standard treatment option available for patients with advanced/metastatic NSCLC after prior systemic therapy is chemotherapy. In the second line, the most common therapeutic option is docetaxel (with/without ramucirumab or nintedanib) if targeted therapy is not indicated or available. However, the outcomes with docetaxel (with/without ramucirumab or nintedanib) are sub-optimal with a median overall survival (OS) of 10–12 months (14,15). T-DXd is an FDA-approved and preferred option in patients with pretreated NSCLC harboring an activating HER2 mutation.

A phase I dose expansion study of T-DXd showed encouraging clinical activity in a small cohort of patients with HER2 mutant metastatic NSCLC. The objective response rate (ORR) was 72.7% [n=8/11; 95% confidence interval (CI): 39.0% to 94.0%]. Notably, drug-induced interstitial lung disease (ILD) was documented as a specific safety signal in this study (6). The clinical activity was further established in the open-label phase 2 trial (DESTINY-Lung01). This trial included patients with treatment-refractory HER2 mutant metastatic NSCLC. The dose of T-DXd used in DESTINY-Lung01 was 6.4 mg/kg. The ORR was 54.9% (95% CI: 44.2% to 65.4%). The median duration of response (DOR), progression-free survival (PFS) and OS was 9.3 (95% CI: 5.7 to 14.7), 8.2 (95% CI: 6.0 to 11.9), and 18.6 months (95% CI: 13.8 to 25.8), respectively, in a cohort of 91 patients (7,8). Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher adverse events (AEs) and drug-related ILD were seen in 46% and 27.5% of patients, respectively. National Comprehensive Cancer Network (NCCN) gives a category 2A recommendation for T-DXd in patients with previously treated HER2 mutant metastatic NSCLC based on the results of the DESTINY-Lung01 trial.

Although T-DXd showed good clinical efficacy, the frequency of grade 3 or higher toxicity (up to half of the patients) and ILD (27.5%) was concerning. Several strategies are being employed to improve the tolerability of ADCs. Investigation of different doses within randomized clinical trials (RCTs) is one such strategy to increase the therapeutic value (16). For example, an RCT comparing T-DXd doses 5.4 vs. 6.4 mg/kg in patients with HER2-positive breast cancer showed that the two doses had a comparable ORR (56.5% and 61.5%, respectively), although, the incidence of ILD (12% and 21%) and grade 3 or higher treatment-emergent AEs (39% and 58%) were lower with the 5.4 mg/kg dose (17).

DESTINY-Lung02 was a similar study to delineate the optimal dose (5.4 vs. 6.4 mg/kg, every 3 weeks) in patients with HER2 mutant metastatic NSCLC. It was a blinded, multicenter, phase II study in patients with previously treated (including platinum-containing therapy) HER2 mutant metastatic NSCLC. In the trial, patients having current or suspected ILD and those with a history of non-infectious ILD requiring steroids were excluded. HER2 mutation was defined as a single-nucleotide variant (SNV) and exon 20 insertion. The primary endpoint of the study was blinded and independent centrally reviewed ORR. Patients (n=152) were randomized to either a dose of 5.4 or 6.4 mg/kg in 2:1 ratio. The interim analysis showed an ORR of 53.8% (n=28/52) and 42.9% (n=12/28) at doses 5.4 and 6.4 mg/kg, respectively. Responses were similar irrespective of the previous systemic anticancer therapy and presence/absence of baseline central nervous system (CNS) metastasis. Importantly, reduced toxicity was seen at the lower dose of 5.4 mg/kg (AEs ≥ grade 3; 38.6% vs. 58% at doses 5.4 and 6.4 mg/kg, respectively). The rate of adjudicated drug-related ILD was also noticeably less at lower dose [5.9% (n=6/101) vs. 14% (n=7/50)] (18). Based on these interim results, the US FDA granted accelerated approval to T-DXd at the 5.4 mg/kg dose for patients with previously treated HER2 mutant metastatic NSCLC. The risk-benefit ratio was further confirmed in the recent report describing the primary results of this trial (9). The median duration of follow-up was 11.5 (range, 1.1–20.6) and 11.8 (range, 0.6–21.0) months in the 5.4 and 6.4 mg/kg cohorts, respectively. The ORR was 49.0% (95% CI: 39.0% to 59.1%) and 56.0% (95% CI: 41.3% to 70.0%). The median DOR was 16.8 months [95% CI: 6.4 to not reached (NR)] and NR (95% CI: 8.3 to NR) with 5.4 and 6.4 mg/kg, respectively. The median duration of treatment was 7.7 (range, 0.7–20.8) months with 5.4 mg/kg and 8.3 (range, 0.7–20.3) months with 6.4 mg/kg dose. Concerning toxicities, the frequency of grade 3 or higher drug/treatment-related AEs (TRAEs) was similar and occurred in 38.6% and 58.0% of patients with doses 5.4 and 6.4 mg/kg, respectively. The most common (any-grade) AEs were nausea (67.3% and 82.0%), neutropenia (42.6% and 56.0%), fatigue (44.6% and 50.0%), and decreased appetite (39.6% and 50.0%); and the most common grade 3 or higher AEs were neutropenia (18.8% and 36.0%) and anemia (10.9% and 16.0%). In total, 12.9% and 28.0% of patients had adjudicated drug-related ILD in the 5.4 and 6.4 mg/kg arm, respectively. ILD was predominately grade 1 or 2 with 2% of patients in each arm having grade 3 or more ILD. ILD led to death in one patient in each arm. Cardiotoxicity [left ventricular (LV) dysfunction, myocarditis, and hypertension] was rare in both arms. The median time to onset of drug-related ILD was 88.0 (range, 40–421) and 83.5 (range, 36–386) days with T-DXd 5.4 and 6.4 mg/kg, respectively. A greater proportion of patients in the 6.4 mg/kg arm required dose reduction, drug discontinuation, or drug interruption. The most common reasons for discontinuing T-DXd were ILD and pneumonitis (9).

While the rates of fatigue, hematological, and gastrointestinal (GI) toxicities are lower with a 5.4 mg/kg dose, a significant proportion of patients still encounter this toxicity. Dose reductions to 4.4 mg/kg and further to 3.2 mg/kg are possible, as detailed in the DESTINY-Lung02 protocol if patients have grade 3 or 4 toxicities. A change in dose frequency to every 4 weeks from every 3 weeks may be another strategy, although not widely recommended. Other strategies include capping treatment duration and response-guided dosing.

Pulmonary toxicity, especially ILD, is a toxicity of concern with some ADCs including T-DXd. This toxicity appears to be dose and frequency-dependent. The incidence of ILD/pneumonitis was 15.4% in a pooled analysis of nine studies in patients with solid tumors treated with T-DXd. This study identified potentially associated factors with ILD/pneumonitis, including treatment in Japan, dose of T-DXd, baseline oxygen saturation (<95% vs. ≥95%), moderate or severe nephrotoxicity, presence of lung comorbidities [asthma, chronic obstructive pulmonary disease (COPD), prior ILD/ or pneumonitis, pulmonary fibrosis, pulmonary emphysema, or radiation pneumonitis] and time since initial diagnosis (19). A meta-analysis including 15 studies with 1,970 patients in patients with metastatic breast cancer showed that the incidence of ILD was 22.7% and 9.3% (P<0.01) with T-DXd doses of 6.4 and 5.4 mg/kg, respectively. Of these, most cases were grade 1 or 2 (80.2%); grade 3 or 4 ILD was reported in 13.4% and grade 5 in 6.4% (n=5) (20).

In addition to toxicity, the effect of drug dosage on the quality of life (QoL) is important, but unfortunately, there is lack of such data on patients with NSCLC. Although improved efficacy is important, toxicity and its effect on QoL are significant and equally important to patients and caregivers when they decide on the further line of treatment. As such, trials should measure and report patient-reported outcomes (PROs). Such data is lacking for patients treated with NSCLC treated with T-DXd. However, there is evidence showing preserved global health status/QoL in patients with breast cancer treated with T-DXd, compared to treatment of physician’s choice and TDM1, in DESTINY-Breast04 and DESTINY-Breast03 studies, respectively (21,22).

Although the exact mechanism is unclear, it is understood that possible mechanisms for drug-induced ILD include direct toxicity due to cytotoxic and indirect immune-mediated toxicity (23). A study showed that target-independent uptake of T-DXd in pulmonary macrophages followed by the discharge of free DXd might be related to lung toxicity in monkeys (24). The diagnostic and management challenges for ILD are particularly high in patients with pre-treated lung cancer due to diminished pulmonary reserves associated with tumor burden in the lung, comorbidities such as COPD and radiation-associated pneumonitis or immunotherapy-associated pneumonitis, making clinical decision-making challenging. Careful monitoring to pick up asymptomatic ILD, multidisciplinary approach and early consultation with a pulmonologist for management and exclusion are warranted to manage ILD (25). Retreatment may be possible after the resolution of grade 1 ILD.

The limitation of the non-comparator arm in the DESTINY-Lung02 trial has been supported by the fact that currently available therapies for pretreated patients with HER2 mutant metastatic NSCLC have limited efficacy. Ideally, a phase 3 RCT comparing T-DXd to standard-of-care chemotherapy would provide level I evidence for this population. However, there are several challenges to conducting such a study, including the rarity of the HER2 mutation coupled with the large sample which makes accrual difficult and is also associated with a high financial burden. As such, for uncommon mutations such as HER2, a different design (platform trials, basket trials, and Bayesian designs) and pragmatic endpoints are needed to make sure patients get access to better drugs. Another limitation of the DESTINY-Lung02 trial was that it was not powered to statistically compare the two arms. Preferably, a non-inferiority trial design is ideal although it requires a large sample size. The lack of data on PROs is another limitation. There is also a lack of data on the intracranial response rate from DESTINY-Lung02. Notably, T-DXd has shown good intracranial control (overall intracranial response rate =73.3%) in a single-arm study that enrolled patients with HER2-positive breast cancer with brain metastases (26).

Further RCTs such as DESTINY-Lung04 are evaluating the same dose of T-DXd (5.4 mg/kg) against standard of care (platinum-pemetrexed and pembrolizumab combination) in the first-line setting in patients with advanced/metastatic HER2-mutant metastatic NSCLC (27). In patients with previously treated recurrent/metastatic HER2-OE [immunohistochemistry (IHC) 3+ or IHC 2+] non-squamous NSCLC, a phase 1b study (DESTINY-Lung03) is studying T-DXd in combination with durvalumab and chemotherapy (28). The safety and clinical activity of the combination of T-DXd and pembrolizumab in locally advanced/metastatic HER2 positive or HER2 mutant NSCLC is being studied in a phase 1 study (29). It would be interesting to see if combining T-DXd and immune checkpoint inhibitors is associated with an increased rate of pneumonitis or ILD. Dose optimization strategies and studies would be important for combination approaches. Interestingly, in the 5.4 mg/kg arm of the DESTINY-Lung02 trial, patients with prior anti-PD-L1 therapy had higher ILD rates than those without prior anti-PD-L1 therapy, although the rates were similar between patients with and without anti-PD-L1 therapy in the T-DXd 6.4 mg/kg arm.

Furthermore, cost-effectiveness analyses of a cancer drug may guide regulatory and approval bodies, particularly in a public-funded healthcare system. Docetaxel (with or without ramucirumab), the other option in patients with HER2 mutant metastatic NSCLC who have had disease progression on first-line platinum doublet and immunotherapy has a considerably less financial burden compared to T-DXd. Thus, QoL data and PROs may help to support the use of T-DXd. Although DESTINY-Lung02 presents promising efficacy of T-DXd in HER2 mutated metastatic NSCLC, the data on real-world and financial ‘effectiveness’ are lacking.

In conclusion, the DESTINY-Lung02 trial establishes that the preferred dose of T-DXd for patients with previously treated HER2 mutant metastatic NSCLC is 5.4 mg/kg (19). In the real world, very careful monitoring for toxicity, especially ILD, can allow early detection and multidisciplinary management to prevent morbidity and mortality. Real-world data on patients with metastatic NSCLC treated with T-DXd can shed more light on rates of hematologic, GI, or respiratory toxicities, as well as on dose intensity, dose schedule, and toxicity management. The combination strategies with immune checkpoint inhibitors and cytotoxics would require careful elucidation of doses of T-DXd.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-41/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-41/coif). J.R. has participated in advisory boards for Lilly and Astrazeneca. The other author has no conflicts of interest to declare.

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References

1. Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase domain in lung adenocarcinomas. Cancer Res 2005;65:1642-6. [Crossref] [PubMed]
2. Yu X, Ji X, Su C. HER2-Altered Non-Small Cell Lung Cancer: Biology, Clinicopathologic Features, and Emerging Therapies. Front Oncol 2022;12:860313. [Crossref] [PubMed]
3. Fan Y, Chen J, Zhou C, et al. Afatinib in patients with advanced non-small cell lung cancer harboring HER2 mutations, previously treated with chemotherapy: A phase II trial. Lung Cancer 2020;147:209-13. [Crossref] [PubMed]
4. Han H, Li S, Chen T, et al. Targeting HER2 Exon 20 Insertion-Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib. Cancer Res 2021;81:5311-24. [Crossref] [PubMed]
5. Cornelissen R, Prelaj A, Sun S, et al. Poziotinib in Treatment-Naive NSCLC Harboring HER2 Exon 20 Mutations: ZENITH20-4, A Multicenter, Multicohort, Open-Label, Phase 2 Trial (Cohort 4). J Thorac Oncol 2023;18:1031-41. [Crossref] [PubMed]
6. Tsurutani J, Iwata H, Krop I, et al. Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors. Cancer Discov 2020;10:688-701. [Crossref] [PubMed]
7. Li BT, Smit EF, Goto Y, et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med 2022;386:241-51. [Crossref] [PubMed]
8. Li BT, Smit EF, Goto Y, et al. 976P Phase II trial of trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutated (HER2m) metastatic non-small cell lung cancer (NSCLC): Registrational data from DESTINY-Lung01. Ann Oncol 2022;33:S995-6. [Crossref]
9. 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;41:4852-63. [Crossref] [PubMed]
10. Hotta K, Aoe K, Kozuki T, et al. A Phase II Study of Trastuzumab Emtansine in HER2-Positive Non-Small Cell Lung Cancer. J Thorac Oncol 2018;13:273-9. [Crossref] [PubMed]
11. Nakada T, Sugihara K, Jikoh T, et al. The Latest Research and Development into the Antibody-Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy. Chem Pharm Bull (Tokyo) 2019;67:173-85. [Crossref] [PubMed]
12. Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med 2020;382:610-21. [Crossref] [PubMed]
13. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med 2020;382:2419-30. [Crossref] [PubMed]
14. Garon EB, Visseren-Grul C, Rizzo MT, et al. Clinical outcomes of ramucirumab plus docetaxel in the treatment of patients with non-small cell lung cancer after immunotherapy: a systematic literature review. Front Oncol 2023;13:1247879. [Crossref] [PubMed]
15. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014;15:143-55. [Crossref] [PubMed]
16. Tarantino P, Ricciuti B, Pradhan SM, et al. Optimizing the safety of antibody-drug conjugates for patients with solid tumours. Nat Rev Clin Oncol 2023;20:558-76. [Crossref] [PubMed]
17. Tamura K, Tsurutani J, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase 1 study. Lancet Oncol 2019;20:816-26. [Crossref] [PubMed]
18. Goto K, Sang-We K, Kubo T, et al. LBA55 Trastuzumab deruxtecan (T-DXd) in patients (Pts) with HER2-mutant metastatic non-small cell lung cancer (NSCLC): Interim results from the phase 2 DESTINY-Lung02 trial. Ann Oncol 2022;33:S1422. [Crossref]
19. Powell CA, Modi S, Iwata H, et al. Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies. ESMO Open 2022;7:100554. [Crossref] [PubMed]
20. Soares LR, Vilbert M, Rosa VDL, et al. Incidence of interstitial lung disease and cardiotoxicity with trastuzumab deruxtecan in breast cancer patients: a systematic review and single-arm meta-analysis. ESMO Open 2023;8:101613. [Crossref] [PubMed]
21. Ueno NT, Jacot W, Yamashita T, et al. 217O Patient-reported outcomes (PROs) from DESTINY-Breast04, a randomized phase III study of trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low metastatic breast cancer (MBC). Ann Oncol 2022;33:S632-3. [Crossref]
22. Curigliano G, Dunton K, Rosenlund M, et al. Patient-reported outcomes and hospitalization data in patients with HER2-positive metastatic breast cancer receiving trastuzumab deruxtecan or trastuzumab emtansine in the phase III DESTINY-Breast03 study. Ann Oncol 2023;34:569-77. [Crossref] [PubMed]
23. Matsuno O. Drug-induced interstitial lung disease: mechanisms and best diagnostic approaches. Respir Res 2012;13:39. [Crossref] [PubMed]
24. Kumagai K, Aida T, Tsuchiya Y, et al. Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys. Cancer Sci 2020;111:4636-45. [Crossref] [PubMed]
25. Rugo HS, Crossno CL, Gesthalter YB, et al. Real-World Perspectives and Practices for Pneumonitis/Interstitial Lung Disease Associated With Trastuzumab Deruxtecan Use in Human Epidermal Growth Factor Receptor 2-Expressing Metastatic Breast Cancer. JCO Oncol Pract 2023;19:539-46. [Crossref] [PubMed]
26. Bartsch R, Berghoff AS, Furtner J, et al. Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial. Nat Med 2022;28:1840-7. [Crossref] [PubMed]
27. Li BT, Ahn MJ, Goto K, et al. Open-label, randomized, multicenter, phase 3 study evaluating trastuzumab deruxtecan (T-DXd) as first-line treatment in patients with unresectable, locally advanced, or metastatic non–small cell lung cancer (NSCLC) harboring HER2 exon 19 or 20 mutations (DESTINY-Lung04). J Clin Oncol 2022;40:TPS9137. [Crossref]
28. Planchard D, Brahmer JR, Yang JCH, et al. 1507TiP Phase Ib multicenter study of trastuzumab deruxtecan (T-DXd) and immunotherapy with or without chemotherapy in first-line treatment of patients (pts) with advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) and HER2 overexpression (OE): DESTINY-Lung03. Ann Oncol 2023;34:S848-9. [Crossref]
29. Borghaei H, Besse B, Bardia A, et al. P01. 02 Trastuzumab deruxtecan plus pembrolizumab in advanced/metastatic breast or non-small cell lung cancer: a phase 1b study. J Thorac Oncol 2021;16:S236. [Crossref]