ADCs and TKIs Look to Carve Out Their Place in the HER2-Mutant NSCLC Treatment Paradigm

Lyudmila A. Bazhenova, MD

Non–small cell lung cancer (NSCLC) comprises approximately 80% to 85% of all lung cancer diagnoses, with 1% to 4% of these patients’ disease harboring mutations in HER2, a tyrosine kinases receptor that plays an important role in cell growth and differentiation. The longtime standard of care in the space, chemotherapy, has produced a median progression-free survival (PFS) of only approximately 4 months historically, underscoring the need for more effective treatment options in the space (Figure).¹

“For patients with metastatic lung cancer, PD-L1 expression, as well as broad molecular profiling, is recommended. Currently, we have 11 types of molecular alterations that we are looking for in lung cancer; we are making our treatment decisions based on those alterations, and the HER2 mutation is one of those alterations,” Lyudmila A. Bazhenova, MD, explained.

During a recent OncLivePeer Exchange®, a panel of expert clinicians in NSCLC discussed the treatment landscape of HER2-mutantNSCLC. They highlight the current roles of antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) in the treatment arsenal, as well as touching on the unmet needs that remain in the space.

Figure

ADCs in HER2-Mutant NSCLC

The ADC that has made the most waves in the HER2-positive (HER2+) NSCLC space is fam-trastuzumab-nxki deruxtecan (Enhertu), which first gained significant traction in treatment of HER2+ breast cancer. Following preliminary antitumor activity in the first-in-human study (NCT02564900), the HER2-directed ADC was evaluated in patients with HER2-mutant NSCLC that was refractory to standard treatment exclusively in the phase 2 DESTINY-Lung01 trial (NCT03505710). The primary end point was objective response rate (ORR); secondary end points included PFS, duration of response (DOR), overall survival (OS), and safety.²

“ADCs are a relatively new area for NSCLC,” Edward S. Kim, MD, MBA, said. “We’re now seeing these ADCs becoming approved in the clinic, [which] first started with HER2+ metastatic breast cancer and then HER2-low metastatic breast cancer, which was a quite an achievement—you have evenHER2+ stomach cancer. What we’re observing is that the utilization of chemotherapy and some of these other agents just don’t work very well in these [patients with HER2-mutant disease], so finding alternatives to treat these folks is going to be very important.”

At a median follow-up of 13.1 months (range, 0.7-29.1), findings from the primary analysis of DESTINY-Lung01 demonstrated that patients who received trastuzumab deruxtecan 6.4 mg/kg (n = 91) achieved a centrally confirmed ORR of 55% (95% CI, 44%-65%) and a median DOR of 9.3 months (95% CI, 5.7-14.7). In terms of survival outcomes, the median OS and PFS were 17.8 months (95% CI, 13.8-22.1) and 8.2 months (95% CI, 6.0-11.9), respectively. “DESTINY-Lung01 was the backbone of the development of trastuzumab deruxtecan in relapsed or refractory NSCLC,” Edgardo Santos, MD, FACP, FCCP, FASCO, noted.

“We did see toxicities; it’s an ADC, so it’s a chemotherapy-like molecule,” Bazhenova said. “The most common toxicities were nausea, vomiting, fatigue, and [approximately] half of the patients had alopecia. One adverse effect that gave us a little bit of a pause, at least initially, was pneumonitis; approximately 26% of patients were reported to have interstitial lung disease [ILD] or pneumonitis.”

“If [a patient] gets pneumonitis, that’s really bad news, especially if it’s higher grade. But some other patients have just felt extremely fatigued. Depending on [a patient’s] reserve, most individuals can probably cope with it. But if a patient has no reserve to cope with a bump in the road, we shouldn’t forget that this is just a relatively sophisticated chemotherapy,” D. Ross Camidge, MD, PhD, added.

In another phase 2 trial, DESTINY-Lung02 (NCT04644237), investigators evaluated trastuzumab deruxtecan at 2 different dose levels, 6.4 mg/kg and 5.4 mg/kg, in patients with HER2-mutant NSCLC who previously received platinum-based therapy. The primary end point was ORR per blinded independent central review, and patients were randomly assigned 2:1 to the 5.4 mg/kg (n = 102) or 6.4 mg/kg (n = 50) arms.³

The confirmed ORR in the 5.4 mg/kg and 6.4 mg/kg groups was 49.0% (95% CI, 39.0%-59.1%) and 56.0% (95% CI, 41.3%-70.0%), respectively. The median DOR was 16.8 months (95% CI, 6.4-not estimable [NE]) and NE (95% CI, 8.3-NE), respectively. At respective median follow-ups of 11.5 months (range, 1.1-20.6) and 11.8 months (range, 0.6-21.0), the median PFS was 9.9 months (95% CI, 7.4-NE) and 15.4 months (95% CI, 8.3-NE), respectively, and the median OS was 19.5 months (95% CI, 13.6-NE) and NE (95% CI, 12.1-NE), respectively.

“It’s going to be interesting to see whether the dose-adjusted patients actually have worse outcomes,” Martin Dietrich, MD, PhD, said. “There is sort of a confidence about dose adjusting these patients. Those 2 data sets were relatively congruent, which helped us to confirm that 5.4 mg/kg of body weight [should be] the standard here.”

Trastuzumab deruxtecan was granted accelerated approval at a recommended dose of 5.4 mg/kg given intravenously every 3 weeks by the FDA in August 2022 for the treatment of adult patients with HER2-mutant NSCLC, as detected by an FDA-approved test, who were previously treated with systemic therapy. The regulatory decision made trastuzumab deruxtecan the first agent approved for HER2-mutant NSCLC and was supported by findings from DESTINY-Lung02.⁴

“In [terms of efficacy and toxicities] including ILD, the confidence intervals overlap, but there was enough of a trend all heading in the same direction to say that the efficacy looks about the same, but the lower dose seems to be better tolerated. This is really the key to the accelerated approval of trastuzumab deruxtecan; [the] bigger data set followed up with saying, ‘This is the dose.’ This is the poster child for the FDA’s Project Optimus,” Camidge said.

Then, in April of this year, the FDA granted another accelerated approval to trastuzumab deruxtecan for adult patients with any unresectable or metastatic HER2+ solid tumors who have received previous systemic therapy and do not have any treatment alternatives. The approval was supported by findings from DESTINY-Lung01, DESTINY-PanTumor02 (NCT04482309), and DESTINY-CRC02 (NCT04744831).⁵

Following the positive phase 2 findings observed with trastuzumab deruxtecan in HER2-mutant NSCLC, investigators initiated the phase 3 DESTINY-Lung04 trial (NCT05048797). DESTINY-Lung04 is comparing trastuzumab deruxtecan with standard of care chemotherapy with either cisplatin or carboplatin in combination with pemetrexed (Alimta) and pembrolizumab (Keytruda) in adult patients with unresectable, locally advanced, or metastatic nonsquamous NSCLC with HER2 exon 19 or 20 mutations.⁶

To be eligible for DESTINY-Lung04, patients must be treatment naive in the locally advanced or metastatic setting and have measurable disease per RECIST 1.1 criteria, adequate organ function, and an ECOG performance status of 1 or less. The primary end point is PFS per blinded independent central review; secondary end points include PFS per investigator assessment, ORR, DOR, OS, and safety.

“We’ve been seeing consistent outcomes throughout the different lines of therapy, so hopefully we’ll see similar things [in DESTINY-Lung04],” Kim said. “This trial does allow patients with brain metastases, but they needed to have completed local therapy for it. We hope to see a similar safety profile and a similar efficacy profile [as observed in DESTINY-Lung01 and DESTINY-Lung02].”

TKIs in HER2-Mutant NSCLC

Although there are currently no HER2-directed TKIs approved by the FDA in NSCLC, investigators are examining the HER2-selective TKI zongertinib (formerly BI 1810631) in the phase 1a/1b Beamion LUNG-1 trial (NCT04886804) in patients with HER2-mutant solid tumors. Zongertinib binds covalently to wild-type and mutant HER2, including HER2 exon 20 insertion mutations, and spares EGFR signaling.⁷

Beamion LUNG-1 is examining zongertinib at a starting dose of 15 mg twice daily, with successive cohorts receiving increasing doses until at least 1 level above the estimated therapeutic dose is reached. The primary end point of the nonrandomized trial in phase 1a is safety by dose-limiting toxicities (DLTs) and determining the maximum tolerated dose (MTD), as well as ORR in phase 1b.

During the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer in September, study authors presented preliminary efficacy and safety findings from Beamion LUNG-1. In phase 1a (n = 46), patients received twice-daily doses of zongertinib from 15 mg to 150 mg or once-daily doses between 60 mg and 360 mg. Phase 1b (n = 42) included patients with pretreated, HER2 tyrosine kinase domain (TKD)–mutant NSCLC (cohort 1); treatment-naive, HER2 TKD–mutant NSCLC (cohort 2); NSCLC with a non–HER2 TKD mutation (cohort 3); NSCLC with active brain metastases (cohort 4); and NSCLC previously treated with a HER2-directed ADC (cohort 5).⁸

At the July 17, 2023, data cutoff, the MTD had not yet been reached; on-treatment DLTs consisted of grade 2 edema (n = 1; 60 mg twice daily), grade 2 diarrhea (n = 1; 150 mg twice daily), grade 3 platelet count decrease (n = 1; 360 mg once daily), grade 3 alanine aminotransferase increase (n = 1; 180 mg once daily), grade 2 blood bilirubin increase (n = 1; 180 mg once daily), and grade 2 aspartate aminotransferase increase (n = 1; 180 mg once daily). The ORR in phase 1a was 41.3%, including 50.0% in patients with NSCLC (n = 34); all responses were partial. Efficacy-evaluable patients in phase 1b who received 2 to 5 treatment cycles (n = 23) achieved an ORR of 73.9% (95% CI, 53.5%-87.5%).

“More data are still needed. It’s [a] very small but very promising data set and we know that in an active TKI/driver mutation setting, it doesn’t take a lot of patients to show efficacy. Hopefully, this is a sign of better things to come. But I think everybody’s still waiting because of the prior data that we’ve seen with this type of class of agents,” Kim commented.

Updated data from phase 1a of Beamion LUNG-1, including PFS findings, are expected to be presented during this year’s American Society of Clinical Oncology Annual Meeting (ASCO 2024) in June.⁹

“I’m excited to see where the drug is being taken forward and excited to see the first-line data because we’ve had discussions that trastuzumab deruxtecan does have toxicity,”Bazhenova said. “How [is] the field going to shake up if we see efficacy [with a] TKI in [the] first line, and how are we going to decide what goes first and what goes second? It remains to be seen.”

Another TKI being developed in HER2-mutant NSCLC is the oral agent BAY2927088, which selectively targets both HER2 and EGFR driver mutations, including exon 20 insertions; this preferential activity indicates a potentially wide therapeutic window for the agent. In the phase 1/2 trial SOHO-01 (NCT05099172), BAY2927088 is being examined in patients with advanced NSCLC with HER2 or EGFR mutations following disease progression after at least 1 systemic therapy. The coprimary end points are safety, tolerability, pharmacokinetics, and MTD. Secondary end points include ORR and determining the recommended phase 2 dose.¹⁰

Preliminary findings presented during the 2023 European Society for Medical Oncology Congress in October showed that the ORR among all efficacy-evaluable patients (n = 69) was 26.1% (95% CI, 16.3%-38.1%), including 1 patient who achieved a complete response (CR). Among those with HER2 exon 20 insertions (n = 20), the ORR was 60.0% (95% CI, 36.1%-80.9%) with 1 CR. In the overall population (n = 76) most patients experienced a treatment-related adverse effect (TRAE; 86.8%), there were 5 DLTs, and no patients were forced to discontinue treatment due to TRAEs.

In February 2024, Bayer announced that the FDA had granted BAY2927088 breakthrough therapy designation for the treatment of patients with NSCLC harboring HER2 activating mutations who received a previous systemic therapy. Additional safety and efficacy findings from an expansion cohort of SOHO-01 are expected to be presented during ASCO 2024.^11,12

“The most important thing is recognizing the role of HER2 as an oncogenic driver,” Dietrich said in conclusion. “These mutations look unfamiliar, and they come in many flavors, so it’s important to identify them properly. Oftentimes, we forget mutations that have been identified in the first-line setting to utilize them in a second-line setting. There’s a growing portfolio of clinical trials that are available for patients. HER2 needs to be recognized and channeled accordingly. HER2 is going to get more complex when we have the expression data. The inclusion of HER2 immunohistochemistry at some point in the treatment paradigm is going to be helpful. But [I am] very excited about the field of HER2 developing and finally getting ready for clinical application.”

References

1. Zhang J, Han W, Guo J, et al. Efficacy of immunotherapy in HER2-mutated non-small cell lung cancer: a single-arm meta-analysis. J Cancer Res Clin Oncol. 2024;150(2):42. doi:10.1007/s00432-023-05509-0
2. Li BT, Smit EF, Goto Y, et al. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431
3. 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. doi:10.1200/JCO.23.01361
4. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. FDA. August 16, 2022. Accessed May 8, 2024. bit.ly/3ycj8Vv
5. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed May 8, 2024.
   bit.ly/3UUaNyg
6. 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(suppl 16):TPS9137. doi:10.1200/JCO.2022.40.16_suppl.TPS9137
7. Heymach J, Opdam F, Barve M, et al. A phase I, open-label, dose confirmation, escalation, and expansion trial of BI 1810631 as monotherapy in patients with advanced or metastatic solid tumors with HER2 aberrations. Clin Lung Cancer. 2023;24(2):e65-e68. doi:10.1016/j.cllc.2022.10.008
8. Yamamoto N, Opdam F, Barve M, et al. Beamion Lung-1, a phase 1a/b trial of the HER2 TKI, zongertinib (BI 1810631), in patients with advanced solid tumors with HER2 aberrations. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract MA13.08.
9. Heymach J, Opdam F, Barve M, et al. Phase Ia/Ib trial of zongertinib (BI 1810631), a HER2-specific tyrosine kinase inhibitor (TKI), in patients (pts) with HER2 aberration-positive solid tumors: updated phase Ia data from Beamion LUNG-1, including progression-free survival (PFS) data. J Clin Oncol.2024;42(suppl 16):8514. doi:10.1200/JCO.2024.42.16_suppl.8514
10. Loong HHF, Daniele G, Yang TY, et al. Early evidence of efficacy in patients (pts) with non-small cell lung cancer (NSCLC) with HER2 exon20 insertion (ex20ins) mutations treated in a phase I study with BAY 2927088. Ann Oncol. 2023;34(suppl 2):S761-S762. doi:10.1016/j.annonc.2023.09.2409
11. Bayer receives U.S. FDA breakthrough therapy designation for BAY 2927088 for non-small cell lung cancer harboring HER2 activating mutations. News release. Bayer. February 26, 2024. Accessed May 10, 2024. bit.ly/4bfTSfw
12. Girard N, Kim TM, Kim HR, et al. Safety and anti-tumor activity of BAY 2927088 in patients with HER2-mutant NSCLC: results from an expansion cohort of the SOHO-01 phase I/II study. J Clin Oncol.2024;42(suppl 17):LBA8598. doi:10.1200/JCO.2024.42.17_suppl.LBA8598