ADCs Showcase Impressive Activity, Second-Line Combos Seek to Raise the Bar in Quest to Target HER2+ NSCLC


Antibody-drug conjugates appear to have the most activity in those with non–small cell lung cancer and HER2 expression.

Lyudmila Bazhenova, MD

Lyudmila Bazhenova, MD

Antibody-drug conjugates (ADCs) like fam-trastuzumab deruxtecan-nxki (Enhertu) appear to have the most activity in those with non–small cell lung cancer (NSCLC) and HER2 expression, according to Lyudmila Bazhenova, MD, who added that novel TKI/ADC combinations are seeking to move the needle forward even further for this patient subset in the second-line setting.

HER2 is an emerging target, and the most promising responses are seen with ADCs,” Bazhenova, a professor of medicine, director of the Hematology Oncology Training Program, and leader of the Lung Cancer Unit at UC San Diego Moores Cancer Center, said in a presentation delivered during the 19th Annual Winter Lung Cancer Conference®, an event hosted by Physicians’ Education Resource®, LLC.1 “Trastuzumab deruxtecan produced a response rate of 55%, but you need to monitor for interstitial lung disease [ILD]. Targeted options should be considered in the second line for patients [in whom] platinum doublets [have failed].”

In her presentation, Bazhenova highlighted efforts made to target HER2-altered NSCLC, the success observed with trastuzumab deruxtecan in this population, and novel combination regimens under investigation.

Targeting HER2 in NSCLC: Past Efforts and Revelations

HER2 can be altered in several ways, Bazhenova noted. HER2 overexpression occurs in approximately 59% of patients with NSCLC, with high overexpression (defined as 3+ on immunohistochemistry [IHC]) detected in 2% to 6% of patients. HER2 amplification, as determined by FISH, is known to occur in 2% to 6% of patients with this disease, and HER2 can be mutated in 1% to 5% of patients.

The most common HER2 mutations in lung cancer are in the tyrosine kinase domain, and they are exon 20 insertion mutations, Bazhenova added. Less common mutations such as S310F and V659E, occur in the Furin-like and transmembrane domains, respectively. “Contrary to breast and gastric cancers, overexpression does not always co-occur with amplification,” Bazhenova said.

Several TKIs have been evaluated in those with HER2-altered disease, with limited success. Data have shown that in patients with HER2-mutated disease, the overall response rate (ORR) achieved with dacomitinib (Vizimpro) was 12%;2 neratinib (Nerlynx) has elicited ORRs ranging from 0% to 4% in this population,3,4 afatinib (Gilotrif) has induced ORRs ranging from 0% to 14%,5,6 and ado-trastuzumab emtansine (Kadcyla; T-DM1) has produced ORRs ranging from 44% to 51%.7,8

Among those with HER2-amplified disease, ORRs produced with dacomitinib, trastuzumab (Herceptin) plus pertuzumab (Perjeta), and T-DM1 were 0%, 24%, and 43%, respectively.2,9-10

Enter, the New Kid on the Block: Trastuzumab Deruxtecan

Trastuzumab deruxtecan is an ADC with the following 3 components: a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab; a topoisomerase I inhibitor payload, an exatecan derivate; and a tetrapeptide-based cleavable linker.

“The ADC is rationally designed with some key attributes that are specific to the drug, which include a high drug-to-antibody ratio, a payload with a short systemic half-life, and a stable linker-payload, which potentially makes the drug more effective than other HER2-targeted ADCs that are available on the market,” Bazhenova explained.

Data from the phase 3 DESTINY-Lung01 trial (NCT03505710) showed that among 91 evaluable patients with metastatic HER2-mutated NSCLC that was refractory to standard treatment, who received trastuzumab deruxtecan at 6.4 mg/kg every 3 weeks, the ADC induced an ORR of 55% (95% CI, 44%-65%) at median follow-up of 13.1 months (range, 0.7-29.1).11

“Notably, responses were quick, with a median time to response of 1.5 months,” Bazhenova noted. The median duration of response (DOR) was 9.3 months (95% CI, 5.7-14.7), the median progression-free survival (PFS) was 8.2 months (95% CI, 6.0-11.9), and the median overall survival (OS) was 17.8 months (95% CI, 13.8-22.1).

“Responses occurred regardless of where the mutation existed…and regardless of prior exposure to EGFR TKIs,” Bazhenova added.

Regarding safety, grade 1 to 2 drug-related adverse effects (AEs) were observed in 51% of patients; 41% of patients experienced a grade 3 event, 4% experienced a grade 4 event, and 1% experienced a grade 5 event. The most common grade 3 or higher drug-related toxicities included nausea (grade 3, 9%), fatigue (grade 3, 7%), vomiting (grade 3, 3%), neutropenia (grade 3, 15%; grade 4, 3%), anemia (grade 3, 10%), diarrhea (grade 3, 2%; grade 4, 1%), and leukopenia (grade 3, 4%).

“Toxicity of the compound is probably more known to those who treat breast cancer, because the drug is approved for breast and gastric cancers; it is new to us thoracic oncologists,” Bazhenova said. “Because it’s an ADC, the toxicity is what I would expect with [this class of] drugs. [It comes with] nausea and fatigue, as well as alopecia and vomiting. One important thing to note is that it can also cause pneumonitis.”

Any-grade adjudicated drug-related ILD/pneumonitis was experienced by 26.4% of patients.12 Although the majority of these effects were low grade, 4.4% of patients experienced a grade 3 event and 2.2% experienced fatal grade 5 events.

Of the 24 patients who had drug-related ILD/pneumonitis, 21 were given at least 1 dose of glucocorticoids. At the time of the presentation on the data that were delivered during the 2021 ESMO Congress, 54% of the investigator-reported cases had fully resolved.

“[It is important to note that] not all HER2 alterations are created equal,” Bazhenova added. “In HER2-overexpressing lung cancer, which is defined by IHC 2+ or 3+, trastuzumab deruxtecan produced an ORR of about 24%. To remind you, the ORR [achieved with the agent] in those with HER2-mutated disease was 55%.”

Second-Line Therapeutic Approaches Under Investigation

Other agents and novel combinations are under exploration to further improve outcomes for those with lung cancer and HER2 mutations. For example, data from cohort 2 of the phase 2 ZENITH20 trial (NCT03318939) showed that single-agent poziotinib produced an ORR of 27.8% (95% CI, 18.9%-38.2%) in previously treated patients with locally advanced or metastatic NSCLC with HER2 exon 20 insertion mutations.13 Moreover, the median DOR with the agent was 5.1 months (95% CI, 4.2-5.5), and the median PFS was 5.5 months (95% CI, 3.9-5.8). These data supported the submission of a new drug application in December 2021, seeking the approval of poziotinib as a potential therapeutic option for this population.14

Data from a phase 2 trial (NCT02834936) showed that among 60 patients with stage IIIB or IV HER2-mutated lung adenocarcinoma who previously received platinum-based chemotherapy and who received pyrotinib monotherapy at a daily dose of 400 mg for 21-day cycles, experienced an ORR of 31.3% (95% CI, 18.7%-46.3%), a median DOR of 6.9 months (95% CI, 5.5-9.6), a median PFS of 6.9 months (95% CI, 5.5-8.3), and a median OS of 14.4 months (95% CI, 12.3-21.3).15

When pyrotinib was paired with apatinib (Rivoceranib) in 14 patients with metastatic HER2-mutant lung adenocarcinoma who were pretreated with chemotherapy or other TKIs, the regimen resulted in an ORR of 35.7%, a median DOR of 5.3 months (95% CI, 3.6-7.0), a median PFS of 8.0 months (95% CI, 5.8-10.2), and a median OS of 12.9 months (95% CI, 3.8-22.0).16

When neratinib was used as a monotherapy and given at a once-daily dose of 240 mg in the phase 2 PUMA-NER-4201 (NCT01827267) and SUMMIT (PUMA-NER-5201; NCT01953926) trials, it produced ORRs of 0% (95% CI, 0.0%-19.5%) and 4% (95% CI, <1%-20%) among 17 and 26 patients with HER2-mutated NSCLC, respectively. However, when the agent was paired with trastuzumab (n = 52) or temsirolimus (Torisel; n = 43),17 the ORRs were 8% (95% CI, 2%-19%) and 14% (95% CI, 5%-28%), respectively.

Moreover, data from a phase 1/2 trial (NCT02716116), which examined mobocertinib (Exkivity) in 5 patients showed that the agent can produce an ORR as high as 20%, according to Bazhenova.18 Lastly, an ORR of 28.9% (95% CI, 17.8%-40.0%) has been achieved with a triplet regimen comprised of trastuzumab, pertuzumab, and docetaxel among 45 patients with HER2-mutated advanced NSCLC who progressed after 1 or more platinum-based chemotherapy.19

“The challenge with all of those TKIs is that there is a very high risk of diarrhea,” Bazhenova concluded.


  1. Bazhenova L. HER2-targeted therapy (including EGFR exon20). Presented at: 19th Annual Winter Lung Cancer Conference; February 4-6, 2022; Miami, FL. Accessed February 7, 2022.
  2. Kris MG, Camidge DR, Giaccone G, et al. Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors. Ann Oncol. 2015;26(7):1421-1427. doi:10.1093/annonc/mdv186
  3. Gandhi L, Besse B, Mazieres J, et al. Neratinib +/- temsirolimus in HER2-mutant lung cancers: an international, randomized phase II study. J Thorac Oncol. 2017;12(1):S353-S359. doi:10.1016/j.jtho.2016.11.398
  4. Hyman [KR3] DM, Piha-Paul SA, Rodon J, et al. Neratinib in HER2 or HER3 mutant solid tumors: SUMMIT, a global, multi-histology, open-label, phase 2 “basket” study. Cancer Res. 2017;77(13). doi:10.1158/1538-7445.AM2017-CT001
  5. Smit EF, Peters S, Dziadziuszko R, et al. A single-arm phase II trial of afatinib in pretreated patients with advanced NSCLC harboring a HER2 mutation: The ETOP NICHE trial. J Clin Oncol. 2017;35(suppl 15):9070. doi:10.1200/JCO.2017.35.15_suppl.9070
  6. Lai W-CV, Lebas L, Milia J, et al. Afatinib in patients with metastatic HER2-mutant lung cancers: an international multicenter study. J Clin Oncol. 2017;35(suppl 15):9071. doi:10.1200/JCO.20217.35.15_suppl.9071
  7. Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine for patients with HER2-mutant lung cancers: results from a phase II basket trial. J Clin Oncol. 2018;36(24):2532-2537. doi:10.1200/JCO.2018.77.9777
  8. Mazières J, Barlesi F, Filleron T, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol. 2016;27(2):281-286. doi:10.1093/annonc/mdv573
  9. Meric-Bernstam F, Hainsworth JD, Bose R, et al. MyPathway HER2 basket study: pertuzumab (p) + trastuzumab (h) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors. J Clin Oncol. 2021;39(suppl 15):3004. doi:10.1200/JCO.2021.39.15_suppl.3004
  10. Li BT, Makker V, Buonocore DJ, et al. A multi-histology basket trial of ado-trastuzumab emtansine in patients with HER2 amplified cancers. J Clin Oncol. 2018;36(suppl 15):2502. doi:10.1200/JCO.2018.36.15_suppl.2502
  11. 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
  12. Li BT, Smit EFF, Goto Y, et al. Primary data from DESTINY-Lung01: a phase II trial of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-mutated (HER2m) metastatic non-small cell lung cancer (NSCLC). Ann Oncol. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc741
  13. Socinski MA, Cornelissen R, Garassino MC, et al. ZENITH20, a multinational, multi-cohort phase II study of poziotinib in NSCLC patients with EGFR or HER2 exon 20 insertion mutations. Ann Oncol. 2020;31(suppl 4):S1188. doi:10.1016/j.annonc.2020.08.2293
  14. Spectrum Pharmaceuticals submits new drug application for poziotinib. News release. Spectrum Pharmaceuticals; December 6, 2021. Accessed February 7, 2022.
  15. Zhou C, Li X, Wang O, et al. Pyrotinib in HER2-mutant advanced lung adenocarcinoma after platinum-based chemotherapy: a multicenter, open-label, single-arm phase II study. J Clin Oncol. 2020;38(24):2753-2761. doi:10.1200/JCO.20.00297
  16. Yang G, Xu H, Xu F, et al. Pyrotinib combined with apatinib for HER2-mutant non-small cell lung cancer: interim analysis from a phase II clinical study. J Thorac Oncol. 2021;16(suppl 3):S672-S673. doi:10.1016/j.jtho.2021.01.1231
  17. Li B, Gandhi L, Besse B, et al. Neratinib-based combination therapy in HER2-mutant lung adenocarcinomas: findings from two international phase 2 studies. J Thorac Oncol. 2021;16(3):S234. doi:10.1016/j.jtho.2021.01.158
  18. Neal J, Doebele R, Riely G, et al. Safety, PK, and preliminary antitumor activity of the oral EGFR/HER2 exon 20 inhibitor TAK-788 in NSCLC. J Thorac Oncol. 2018;13(10):S599. doi:10.1016/j.jtho.2018.08.901
  19. Mazieres J, Lafitte C, Ricordel C, et al. Combination of trastuzumab, pertuzumab and docetaxel in patients with advanced non-small cell lung cancer (NSCLC) harboring HER2 mutation: final results from the IFCT-1703 R2D2 trial. J Clin Oncol. 2021;39(suppl 15):9015. doi:10.1200/JCO.2021.39.15_suppl.9015
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