HER2-Mutated NSCLC Treatment Evolves From Mainstay TKIs to Novel ADCs and Beyond

Antibody-drug conjugates have demonstrated substantial activity in patients with HER2-mutated non–small cell lung cancer, with fam-trastuzumab deruxtecan-nxki showcasing the strongest response rate and progression-free survival benefit to date.

Corey J. Langer, MD, FACP

Corey J. Langer, MD, FACP

Antibody-drug conjugates (ADCs) have demonstrated substantial activity in patients with HER2-mutated non–small cell lung cancer (NSCLC), with fam-trastuzumab deruxtecan-nxki (Enhertu) showcasing the strongest response rate and progression-free survival (PFS) benefit to date, according to Corey J. Langer, MD, FACP. Now, research efforts are underway to better decipher HER2 signaling and HER2-targeted combinations, as well as neoadjuvant and adjuvant utility.

“Without question, trastuzumab deruxtecan holds the greatest promise…it is unclear whether this should move to the first line; I am on the fence myself,” Langer, who is director of Thoracic Oncology at Abramson Cancer Center, said in a presentation delivered during the 23rd Annual International Lung Cancer Congress®.1 “We need more data on emerging agents, including mobocertinib [Exkivity], and certainly, we need to balance toxicity against efficacy.”

HER2 is overexpressed in 59% of all cases of NSCLC, according to Langer, who is also a professor of medicine at the University of Pennsylvania. HER2 mutations are rare, occurring in 3% of adenocarcinomas, mostly in the form of exon 20 in-frame insertions. “Phenotypically, these patients look very similar to EGFR- and ALK-mutated NSCLC: mostly never smokers and worse survival…than some of the other mutation-driven tumors,” Langer noted.

Data leveraging the tumor-profiling multiplex panel, MSK-IMPACT, between 2014 and 2022 showed that 409 of 7993 patients harbored a HER2 aberration. Eight percent of patients with mutations had amplification and 20% with amplifications had mutations.

Data from a study that examined overall survival (OS) from date of diagnosis in HER2-, EGFR-, and KRAS-mutated lung cancers showed that “as least predating the ADC era, outcomes for those with HER2 mutations are not much different from KRAS mutations, but certainly worse compared with EGFR mutations,” Langer said.2

Most agents leveraged in NSCLC have been adapted from research that has been conducted in metastatic breast cancer, including lapatinib (Tykerb), afatinib (Gilotrif), dacomitinib (Vizimpro), trastuzumab (Herceptin), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla; T-DM1), and trastuzumab deruxtecan.

Examining the Role of FDA-Approved TKIs

In patients with HER2-mutated NSCLC (n = 26), dacomitinib has been shown to elicit an overall response rate (ORR) of 12% (95% CI, 2%-30%), according to data from a phase 2 trial (NCT00818441).3 In 4 patients with HER2-amplified disease, the ORR with the agent was 0% (95% CI, 0%-60%). Another study showed that among 23 evaluable patients with stage IV or recurrent HER2-mutated lung cancer, afatinib elicited an ORR of 13% (95% CI, 4%-33%).4

“We see relatively low response rates [with these older agents],” Langer noted. “Newer TKIs seem to yield better responses.”

Data from a phase 2 trial (NCT03066206) showed that among 12 evaluable patients with HER2 exon 20–mutant NSCLC, poziotinib (NOV120101; HM781-36B) elicited an ORR of 50% (95% CI, 21.1%-78.9%).5Additionally, the irreversible pan-HER TKI, pyrotinib, was found to elicit an ORR of 53.3% in a phase 2 cohort of 15 patients with HER2-mutant NSCLC, according to data from another trial (NCT02535507).6

“[However, these agents have] lots of toxicity, particularly poziotinib,” Langer said. Safety data showed that 56% of patients who received the agent on the trial experienced grade 3 or 4 treatment-related adverse effects [AEs]. Sixty percent of patients experienced a toxicity that required a dose reduction, and 3% experienced an AE that resulted in discontinuation.5

Entering the Modern Era With the Emergence of ADCs

ADCs are targeted agents that utilize a monoclonal antibody component that identifies a specific antigen or receptor on the cell, delivering and releasing a cytotoxic drug linked to that antibody at the tumor site, Langer explained. Conceptually, these agents are hypothesized to be able to improve the efficacy of chemotherapy, as well as reduce systemic exposure and toxicity.

“The ideal antibody will have high selectivity and affinity for the tumor-associated antigen and low immunogenicity. The selected antigen should have low prevalence on healthy tissues not shed into circulation, and the antibody should have a long circulating half-life,” Langer said. “The linker that helps to pair the payload with the antibody should be stable in circulation and easily cleavable at the tumor site. The payload also must be effective enough to induce cell death with low toxicity. Ideally, there should be a short half-life and a high drug-antibody drug ratio.”

The 2 key ADCs that have emerged in the paradigm are T-DM1 and trastuzumab deruxtecan.

Data from a phase 2 basket trial (NCT02675829) conducted at Memorial Sloan Kettering Cancer Center showed that in 49 patients with ERBB2-amplified or -mutant lung cancer, T-DM1 elicited an ORR of 51%.7 In patients with HER2-mutant NSCLC (n = 18), the response was slightly lower, at 44% (95% CI, 22%-69%) with a median duration of response of approximately 4 months.8

“Toxicity is certainly acceptable,” Langer noted. The most common AEs reported with T-DM1 were elevated aspartate or alanine aminotransferase levels (grade 1, 39%; grade 2, 6%), thrombocytopenia (grade 1, 33%), fatigue (grade 1, 28%; grade 2, 6%), infusion reaction (grade 1, 11%; grade 2, 17%), and nausea (grade 1, 33%). Only 1 patient experienced a grade 3 effect, which was anemia, and no grade 4 or 5 toxicities were reported.8

“Trastuzumab deruxtecan, first reported at ASCO 2 years ago in lung cancer, took us by storm,” Langer noted.

The novel ADC was evaluated at a dose of 6.4 mg/kg every 3 weeks in patients with nonsquamous NSCLC overexpressing HER2 or containing a HER2-activating mutation, as part of the pivotal phase 2 DESTINY-Lung01 trial (NCT03505710).

Initial data from the cohort of patients with HER2 mutations (n = 42) showed that at a median follow-up of 8.0 months (range, 1.4-14.2), the agent elicited an ORR of 61.9% (95% CI, 45.6%-76.4%) per independent central review (ICR).9 The median PFS was 14.0 months (95% CI, 6.4-14.0), and the OS was not yet reached (95% CI, 11.8–not evaluable).

At a median follow-up of 13.1 months (range, 0.7-29.1), trastuzumab deruxtecan elicited a centrally confirmed objective response in 55% (95% CI, 44%-65%) of patients per ICR assessment.10

“There is nothing more sobering than additional phase 1 data, although the response rate is holding up for the most part,” Langer noted. “Remember, these are previously treated patients. The median number of prior [therapies received] was 2, and 95% of patients had prior platinum-based treatment. Two-thirds had prior immunotherapy.”

The median PFS with this additional follow-up was 8.2 months (95% CI, 6.0-11.9), and the median OS was 17.8 months (95% CI, 13.8-22.1).10 “[Although] the PFS has come down from 14 months to 8.2 months…that is still quite respectable,” Langer said.

The most common treatment-emergent AEs experienced with trastuzumab deruxtecan were nausea and fatigue. Moreover, neutropenia and lung infections required dose interruptions and reductions.9 “Interstitial lung disease is a big class concern, and certainly an AE of interest,” Langer said. “Eleven percent of patients had this, [although these effects] were mostly grade 2 and mostly responsive to steroids.”

TEAEs resulted in dose reductions for 38.1% of the 42 patients and dose interruptions in 59.5% of patients; these effects were drug related in 38.1% and 47.6% of patients, respectively. Moreover, 23.8% of patients experienced TEAEs that resulted in treatment discontinuation; 19.0% of these cases were related to the study drug.9

“[When looking at the] 2 ADCs side by side, clearly, trastuzumab deruxtecan looks somewhat more active. That holds true when we compare this with other agents, including the TKIs that have been tested,” Langer said. “Response rates for the older drugs, for the most part, are below 50%, and [they also have] a shorter PFS and [OS].”

Is There a Role for Checkpoint Inhibitors in HER2-Mutated NSCLC?

In another study, investigators evaluated the landscape of PD-L1 and tumor mutational burden (TMB) in HER2-mutant lung cancers and their response to immune checkpoint blockade.11 They identified 122 patients with HER2 mutations; 87 were identified through PD-L1 immunohistochemistry and 84 through next-generation sequencing.

Twenty-six patients received treatment. In these patients, the ORR was 12% (95% CI, 3%-30%), and this included 3 partial responses (PRs); 8 patients had stable disease, and 15 patients experienced disease progression. Notably, all responders had a PD-L1 expression of 50% or higher and/or a high TMB.

“The general consensus is that the response rate was low,” Langer said.

In another study, investigators retrospectively examined outcomes of patients with HER2-mutated NSCLC treated with an immune checkpoint inhibitor alone or in combination with chemotherapy.12 Twenty-seven patients received this is in the first-line setting, and 34 received it in the second or subsequent lines.

In treatment-naïve patients who received chemoimmunotherapy, the ORR was 52%, the median PFS was 6 months, and the 1-year OS rate was 88%. In those who received an immune checkpoint inhibitor alone in second or subsequent lines of treatment, the ORR was 16%, the median PFS was 4 months, and the median OS was 10 months.

“You see a short median PFS, even with the addition of chemotherapy,” Langer noted.

Trastuzumab Deruxtecan: Which Line to Leverage?

A study led by Mark G. Kris, MD, the William and Joy Ruane Chair in Thoracic Oncology at Memorial Sloan Kettering Cancer Center, examined whether colleagues would administer trastuzumab deruxtecan in the frontline or the second line.

Thirty-eight percent of MSK attendings shared that they would administer the ADC in the frontline setting followed by pemetrexed or cisplatin/carboplatin with or without pembrolizumab (Keytruda). Sixty-two percent shared they would use it in the second-line setting after chemotherapy with or without pembrolizumab.

“I was involved in a Research-to-Practice survey and the number for frontline [use] crept up a little bit, to 45%,” Langer said. “However, I still think the field is split on whether it should be [utilized] in the frontline [setting] or not. There is certainly interest in moving this [agent] earlier in treatment, potentially to the frontline setting.”

A phase 2 trial will evaluate neoadjuvant trastuzumab deruxtecan in patients with resectable stage II to III HER2-amplified and HER2-mutant lung cancer. To be eligible, patients will need to have an ECOG performance status of 0 or 1.

Study participants will receive the ADC at 5.4 mg/kg every 3 weeks for 2 cycles as neoadjuvant treatment, and then they will proceed to surgery. Following their procedure, and a pathological response assessment, they will receive adjuvant treatment with standard-of-care platinum-based chemotherapy with or without immunotherapy per physician discretion and enter follow-up.

The primary end point of the trial is major pathological response, and secondary end points include pathologic complete response, ORR, nodal downstaging, event-free survival, disease-free survival, OS, and cell-free DNA clearance rate.


  1. Langer C. HER2 Tx in advanced NSCLC: from TKIs to ADCs. Presented at: 23rd Annual International Lung Cancer Congress®; July 28-30, 2022; Huntington Beach, CA. Accessed July 28, 2022.
  2. Offin M, Feldman D, Ni A, et al. Frequency and outcomes of brain metastases in patients with HER2-mutant lung cancers. Cancer. 2019;125(24):4380-4387. doi:10.1002/cncr.32461
  3. 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(17):1421-1427. doi:10.1093/annonc/mdv186
  4. Lai WV, Lebas L, Barnes TA, et al. Afatinib in patients with metastatic or recurrent HER2-mutant lung cancers: a retrospective international multicentre study. Eur J Cancer. 2019;109:28-35. doi:10.1016/j.ejca.2018.11.030
  5. Heymach J, Negrao M, Robichaux J, et al. OA02.06 a phase II trial of poziotinib in EGFR and HER2 exon 20 mutant non-small cell lung cancer (NSCLC). J Thorac Oncol. 2018;13(10):S323-S324. doi:10.1016/j.jtho.2018.08.243
  6. Wang Y, Jiang T, Qin Z, et al. HER2 exon insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib. Ann Oncol. 2019;30(3):447-455. doi:10.1093/annonc/mdy542
  7. Li BT, Michelini F, Misale S, et al. HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers. Cancer Discov. 2020;10(5):674-687. doi:10.1158/2159-8290.CD-20-0215
  8. 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
  9. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504
  10. 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
  11. Lai W-CV, Feldman DL, Buonocore DJ, et al. PD-L1 expression, tumor mutation burden and response to immune checkpoint blockade in patients with HER2-mutant lung cancers. J Clin Oncol. 2018;36(suppl 15):9060. doi:10.1200/JCO.2018.36.15_suppl.9060
  12. Saalfeld FC, Wenzel C, Christopoulos P, et al. Efficacy of immune checkpoint inhibitors alone or in combination with chemotherapy in NSCLC harboring ERBB2 mutations. J Thorac Oncol. 2021;16(11):1952-1958. doi:10.1016/j.tho.2021.06.025
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