Ado-Trastuzumab Emtansine Shows Activity in HER2-Mutated, Amplified Lung Cancer

Bob T. Li, MD, MPH

Ado-trastuzumab emtansine (Kadcyla) is active and well tolerated in patients with advanced HER2-mutant or amplified lung cancers as identified by next generation sequencing (NGS), according to results of a phase II basket trial presented at the IASLC 18th World Conference on Lung Cancer in Yokohama, Japan.

HER2 mutations and amplifications are known oncogenic drivers that occur in about 2% of lung cancer cases, but clinical trials of HER2 kinase inhibitors over the past decade or so have been “rather disappointing,” said lead presenter Bob T. Li, MD, MPH, a medical oncologist at Memorial Sloan Kettering (MSK) Cancer Center.

Studies of trastuzumab therapy have also been failures, but they have largely targeted HER2 protein expression, and very few patients with HER2 amplification have been studied. The result has been that there is no approved therapy for these patients, he noted.

However, there are preclinical data with in vitro sensitivity in HER2-mutant lung cancer. There are also published case reports and case theories of trastuzumab activity in patients with HER2-mutant and amplified lung disease. There has also been single agent response to ado-trastuzumab emtansine for HER2-mutant lung cancer.

MSK Cancer Center designed a basket trial to address these issues, using next generation sequencing (NGS) to identify patients with HER2 amplification and HER2-mutant cancers. Patients were classified according to HER2-mutant and HER2-amplified cancers, and in the latter group, there were several subgroups, including lung, bladder and urinary tract, and other solid tumors.

Ado-trastuzumab emtansine was given intravenously at 3.6 mg/kg once every 3 weeks until progression. The primary endpoint was objective response rate (ORR) in patients with HER2-activating mutations. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events (AEs).

Using NGS, in just over a year at MSK, 33 patients with lung cancer have been accrued into the study despite the low incidence of HER2-mutant and amplified cancers, Li said. These were heavily pretreated patients with up to 4 lines of prior therapy—including neratinib (Nerlynx), afatinib (Gilotrif), and trastuzumab (Herceptin). There were 18 patients in the HER2-mutant subgroup, 9 in the HER2-mutant by PERCIST classification, and 6 in the HER2-amplified cancer group.

In the first group, the ORR was 44% or 8 of 18 patients (95% CI, 22%-69%), and the study met its primary endpoint. Investigators also saw patients who had tumor shrinkage but did not meet RESIST v1.1 criteria for objective response, Li noted.

As for duration of patient benefit, in the same subgroup, median progression-free survival (PFS) was 5 months (95% CI, 3-no response [NR]). Six of 8 responders were heavily pretreated and had shown response to prior targeted therapy, including neratinib, afatanib, and trastuzumab. “This highlights the message that those patients can benefit from a new HER2 antibody drug conjugate, and further, future clinical trials of HER2 targeted agents should not exclude these patients,” Li said.

In the HER2 mutant category by PERCIST tumor evaluation, the ORR was 50% (n = 2 of 4) and median PFS was 6 months (95% CI, 3-NR). In the HER2-amplified lung cancer group, the ORR was also 50% (n = 3 of 6) and, of note, 1 of the patients with a confirmed partial response had a concurrent EGFR L858R mutation with no response to first-line erlotinib (Tarceva).

“HER2 amplification is a well-documented mechanism of both de novo and acquired resistance, so this is an example of how HER2 targeted therapy would overcome resistance to EGFR inhibitors,” Li remarked. The median PFS was 6 months (95% CI, 6-NR), and median OS was 12 months (95% CI, 12-NR).

There were no treatment related deaths, and grade 3 AEs were limited to 1 instance each for anemia, neutropenia, and thrombocytopenia. The most common grade 1/2 AEs included fatigue, rash, nausea, and elevated enzyme levels. There were “no major surprises” from AEs, except for infusion reactions among 15% of patients (n = 5), which Li said was somewhat higher than what is generally observed in breast cancer.

Li noted a wide range of mutation subtypes in the HER2-mutant cancer subgroup, including the “prototypical” exon 20 insertions, especially YVMA, but also kinase, transmembrane, and extracellular domain mutations. All of them responded [to treatment] but immunohistochemistry (IHC) measures of protein expression ranged from 0 to 2 or more, which meant that “IHC is not predictive of response in these patients,” Li said.

They went a step further to look at quantitative protein expression by laser micro-dissection and mass spectrometry, “and we found that, indeed, for many of those responses, HER2 expression was not high. It was actually quite low. This indicates an alternate mechanism for how the T-DM1 molecule will get into the cell, other than just protein expression,” Li said.

Among the 3 responders in the HER2-amplified cohort, scores by IHC were 3+ and the proteomics assay showed “very high levels of protein,” which Li said was consistent with what is observed in breast cancer mechanisms.

He said investigators concluded the study was worthy of follow-up.

Li B, Shen R, Buonocore Z, et al. Phase 2 basket trial of ado-trastuzumab emtansine in patients with HER2 mutant or amplified lung cancers. Presented at: IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract: OA 14.05.