Targeting HER2 in NSCLC Remains Work in Progress

Corey Langer, MD

Although targeting HER2 mutations is primarily associated with breast cancer, there may be therapeutic potential with anti-HER2 agents in non—small cell lung cancer (NSCLC). At the 2015 International Lung Cancer Congress, Corey Langer, MD, discussed the potential for afatinib and neratinib—dual inhibitors of EGFR and HER2—in NSCLC and the need for additional research to truly understand HER2 targeted therapy in this setting.

HER2 mutations occur in about 2% to 4% of patients with NSCLC and for the most part, they are mutually exclusive with other molecular drivers (eg, EGFR, KRAS), according to Langer, director of Thoracic Oncology at the Abramson Cancer Center of the University of Pennsylvania. “Similar to EGFR and ALK, the HER2 mutations are more common in women, never-smokers, and adenocarcinoma histology,” Langer added.

Regarding use of afatinib in these patients, Langer said, “There are limited but encouraging data in patients with HER2-mutant NSCLC treated with either afatinib or afatinib plus paclitaxel.”

A single-arm, open-label phase II study evaluated afatinib in five patients with HER2-positive metastatic lung adenocarcinomas who were non-smokers.¹ Three patients were evaluable for response, with two patients discontinuing early due to toxicities. All three patients evaluated had an objective response and Langer presented their case histories.

The first patient was a woman aged 72 years who had never smoked. She had progressed on chemotherapy and had a HER2 exon 20 insertion mutation. She had a partial response (PR) to afatinib that she maintained for 3 months and continued on single-agent afatinib for a total of 9 months. Combination afatinib/paclitaxel was initiated, but she developed progressive disease in the brain and died shortly after.

The second case was a 62-year-old female never-smoker who had point mutations in EGFR (exon 21) and HER2 (exon 20). She had progressive disease after chemotherapy, progressive disease with gefitinib (Iressa), and a PR with trastuzumab (Herceptin) plus paclitaxel. When administered afatinib, she had a PR with significant clinical improvement. After 4 months, she progressed but remained on afatinib monotherapy for another 2 months. She then started the afatinib/paclitaxel combination and had stable disease for 4 months.

Patient three was a 49-year-old female never-smoker with a HER2 exon 20 insertion mutation and progressive disease following multiple lines of therapy. She quickly responded to afatinib, maintaining stable disease for 3 months. She subsequently had a PR to paclitaxel plus afatinib, which she maintained for 11 months.

Langer said there are several remaining questions with afatinib in this setting, including efficacy outcomes in patients with extracellular domain HER2 mutations, and the potential for combinations with other targeted agents.

With neratinib, Langer discussed a phase II study in which patients with stage IIIb/IV NSCLC with HER2 somatic mutations received the drug as a single agent or in combination with the mTOR inhibitor temsirolimus.²

Patients were randomized in a 1:1 ratio to 240 mg of oral neratinib once daily either alone (n = 13) or in combination with IV temsirolimus (n = 14) at 8 mg/week (escalated to 15 mg/week after one 3-week cycle if tolerated). Patients in the monotherapy arm could cross over and receive the combination at disease progression. Because neratinib is associated with significant GI toxicity, it was mandatory that patients receive high-dose loperamide prophylaxis for diarrhea throughout cycle 1.

In the overall study population, the median age was 65 years, 52% of the patients were male, and 63% were never-smokers. The primary outcome measure was objective response rate (ORR), with secondary endpoints including overall survival, progression-free survival (PFS), and safety.

ORR was 21% in the combination arm versus 0 in the monotherapy group. Six patients had stable disease lasting ≥12 weeks with the combination versus four with neratinib alone. Median PFS was 2.9 versus 4.0 months in the single-agent versus combination arms, respectively.

“Inhibition of both HER2 and PI3K pathways appeared to be superior to HER2 pathway blockade alone,” said Langer.

There were no unexpected safety issues that emerged in the study. Diarrhea of any grade occurred in 24 of 27 patients. One patient in the monotherapy arm and two patients receiving the combination had grade 3 diarrhea. Despite the high incidence, the authors noted that with aggressive upfront management, diarrhea was not a limiting toxicity.

The neratinib/temsirolimus arm met the prespecified criteria for initiating a stage 2 expanded cohort portion of the study, for which enrollment is now complete.

In his concluding remarks, Langer said these small studies with HER-targeted therapies show promise, but more research is needed. “Anti-HER2 agents and, particularly, monoclonal antibodies, seem to be effective in the HER2-mutant NSCLC population; however, we desperately need more prospective data.”

References

1. De Grève J, Teugels E, Geers C, et al. Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu. Lung Cancer. 2012;76(1):123-127.
2. Besse B, Soria J, Yao B, et al. Neratinib (N) with or without temsirolimus (TEM) in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2 somatic mutations. Ann Oncol. 2014;25(5):1-41.