T-DM1 in HER2 Overexpressing, Amplified or Mutated Metastatic NSCLC

Highlights from ASCO 2017 Annual Meeting Clinical Science Symposium

In the Clinical Science Symposium entitled “Old Targets, New Drugs: HER2 and MET” held on 4 June during the ASCO 2017 Annual Meeting in Chicago, US, the researchers presented the results from the first study to report on the clinical activity of T-DM1 in HER2 overexpressing locally advanced or metastatic non-small cell lung cancer (NSCLC). Second presented study, the basket trial showed that T-DM1 is active and well tolerated in patients with lung cancer with HER2 activating mutations.

Efficacy, safety, and biomarker results of T-DM1 in patients with previously treated HER2 overexpressing locally advanced or metastatic NSCLC

T-DM1 is an antibody-drug conjugate approved for management of HER2-positive metastatic breast cancer. HER2 overexpression assessed by immunohistochemistry (IHC) is associated with poor prognosis in NSCLC (adenocarcinoma). In contrast to breast and gastric cancers, in NSCLC HER2 overexpression does not always co-occur with HER2 amplification. HER2 amplifications and HER2 mutations are generally mutually exclusive in NSCLC.

At ASCO 2017 Annual Meeting the researchers reported primary results from a fully enrolled, ongoing phase II study (NCT02289833) in patients with previously treated HER2 overexpressing metastatic NSCLC who received single-agent T-DM1.

Eligible patients had HER2 overexpressing metastatic NSCLC and were previously treated with platinum-based therapy. Patients received T-DM1 3.6 mg/kg every 3 weeks and were analyzed in 2 cohorts based on centrally determined HER2 status by IHC (IHC2+ vs IHC3+ [≥10% cells stained with 2+ or 3+ intensity, respectively]). HER2 amplification was assessed via ISH (HER2 gene ratio ≥2.0).

The primary endpoint is objective response rate (ORR; proportion of patients with confirmed [≥4 weeks] complete or partial response per RECIST v1.1 criteria). The clinical cut-off date for this analysis was 26 October, 2016.

Of 393 screened patients, 102 (26%) were IHC2+ and 31 (8%) were IHC3+. In total, 49 patients (IHC2+, n = 29; IHC3+, n = 20) received T-DM1. At cut-off, median follow-up was 16.3 (range 0.9*–22.4; * = censored observation) months. No IHC2+ patient had a response (0%, 95% CI 0–11.9); 4 IHC3+ patients had partial responses (20%, 95% CI 5.7–43.7) with a median duration of response of 7.3 (range 2.9–8.3) months.

Median progression-free survival (PFS) in IHC2+ and IHC3+ patients was 2.6 (95% CI 1.4–2.8) and 2.7 (95% CI 1.4–8.3) months, respectively. At 6 months after start of study treatment, 9 patients (IHC2+, n = 4; IHC3+, n = 5) were still at risk for a PFS event.

Median overall survival was 12.2 (95% CI 3.8–not estimable [NE]) months in IHC2+ patients and 12.1 (95% CI 9.3–NE) months in IHC3+ patients.

An exploratory biomarker analysis suggested that responses may be more likely in patients with both HER2 IHC 3+ and HER amplification by next-generation sequencing. Of five patients meeting these criteria, two had objective responses to T-DM1.

Eleven patients (22%) experienced a grade 3–4 adverse event, with fatigue and dyspnoea being the only events reported in > 1 patient (n = 2 each).

The authors concluded that it is the first study to report on the clinical activity of T-DM1 in HER2 overexpressing metastatic NSCLC. Objective responses were observed in IHC3+ patients. Additional investigation into improved detection of HER2 amplification and other biomarkers may help to refine the patient population who is likely to benefit from T-DM1.

T-DM1 in patients with HER2 mutant lung cancers: Results from a phase II basket trial

HER2 mutations occur in 2% of lung cancers, resulting in receptor dimerization and kinase activation with in vitro sensitivity to trastuzumab.

Patients with HER2 mutant lung cancers were enrolled into a cohort of the basket trial (NCT02675829) of ado-trastuzumab emtansine (T-DM1) in HER2 amplified or mutant cancers, treated at 3.6 mg/kg i.v. every 3 weeks. The primary endpoint was ORR using RECIST v1.1 criteria. A Simon two stage optimal design was used. Other endpoints included duration of response (DoR), PFS and toxicity.

HER2 testing was performed on tumour tissue by next generation sequencing (NGS), fluorescence in situ hybridization (FISH) and IHC.

The cohort completed accrual with 18 patients treated. The median age was 63 (range 47-74 years), 72% were female, 39% were never smokers and all had adenocarcinomas. The median lines of prior systemic therapy was 2 (range 0-4).

The study met primary endpoint with ORR of 44% (8/18 confirmed, 95% CI 22-69%). Median DoR was not reached (range 3 to 7+ months), median PFS was 4 months (95% CI 3 months-not reached). Six of 8 responders were heavily pretreated including prior HER2 targeted therapy.

There were 10 (56%) exon 20 insertions and 8 (44%) point mutations and indels in all major domains of HER2. Responders were seen across mutation subtypes (A775_G776insYVMA, G776delinsVC, V659E, S310F). HER2amplification was negative for all patients by NGS and positive for 1 of 12 patients by FISH. There was no IHC3+ in 10 patients tested.

There is ongoing translational work in term of HER2 targeted imaging, HER2 clonality and HER2 functional analysis and PDX models.

Toxicities were mainly grade 1 or 2 including infusion reaction, thrombocytopenia and transaminitis; there were no dose reductions or treatment related deaths.

The authors concluded that ado-trastuzumab emtansine is active and well tolerated in patients with lung cancer and HER2 activating mutations. The study has met its primary endpoint and the results justify a confirmatory multicentre study for patients with lung cancer and HER2 activating mutations.

Antibody drug conjugates in HER2 positive lung cancer

Ado-trastuzumab emtansine, also known as T-DM1, is a HER2 targeted antibody drug conjugate linking trastuzumab with the anti-microtubule agent emtansine.

Leena Gandhi, MD, PhD, of the NYU Langone Medical Center and the Laura and Isaac Perlmutter Cancer Center, who discussed the study results said that HER2 overexpression is more common than amplification or mutation. Prior studies of trastuzumab or pertuzumab in HER2 overexpressing NSCLC showed no benefit. However, in the study presented at this symposium, those patients with IHC3+ or HER2 amplification were a fraction of patients and seemed to have more benefit. She said that in overall, it is difficult to interpret HER2 overexpression as a target. Small numbers make interpretation difficult in term of relationship between amplification/mutation and expression and in term of relationship between amplification and response.

In a part of her discussion entitled “Have we identified the right target?”, she said that HER2 mutation remains the most predictive factor for response to HER2 targeted therapy, including response to T-DM1. High level expression may have some association with amplification and response. Amplification and mutation remain imperfect predictors of response to any HER2 targeted therapy. The results are awaited from the HER2 amplified cohort of the basket trial.

In a part of discussion talk entitled “Have we identified the right targeted therapy?”, she said that T-DM1 has promising response rates. The PFS improvement over chemotherapy remains elusive. Newer kinase inhibitors are under investigation (AP32788, pyrotinib, and poziotinib). She questioned if we are dealing with more complex target. Activated HER2 effect may rely on changes in dimerization partners, downstream effectors and she wondered if combination therapy might be beneficial.

References

Stinchcombe T, Stahel RA, Bubendorf L, et al. Efficacy, safety, and biomarker results of trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC).J Clin Oncol 35, 2017 (suppl; abstr 8509).

Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: Results from a phase II basket trial. J Clin Oncol 35, 2017 (suppl; abstr 8510).