Two New Therapies Active in NSCLC with EGFR/HER2 Exon 20 Mutations
Toronto, Canada—Researchers are chipping away at the genetic subtypes of non–small-cell lung cancer (NSCLC). At the recent International Association for the Study of Lung Cancer World Conference, attention was focused on new drugs for NSCLC associated with EGFR and HER2 exon 20 insertions or mutations, which account for anywhere from 3% to 7% of all cases of NSCLC. The presence of these genetic alterations is associated with primary resistance to tyrosine kinase inhibitors (TKIs), with response rates below 12%.
According to results from early clinical trials, 2 new targeted therapies—TAK-788 and poziotinib—have demonstrated promising activity in this subtype of lung cancer. If later-phase studies confirm these results, these 2 new treatment options will fill an unmet need.
Early Results with TAK-788
Early results reported at the meeting for TAK-788, an EGFR/HER2 exon 20 inhibitor, were promising in patients with NSCLC with these mutations.
“Patients with EGFR exon 20 insertion tumor have historically received chemo and immunotherapy, but responses to these approaches have been relatively disappointing. TAK-788 has exhibited more promising signs of activity than other currently used off-label drugs,” said Joel Neal, MD, PhD, Assistant Professor of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Palo Alto, CA.
The investigational TAK-788 is an oral TKI with potent selective preclinical activity against EGFR and HER2 mutations, including exon 20 insertions.
A phase 1/2 clinical trial enrolled 34 patients with previously treated, advanced NSCLC with EGFR/HER2 exon 20 insertions or mutations who received oral TAK-788 in daily doses of up to 180 mg during the dose-escalation phase. Among patients with EGFR exon 20 insertion who received 80- to 160-mg doses of TAK-788 daily, 39% responded and 94% had radiographically demonstrated disease control.
“Some of the responses have lasted many months,” Dr Neal said. In all, 4 patients had disease control for more than 8 months, and 1 patient had complete radiographic response.
Adverse effects most frequently included diarrhea, nausea, fatigue, and rash, and were mostly mild; these were similar to those with other TKIs.
The researchers plan to study a 160-mg daily dose of TAK-788 in a phase 2 expansion cohort.
“We think somewhere between 3% and 7% of patients with NSCLC have tumors potentially sensitive to TAK-788, so this may fulfill an unmet need for more effective targeted therapy in these patients,” Dr Neal noted.
Poziotinib Potent EGFR/HER2 Exon 20 Inhibitor
The investigational drug poziotinib demonstrated encouraging antitumor activity in heavily pretreated patients with metastatic NSCLC and EGFR or HER2 exon 20 mutations. Encouraging activity was seen in patients who had not previously received a TKI and in patients with NSCLC that is refractory to TKIs. These results of a phase 2 trial were presented by John V. Heymach, MD, PhD, Chair, Department of Thoracic/Head and Neck Medical Oncology, M.D. Anderson Cancer Center, Houston, TX.
“Standard TKIs have generally been infective against exon 20 mutant disease,” Dr Heymach said. “For first- and second-generation TKIs, the response rate ranges from 3% to 8%.”
Poziotinib is a potent inhibitor of EGFR and HER2 exon 20 mutations and is designed to overcome the changes associated with exon 20 insertions or mutations that interfere with drug binding.
An investigator-initiated phase 2 clinical trial with poziotinib enrolled 50 patients in an EGFR cohort; 40 patients were evaluable for response. Of these patients, 65% had received at least 2 lines of treatment for metastatic disease, and 60% had grade ≥3 adverse events (ie, skin rash in 27.5% of patients; diarrhea in 12.5%).
Poziotinib achieved a best response rate of 55%, including a confirmed objective response rate of 43% among evaluable patients with EGFR exon 20 mutation–positive NSCLC. In all, 8 of the 13 patients who previously received a TKI responded, for a response rate of 62%.
A total of 13 patients were enrolled in a HER2 cohort with similar toxicities, with the exception of 1 case of grade 5 pneumonitis. Among 12 evaluable patients, the response rate was 50%.
Poziotinib was given orally at 16 mg daily until disease progression, death, or unacceptable toxicity. Of the 12 patients, 45% required dose reduction to 12 mg, and 17.5% required dose reduction to 8 mg. EGFR-related toxicities (ie, rash, diarrhea, paronychia) were manageable. One patient discontinued treatment because of grade 5 skin rash.
“The encouraging activity has prompted a confirmatory, international multicenter study in patients with EGFR and HER2 exon 20 mutations, which is currently enrolling, and now includes a first-line cohort as well as development of a separate pan-tumor ‘basket’ study,” Dr Heymach said.
Trabectedin: a DNA-Binding Agent That Covalently Interacts with the Minor Groove of the DNA Double Helix
Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by 3 fused tetrahydroisoquinoline rings.1 Trabectedin binds to the minor groove of DNA and alkylates guanine at the N2 position, bending the helix toward the major groove.2,3 In this manner, it is [ Read More ]
In my medical oncology practice at Johns Hopkins, I see approximately 4 patients with nonmetastatic NSCLC per week. Most of these patients are referrals from either pulmonary medicine or thoracic surgery. A patient with early stage disease initially sees a pulmonologist for diagnosis and may then be referred to a thoracic surgeon. The thoracic surgeon may refer the patient to us in medical oncology if there is an indication to enroll the patient in a clinical trial or for systemic therapy. In a community oncology practice, patients tend to go to surgery first and are then referred to the medical oncologist for adjuvant chemotherapy. In academic centers, it is more common for patients to be seen in a multidisciplinary setting.