Novel targeted therapies against ALK, BRAF, and RET have demonstrated promising outcomes in molecularly-defined patients with non-small cell lung cancer.
Sai-Hong Ignatius Ou, MD, PhD
Novel targeted therapies against ALK, BRAF, and RET have demonstrated promising outcomes in molecularly-defined patients with non-small cell lung cancer (NSCLC), according to a collection of phase II studies presented at the 2015 ASCO Annual Meeting.
In the first study, the second-generation ALK inhibitor alectinib demonstrated robust activity in patients with ALK-positive NSCLC following progression on crizotinib (Xalkori), including those with central nervous system metastases.1 In data presented from the phase II trial, alectinib showed an overall response rate (ORR) of 50%, with a duration of response of 11.2 months.
In another study presented during the oral abstract session, the combination of the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) showed promising efficacy and a tolerable safety profile, in a single-arm phase II study. The ORR with the combination was 68% by independent review in patients with BRAFV600E-mutant NSCLC.2
In a third analysis, the multikinase inhibitor cabozantinib demonstrated responses in a relatively rare population of patients with RET-rearranged lung adenocarcinoma.3 In this phase II study, responses were seen in 38% of patients with this rare alteration, which is present in approximately 1% to 2% of individuals with lung cancer.The highly selective oral ALK inhibitor alectinib has potent clinical activity against many of the clinically relevant acquired resistance mutations that render crizotinib ineffective, according to the study presented by Sai-Hong Ignatius Ou, MD, PhD.
This activity allows alectinib to be highly effective following crizotinib resistance. Additionally, alectinib has demonstrated activity in the central nervous system (CNS), which is a common site of progression for patients treated with crizotinib.
In the phase II study, 122 crizotinib-pretreated patients were evaluable for response. The median age of patients was 51.6 years and 60% had baseline central nervous system (CNS) metastases. Most patients (80%) had received prior chemotherapy.
The median progression-free survival (PFS) with alectinib was 8.9 months (95% CI, 5.6-11.3). The ORR in the full population of patients was 50%, which consisted of all partial responses (PR). The stable disease rate was 35%, for a total disease control rate of 96% (95% CI, 70.6-85.6).
"Alectinib achieved a robust response rate in crizotinib-resistant patient populations, a majority of whom received a platinum-based chemotherapy," Ou, a health science associate clinical professor at the University of California, Irvine, said during his presentation.
In all patients enrolled in the study with CNS metastases, the CNS-specific ORR was 57.1%, with a complete response (CR) rate of 27.4%. In those with untreated CNS metastases, the CR rate was 43.5%.
"The disease control rate in the CNS was excellent, with a sustained median duration of 10.3 months," Ou commented. "These data taken together may signal a new standard of care for CNS metastases in ALK-positive non-small cell lung cancer."
Grade 3/4 adverse events were relatively infrequent. Dose reductions due to adverse events were required in 8.7% of patients. Dose delays or interruptions were needed in 19.6% of patients.
"More than 90% of patients were able to tolerate alectinib without dose reductions," Ou said.
In a second study being presented at the ASCO meeting, treatment with alectinib demonstrated an ORR of 47.8%.4 In patients with CNS metastases, the ORR was 68.8% in this study, with a median duration of response of 7.5 months.
Genentech, the company developing alectinib in the United States, plans to submit results from the two clinical trials presented at ASCO to the FDA for a potential approval for patients with ALK-positive NSCLC. Alectinib was approved in Japan for this indication last year, under the name Alecensa.
The phase III ALEX study is comparing alectinib with crizotinib in chemotherapy-naive patients with ALK-positive NSCLC. In this study, alectinib will be administered at 600 mg twice daily with food. The study hopes to enroll 286 patients, with early results expected in 2018.Findings from the first 33 patients enrolled in a phase II study investigating the combination of dabrafenib and trametinib were presented by Bruce E. Johnson, MD, during the oral abstract session. In this study, dabrafenib was administered at 150 mg twice daily and trametinib was given at 2 mg once daily for patients with previously treated BRAFV600E-mutated NSCLC.
Bruce E. Johnson, MD
By investigator assessment, ORR was 63% (comprised of all PRs). The stable disease rate was 25% leading to a disease control rate of 88% (95% CI, 67.6-97.3). In those reviewed independently, the ORR was 68% (all PRs) and the disease control rate was 86% (95% CI, 65.1-97.1).
"Dabrafenib plus trametinib demonstrated clinically meaningful antitumor activity with a higher ORR when compared indirectly with dabrafenib monotherapy in BRAFV600E-mutated NSCLC," Johnson, chief clinical research officer at the Dana-Farber Cancer Institute, said during his presentation. "The safety profile is manageable and similar to previous studies in melanoma."
The most common adverse events observed in the trial were pyrexia, diarrhea, nausea, vomiting, decreased appetite, asthenia, cough, peripheral edema, and rash. Grade 3 toxicity was seen in 39% of patients, including hyponatremia (6%), neutropenia (6%), and dehydration (6%).
Dose reductions were required in 9 patients (27%), and 1 patient (3%) experienced grade 4 hyponatremia. There was one case of fatal pleural effusion. Cutaneous squamous-cell carcinoma and keratoacanthoma were apparent in 6% of patients.
In January 2014, dabrafenib monotherapy received a breakthrough therapy designation from the FDA for its potential as a treatment for patients with metastatic BRAFV600E mutation-positive NSCLC previously treated with chemotherapy. The treatment continues to be assessed across lung cancer indications, including in the frontline setting.
"A third study cohort investigating dabrafenib plus trametinib in previously untreated V600E mutant stage IV NSCLC is actively recruiting," Johnson noted.
The combination of dabrafenib and trametinib became the first FDA-approved combination therapy for patients with metastatic melanoma in January 2014. This approval was based on early phase data, with additional trials conducted to support the approval.
In the phase III COMBI-d trial, which was also presented at the ASCO meeting, dabrafenib plus trametinib demonstrated superior overall survival (OS) compared with dabrafenib alone.5 In the final analysis of the study, the median OS with the combination was 25.1 months compared with 18.7 months for dabrafenib alone. In 16 patients enrolled in the first stage of a phase II study, cabozantinib demonstrated an ORR of 38% (95% CI; 15-85), with a stable disease rate of 56% in patients with RET-rearranged NSCLC. The median PFS was 7 months (95% CI, 5-NA) and the median OS was 10 months (95% CI, 8-NA).
Alexander Drilon, MD
"Cabozantinib is active in patients with RET-rearranged lung adenocarcinomas," lead author Alexander Drilon, MD, Medical Oncologist at Memorial Sloan Kettering Cancer Center, said during his presentation. "This phase II trial has met its primary endpoint, with sufficient total responses to meet the primary endpoint."
Adverse events associated with cabozantinib were mostly grade 1/2; however, they did occur frequently, Drilon noted. The most common side effects were fatigue, diarrhea, palmar-plantar erythrodysesthesia, transaminitis, and thrombocytopenia. A dose reduction was required in the majority of patients (60%).
"Similar with other experience with cabozantinib, at a starting dose of 60 mg daily, most patients required a dose reduction," Drilon said. "Clinical benefit can be maintained despite dose reduction."
The FDA approved Cabozantinib in November 2012, as a treatment for patients with medullary thyroid cancer. In lung cancer, it has been assessed as a single-agent and in combination with other targeted therapies, such as erlotinib.
“Cabozantinib is an active therapy in RET-rearranged lung cancers, as demonstrated by the durable objective responses observed in the first stage of this study,” Drilon said. “While this trial continues to accrue patients to complete its second stage, it has already met its primary endpoint. Further investigation is clearly warranted.”