Emerging Drugs Effectively Tackle Non–Small Cell Lung Cancer Mutations


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James Chih-Hsin Yang, MD, PhD

Enriqueta Felip, MD, PhD

David Planchard, MD, PhD

These findings show the longest median [progression-free survival] we have seen in this broad [NSCLC] patient population, and it is even more striking when you consider that most of them have had up to three rounds of chemotherapy before taking ceritinib as their first ALK inhibitor.

—Enriqueta Felip, MD, PhD

For advanced nonsquamous non–small cell lung cancer (NSCLC), targeting of the epidermal growth factor receptor (EGFR) mutation and the ALK abnormality has become an established strategy. Later-generation drugs in these categories are now showing efficacy in trials, including for the treatment of resistant disease. In addition, promising data are emerging for compounds that target less common mutations. These advances are demonstrated by the results seen in studies presented at the European Society for Medical Oncology (ESMO) 2014 Congress in Madrid.

AZD9291 in NSCLC

The investigational drug AZD9291 holds promise for the treatment of EGFR mutation–positive, T790M-positive advanced NSCLC in patients whose disease has progressed after treatment with an EGFR tyrosine kinase inhibitor. The ongoing AURA phase I and extension study has enrolled 253 pretreated patients, and the 80-mg dose is going forward in a separate study.1

A preliminary analysis of the phase I and extension trial showed that pretreated patients with progressive disease who received AZD9291 had a median progression-free survival of 9.6 months, but these data are still immature and are based on the first 138 patients enrolled in the trial, noted lead author James Chih-Hsin Yang, MD, PhD, of National Taiwan University College of Medicine, Taipei. “We are confident that the progression-free survival will be even longer, given that most patients are still censored before the estimated median time,” he said.

AZD9291 is a highly selective, irreversible inhibitor of both the activating EGFR mutation and the T790M mutation, which is thought to be responsible for resistance in about half of all patients with EGFR-positive advanced NSCLC. Thus far, no treatments are specifically approved for EGFR mutation–positive, T790M mutation–positive patients. The drug has been given Breakthrough Therapy designation, as well as Orphan Drug and Fast Track status by the U.S. Food and Drug Administration (FDA).

Ceritinib in ALK-Positive NSCLC

Data from the pivotal ASCEND-1 trial show that patients with ALK-positive NSCLC treated with ceritinib (Zykadia) as their first ALK inhibitor had a median progression-free survival of more than 18 months.2 Overall data from this study of 246 patients show that ceritinib is efficacious in patients whether or not they received a previous ALK inhibitor. In addition, ceritinib is active in patients with brain metastases and may be an effective therapy for this difficult-to-treat site of disease progression, shrinking brain tumors in about one-third of the 29 patients who entered the study with measurable brain lesions.

“These findings show the longest median [progression-free survival] we have seen in this broad patient population, and it is even more striking when you consider that most of them have had up to three rounds of chemotherapy before taking ceritinib as their first ALK inhibitor,” said lead author Enriqueta Felip, MD, PhD, of Vall d’Hebron University, Barcelona.

In the main trial (including both ALK inhibitor–pretreated and not-pretreated patients), ceritinib achieved an overall response rate of 61.8% and median progression-free survival of 9 months in all patients. Among 83 patients who had not received a previous ALK inhibitor, overall response rate was 72.3% and median progression-free survival was 18.4 months. Among a subset of 163 patients who were previously treated with the ALK inhibitor crizotinib (Xalkori), overall response rate was 56.4% and median progression-free survival was 6.9 months.

Ceritinib is approved by the FDA for the treatment of patients with ALK-positive metastatic NSCLC who have had disease progression on or are intolerant to crizotinib.

Targeting the BRAF V600E Mutation

In patients with BRAF V600E mutations, the BRAF inhibitor dabrafenib (Tafinlar) has become the first drug of its class to demonstrate clinically meaningful antitumor activity and durable responses, according to a study presented by David Planchard, MD, PhD, of Gustave-Roussy in Villejuif, France.3

“NSCLCs with BRAF V600E mutations have histologic features suggestive of an aggressive tumor, and patients with these mutations demonstrate less favorable outcomes with platinum-based chemotherapy,” Dr. Planchard indicated. The Lung Cancer Mutation Consortium has indicated that BRAF V600E mutations occur in < 2% of adenocarcinomas, and the BRAF V600E mutation represented 80% of the BRAF mutants.

The multicenter, open-label phase II BRF113928 trial, involving 70 sites in 11 countries, enrolled 78 NSCLC BRAF V600E–mutated patients who had received at least one prior line of treatment. Patients received dabrafenib at 150 mg twice daily.

Investigator-assessed best confirmed responses included partial responses in 32% and stable disease in 24% of patients (14% were not evaluable), for a disease control rate of 56%. Response rates appeared to be higher in nonsmokers. All but a few patients actually had a reduction in tumor burden but did not meet the criteria of ≥ 30% reduction in diameter (to be labeled responders), he added.

“We saw that 52% of the partial responses are still ongoing,” he said. The median duration of response was 11.8 months, and median progression-free survival was 5.5 months, with 62% of patients having had disease progression or died.

“The safety profile was manageable and generally consistent with previous studies in melanoma,” Dr. Planchard reported. The most common adverse events were pyrexia, asthenia, hyperkeratosis, decreased appetite, nausea, cough, fatigue, and skin papilloma. Cutaneous squamous cell carcinomas and keratoacanthomas were reported in 18% of patients.

A second cohort is to be treated with dabrafenib plus the MEK inhibitor trametinib (Mekinist), and this arm is actively recruiting. Dr. Planchard indicated that a larger phase III trial may not be feasible, considering the rare occurrence of this abnormality.

Targeting the HER2 Mutation

Similar to the frequency of BRAF mutations, somatic HER2 mutations occur in about 2% of NSCLC patients, mostly in tumors with adenocarcinoma histology. Comprehensive molecular profiling suggests that HER2 mutations are mutually exclusive of other driver aberrations in NSCLC, including KRAS, EGFR, and ALK. The most common type of HER2 mutations are in-frame insertions within the kinase domain, according to Benjamin Besse, MD, also of the Institut Gustave-Roussy.

The investigational agent neratinib is a potent, irreversible, pan-HER tyrosine kinase inhibitor that has been shown to inhibit the growth of tumor xenografts that harbor aberrant HER2 pathway activation. Preclinical and phase I data suggest there may be synergistic efficacy with combined HER2 and mTOR inhibition, in HER2 mutation–positive NSCLC, Dr. Besse indicated.

The PUMA-NER-4201 study included 27 advanced NSCLC patients with documented HER2 mutations; all but two patients had received prior treatment.4 In the first stage of the study, patients were randomly assigned to neratinib at 240 mg/d or neratinib plus the mTOR inhibitor temsirolimus (Torisel) at 8 mg/wk. In the absence of toxicity, the dose was increased to 15 mg/wk for cycle 2. Crossover from single-agent neratinib was allowed after disease progression. Antidiarrheal prophylaxis was given to all patients.

The study design calls for expansion to a second stage with 39 patients if there are two or more responders at 12 weeks. At the ESMO meeting, Dr. Besse presented the stage 1 analysis.

In the neratinib/temsirolimus combination arm, partial responses were observed in 21% and stable disease in 79%; no patients demonstrated progressive disease. With neratinib alone, there were no responders, and 54% of patients had stable disease. Median progression-free survival was 4.0 months vs 2.9 months, respectively, Dr. Besse reported.

The median duration of treatment was 17.5 weeks with the combination and 9.1 weeks with neratinib alone. Dose reductions or holds were necessary for neratinib in 13 of 14 patients in the combination arm compared with 6 of 13 patients in the single-agent arm. For temsirolimus, 9 of 14 patients had doses withheld.

“We observed no apparent correlation between HER2 mutation type and response,” he said.

Five patients in the neratinib arm have crossed over to receive the combination, and of them, one is still on treatment while four have had disease progression. ■

Disclosure: Dr. Yang serves on advisory boards for Boehringer Ingelheim, Lilly, Pfizer, Novartis, Roche/Genentech, AstraZeneca, Merck, Bayer, and Clovis Oncology and has received research support from Boehringer Ingelheim. Dr. Felip has served on advisory boards for Boehringer Ingelheim, Novartis, Roche, Bristol-Myers Squibb, and Lilly. Dr. Planchard has received personal fees for participating in advisory boards from AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Roche, and Bristol-Myers Squibb. Dr. Besse has received research grants from Puma.

References

1. Yang JC, Kim D, Planchard D, et al: Updated safety and efficacy from a phase I study of AZD9291 in patients with EGFR-TKI-resistant non-small cell lung cancer. ESMO Congress. Abstract 449PD. Presented September 27, 2014.

2. Felip E, Kim D, Mehra R, et al: Efficacy and safety of ceritinib in patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer: An update of ASCEND-1. ESMO Congress. Abstract 1295P. Presented September 27, 2014.

3. Planchard D, Kim TM, Mazieres J, et al: Dabrafenib in patients with BRAF V600E-mutant advanced non-small cell lung cancer: A multicenter, open-label phase II trial (BRF113928). ESMO Congress. Abstract LBA38_PR. Presented September 29, 2014.

4. Besse B, Soria J-C, Yao B, et al: Neratinib with or without temsirolimus in patients with non-small cell lung cancer carrying HER2 somatic mutations: An international randomized phase II study. ESMO Congress. Abstract LBA39_PR. Presented September 29, 2014.



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