Arsenal of Targeted Therapies Slated to Expand in NSCLC

Badi El-Osta, MD, discusses the targeted agents that are showing the most promise for patients with non–small cell lung cancer who have rare alterations and variants.

Badi El-Osta, MD

Next-generation sequencing is recommended for patients with advanced non—small cell lung cancer (NSCLC) irrespective of smoking status, as there are several emerging agents for patients who harbor historically difficult-to-target alterations.

“These are now druggable mutations that give our patients an opportunity to live longer lives with good quality of life,” said Badi El-Osta, MD, in a presentation during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer.

At the meeting, El-Osta, an assistant professor in the Department of Hematology and Medical Oncology at Winship Cancer Institute, Emory University School of Medicine, discussed the targeted agents that are showing the most promise for patients with rare alterations and variants.

BRAF V600E Mutations

BRAF V600E activating mutations are present in approximately 1% to 2% of lung adenocarcinomas. Since 2018, the FDA-approved standard of care has been the combination of dabrafenib (Tafinlar) and trametinib (Mekinist). The approval was based on phase II results from a cohort of treatment-naïve BRAF-positive patients (n = 36) who experienced an objective response rate of 64% with the combination.1

“The combination has similar efficacy to frontline therapy with earlier-generation EGFR- and ALK-targeted agents,” said El-Osta.

Regarding safety, there were ≥1 grade 3/4 adverse events (AEs) observed in 69% of the study population. Additionally, 22% of patients discontinued treatment due to an AE and up to 47% of patients required a dose reduction. However, given the small sample size, the toxicity profile was likely magnified and should be interpreted with caution, said El-Osta.

NTRK Fusions

In November 2018, larotrectinib (Vitrakvi) became the first FDA-approved tissue-agnostic targeted cancer treatment. The pan-TRK inhibitor was approved for adult and pediatric patients with locally advanced or metastatic solid tumors with an NTRK gene fusion following evaluation in a cohort of 55 adults and children. Only 7% of the study population had lung cancer, and among the entire population the most common gene fusions were found in NTRK1 and NTRK3.

The ORR with the agent was 75% (95% CI, 61-85), within which the complete response rate was 13%, the partial response rate was 62%, and the stable disease rate was 13%.2 In addition to its potency, the agent has been shown to induce rapid and durable responses, with a median time to treatment response of 1.8 months and a PFS of 55% at 1 year.

Most of the AEs reported in the trial were acute and included increased liver transaminase levels, nausea, vomiting, and fatigue. Notably, no patient had to discontinue therapy due to a treatment-related adverse event (TRAE), said El-Osta.

Another agent slated to be approved by the FDA in the NTRK—fusion space is entrectinib. In February 2019, the agency granted a priority review designation to a new drug application for entrectinib as a treatment for select adult and pediatric patients with NTRK fusion—positive locally advanced or metastatic solid tumors, as well as patients with metastatic ROS1-positive NSCLC.

The application is based on results from an integrated analysis of the phase II STARTRK-2, phase I STARTRK-1, and the phase I ALKA-372-001 trials, in which entrectinib elicited a 57.4% ORR in patients with NTRK fusion—positive solid tumors and a median duration of response of 10.4 months.3 Data from the phase I/Ib STARTRK-NG study also supported the application.

RET Fusions

RET fusions are found in approximately 1% to 2% of all NSCLC cases and have several variants, the most common of which is KIF5B. CCDC6 is the second most common variant and has been associated with acquired resistance to osimertinib (Tagrisso), said El-Osta. Patients with RET fusions do not benefit from chemotherapy or immunotherapy and have shown modest response rates to multikinase inhibition.

However, these patients have shown a particular amenability to selective RET inhibition with BLU-667 or LOXO-292, both of which have been granted breakthrough therapy designations by the FDA for use in patients with RET fusion—positive NSCLC after progression on platinum-based chemotherapy.

BLU-667, which has a recommended phase II dose of 400 mg daily, is being evaluated in the ongoing phase II ARROW trial in patients with RET-positive, unresectable, refractory solid tumors. Two-thirds of patients in the NSCLC cohort have been exposed to prior platinum therapy, and one-third of those in the entire NSCLC cohort are current or former smokers, said El-Osta.

At the 2019 ASCO Annual Meeting, updated results from the ARROW study revealed an ORR of 60% with the agent, and a disease-control rate of 100% among patients with prior platinum exposure.4 Moreover, BLU-667 was shown to be active against central nervous system disease, reducing measurable metastasis in 78% of patients.

The agent also appeared to be well tolerated, requiring only 7% of patients to discontinue treatment due to TRAEs, said El-Osta.

MET Exon 14 Alterations

MET exon 14 alterations are slightly more common, comprising 3% to 4% of NSCLC cases. They are more likely to be found in older patients with sarcomatoid histology, added El-Osta. Type I inhibitors under investigation include crizotinib (Xalkori), capmatinib, tepotinib, savolitinib. These agents have demonstrated more favorable responses than what has been observed with Type II inhibitors, such as cabozantinib (Cabometyx) and merestinib, said El-Osta.

To date, capmatinib has shown the most potency, with an ORR of 67.9% in the frontline setting.5

Notably, using these MET TKIs in the frontline setting for patients with MET exon 14-altered NSCLC demonstrate higher clinical activity than the current standard of either pembrolizumab (Keytruda) monotherapy or combination chemoimmunotherapy.

“When you compare the responses with capmatinib or tepotinib with the responses seen with our current standards of care, the ORR is higher and the PFS is similar,” explained El-Osta.

Notably, capmatinib has shown a higher toxicity profile than tepotinib (grade ≥4 AEs, 4.5% vs 0%, respectively) and has resulted in a higher discontinuation rate at 11% versus 4.6%, respectively, he added.

HER2 Activating Mutations

HER2 activating mutations reside in 2% of all lung cancers. Although investigators had hoped to capitalize on the success seen with trastuzumab (Herceptin) in breast cancer by selecting patients based on HER2 expression, disappointing results ensued. Despite the modest activity of additional HER2-targeted therapies like neratinib (Nerlynx), investigators continued to pursue therapies that proved to be of benefit in HER2-positive breast cancer.

One such agent was ado-trastuzumab emtansine (T-DM1; Kadcyla), which was evaluated in a single-center, phase II basket trial of 18 patients, the majority of whom were female. The study was well representative of a smoking and nonsmoking population, and half of patients had received prior HER2-targeted therapy.

In the trial, patients received 3.6 mg/kg of intravenous T-DM1 every 3 weeks until progression. The study exceeded its primary endpoint of >40% ORR by 4% (95% CI, 22-69). Furthermore, the median PFS was 5 months (95% CI, 3-9 months).6

“The AEs were mainly grade 1/2, similar to what we see with T-DM1 in breast cancer,” said El-Osta. Although infusion reactions were higher in the trial than in practice in breast cancer, they were easily managed by slowing infusion times, adding antihistamines, or using acetaminophen with subsequent doses, explained El-Osta.

Ultimately, investigators failed to report a correlation between HER2 amplification and response to T-DM1. However, HER3 overexpression was found in responders, indicating a unique amenability to T-DM1, said El-Osta.

KRASG12C Mutations

KRASG12C mutations were one of the first oncogenes to be discovered, and they are found in approximately 13% of NSCLC cases. These mutations remained elusive for over 30 years, despite various attempts to develop effective targeted therapies. Encouragingly, data from the lung cohort of a phase I basket trial in patients with solid tumors (n = 35), showed that AMG 510 induced a partial response rate of 50% and stable disease rate of 40% in 10 evaluable patients.7

“AMG 510 is a TKI that that binds to the cysteine 12 of the mutated KRAS protein and blocks it irreversibly,” said El-Osta.

Preliminary data have yet to show any amount of grade ≥4 toxicities, he added.

Tumor Mutational Burden (TMB)

TMB has been posited as a potential biomarker for the frontline combination of nivolumab (Opdivo) and ipilimumab (Yervoy). In the phase III CheckMate-227 trial, previously untreated patients with stage IV or recurrent disease who did not harbor an EGFR or ALK alteration were randomized to receive the combination, nivolumab alone, or chemotherapy.

Patients were well balanced between arms in terms of age, sex, smoking status, histology, and PD-L1 expression. However, patients randomized to receive the immunotherapy combination had a slightly better performance status overall.

Notably, patients who had ≥10 mutations/megabase (mut/Mb) experienced a significant improvement in PFS with nivolumab/ipilimumab versus chemotherapy (HR, 0.58; 97.5% CI, 0.41-0.81; P <.001).8

However, in January 2019, Bristol-Myers Squibb (BMS), the manufacturer of both nivolumab and ipilimumab, withdrew its supplemental biologics license application for the combination of nivolumab and ipilimumab for the first-line treatment of patients with advanced NSCLC with TMB ≥10 mut/Mb following discussions with the FDA.9

The application was initially accepted in June 2018 based on additional data from the phase III CheckMate-227 trial, which showed that the 1-year PFS rate was 43% for patients with high TMB assigned to nivolumab/ipilimumab compared with 13% for patients who received platinum-doublet chemotherapy.

In October 2018, BMS submitted an exploratory OS analysis to the FDA from part 1 of the CheckMate-227 trial, which comprised a TMB <10 mut/Mb subgroup of patients with stage IV or recurrent NSCLC who did not have prior therapy. With these new data, the FDA extended the review period by 3 months, which made the new action date May 20, 2019. Yet, the new findings showed no difference in survival between patients whose tumors had high or low levels of TMB.

“The rarity of these mutations and their variants make randomized clinical trials challenging,” concluded El-Osta. “Further studies and worldwide collaboration are needed to develop [selective] therapies alongside adequate molecular selection.”


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  9. Bristol-Myers Squibb Reports Fourth Quarter and Full Year Financial Results. Bristol-Myers Squibb. Published January 24, 2019. Accessed January 24, 2019.