Treating NSCLC with Gene Mutations - Discussion with Dr. Gregory Masters

From MEDPAGE Today

An interview with Dr. Gregory Masters discussing the latest guidelines treating non-small cell lung cancer (NSCLC) with gene mutations.

A year ago, ASCO released a clinical practice guideline on systemic therapy for patients with stage IV non-small cell lung cancer (NSCLC) without driver alterations. Part two has now been released, and it focuses on patients with stage IV NSCLC with driver alterations.

The guideline “is a result of potentially practice-changing evidence published since the last update [in 2017],” noted Gregory Masters, MD, of the ChristianaCare Helen F. Graham Cancer Center and Research Institute in Newark, Delaware, and colleagues.

The updated guideline offers 41 recommendations, including the following:

  • Patients should be offered targeted therapies against ROS-1 fusionsBRAF V600e mutations, RET fusions, MET exon 14 skipping mutations, and NTRK fusions as first- or second-line therapy when not given in the first-line setting
  • Osimertinib (Tagrisso) is the optimal first-line treatment for patients with activating EGFR mutations, such as exon 19 deletion, exon 21 L858R, and exon 20 T790M
  • Alectinib (Alecensa) or brigatinib (Alunbrig) is the optimal first-line therapy for patients with ALK fusions
  • Chemotherapy is still an option at most stages

“For the first time, to our knowledge, the guideline includes recommendations regarding RET, MET, and NTRK alterations,” the panel members noted.

For instance, stage IV NSCLC and MET exon 14 skipping mutation may be treated with MET-targeted therapy — capmatinib (Tabrecta) or tepotinib (Tepmetko) — in the first-line setting, while for patients with stage IV NSCLC and driver alterations in RET, first-line setting, selpercatinib (Retevmo) is an option.

In the following interview, Masters, the co-chair of the Expert Panel, who is also associate professor at Thomas Jefferson University Medical School in Philadelphia, offers more details on the guideline, which was produced along with Cancer Care Ontario in Canada.

Looking at the summary section of the guideline update, the evidence quality for the individual recommendations is often described as “low.” Did that come as a surprise to you and your fellow panel members given the rapid expansion of the NSCLC treatment armamentarium?

Masters: In our summary box, “The Bottom Line,” some of the recommendations, such as 1.7 [“For patients with stage IV NSCLC and driver alterations in EGFR”], are based on low-quality evidence. This is largely related to the lack of randomized clinical trials, or even larger phase II studies in these unique population subsets. We hope that over the coming years there will be additional clinical trials that more definitively answer these questions to confirm (or refute) our recommendations.

In the meantime, we thought it was important to at least address how to tackle some of these unique genetic alterations.

The updated recommendations are very extensive. Are there certain recommendations that lung cancer specialists should take particular note of and/or take as practice-changing?

Masters: The most important components of this updated guideline confirm that osimertinib is the best first-line option for patients with standard activating EGFR mutations, such as L858R and deletion 19 mutations.

Treatment of patients with ALK alterations has become quite complex, with multiple new drugs and not enough comparative trials in a unique population. In fact, there is an NCI clinical trial that attempts to address sequencing of therapy for patients with advanced non-small cell lung cancer with ALK alterations: “NRG LU-003: Biomarker driven protocol for previously treated ALK positive non-squamous non-small cell lung cancer patients.”

There are less common mutations that still have potential targeted drugs, but the data is less definitive in terms of phase III or larger phase II studies.

The guideline addresses patients with stage IV NSCLC in the following histologic or subgroups: EGFR, ALK, ROS1, BRAF, MET, RET, HER2, and NTRK, but not neuregulin-1 or PI3K/AKT/mTOR. Was there a particular reason for that?

Masters: We included clinical trials that specifically addressed the role for targeted treatment in an NSCLC population … i.e., focusing on EGFR, ALK, ROS1, BRAF, MET, RET, HER2, and NTRK. Other less common mutations that may be seen in a variety of tumors but are not well studied in a lung cancer population were not included in this guideline.

There just is not enough data to make a specific recommendation on where the targeted drugs for these gene alterations should be used. In general, for the additional mutations you mention, we recommend treatment according to the other NSCLC guideline for patients without driver mutations.

One of the topics addressed in the guideline is cost, along with a CMS reimbursement and oral drug prices Table.” Canada has a different insurance system in the form of Canadian Medicare. How do you see the guidance outlined in the Cost Implications section applying to these two different payment systems?

Masters: It is always difficult to determine the appropriate balance in terms of cost of care when new treatments come out. Different insurance providers may have a different threshold for covering emerging therapies, so they may not be universally covered until more definitive trials emerge. That is particularly true for government insurance programs.

We hope that as additional clinical trials support the use of targeted therapy, that all payers will recognize the importance of making these options available to patients. Often targeted therapy is more effective and less toxic than standard chemotherapy options, but not always.

One of the most important messages we hope to convey is that ongoing research will provide more opportunities for patients with unique characteristics of their cancer from specific gene mutations to receive optimal therapy.