Optimized Treatment Starts With Molecular Testing in NSCLC

Konstantinos Arnaoutakis, MD

Although survival data from the large, phase 3 ADAURA (NCT02511106)and CROWN (NCT03052608) trials are still anticipated in advanced non–small cell lung cancer (NSCLC), molecular testing should not be withheld from patients with non–small cell lung cancer (NSCLC) in the interim, according to Konstantinos Arnaoutakis, MD, who added that the primary results from both studies warrant discussion with patients.

“Molecular testing is important, and the use of liquid biopsies is also very important. The earlier you have that information, the better and more tailored therapy you can provide to patients,” said Arnaoutakis in an interview with OncLive® following an Institutional Perspectives in Cancer (IPC) webinar on lung cancer.

In the interview, Arnaoutakis, a hematologist, oncologist, and associate professor in the Department of Internal Medicine and Division of Hematology and Oncology at the Winthrop P. Rockefeller Cancer Institute and the University of Arkansas for Medical Sciences, discussed new strategies in the management of ALK-positive NSCLC, frontline immunotherapy, targeting EGFR, and biomarkers and targeted therapies in early-stage and advanced disease.

OncLive®: What do you hope attendees took away from the IPC summit?

Arnaoutakis: The IPC meeting was designed to educate health care professionals on the clinical benefits associated with the science driving lung cancer management. I hope that attendees not only improved their knowledge of new treatment approaches, but also left the event with confidence of how to apply state of the art treatment strategies to care for their patients. We assembled academic physicians, which focused on the most relevant lung cancer topics like EGFR-directed treatments, immunotherapy, ALK-positive disease, and new biomarkers to improve patient care.

Your presentation focused on biomarkers and targeted therapies in NSCLC where you stressed the importance but also the barriers of molecular testing. What could help circumvent some of these challenges?

Molecular testing in the management of lung cancer is very important, and even though testing is important, treatment based on testing doesn’t happen as often as we think for a variety of reasons. [Some of the reasons may be] that tissue is not available, there are delays getting results back, or even the type of testing. Oftentimes, repeat biopsies and circulating tumor DNA testing through a liquid biopsy platform could address these issues. Also, there is a growing number of FDA-approved treatments. We’re in this fortunate position that we have at least 9 FDA-approved biomarkers, including tumor mutational burden and emerging biomarkers like HER2 mutations and MET amplification. However, the growing number of treatments is causing some issues. There’s a learning curve for oncologists to learn how to use these drugs, trying to decide which drug to use and how to manage adverse effects [AEs]. Those are important topics and issues that we need to address and learn about.

What can be done to reduce some of the difficulties in advancing progress for some of these rarer molecular subsets?

Some molecular abnormalities are uncommon, so funding can be an issue. Good trial designs are also important. Many of these new drugs are approved through phase 2 studies because it’s very difficult to have phase 3 randomized studies for these relatively uncommon, molecular abnormalities. Collaboration among different institutions is paramount to gather a good number of participants. A recent example is the NRG1 fusions, which are oncogenic drivers across multiple tumor types, including lung cancer, but these are difficult to study because of their rarity.

There was a recent Journal of Clinical Oncology article; the first author was Dr Alexander Drilon, and Dr Stephen Liu was the last author. This was a global international registry that was established to characterize NRG1 fusion–positive lung cancer. Some of these [series] are examples of international multicenter collaborations that are very important. Another issue is the mechanism of resistance [associated with these agents], which is important since resistance, in some ways is unavoidable, at least for now. Another example is the NTRK fusions, for which we already have 2 agents that try to address that issue. These are drugs that are targeting the NTRK mutations that are causing the resistance.

Anastasios (Tassos) Dimou, MD, talked about new strategies in the management of ALK- positive NSCLC. Which of the ALK inhibitors have become preferred frontline agents?

Dr Dimou discussed the results of the CROWN study where lorlatinib [Lorbrena] was tested. Lorlatinib is now approved by the FDA for use in patients with newly diagnosed ALK-positive NSCLC, joining ceritinib [Zykadia], alectinib [Alecensa], brigatinib [Alunbrig], and crizotinib [Xalkori] as first-line therapy options. It’s a very crowded field, and in the absence of head-to-head data with alectinib, we are left to decide how to use the very promising CROWN data in practice.

Many people propose to use lorlatinib as the preferred frontline TKI since it had probably the best-in-class overall progression-free survival hazard ratio and CNS [central nervous system] efficacy. Patients taking lorlatinib had markedly improved time to CNS progression, and the 12-month cumulative incidence of CNS progression was just 3% compared with 33% with crizotinib and about 9% or 10% with alectinib in the ALEX study [NCT02075840].

For now, some people are favoring using lorlatinib as a frontline option. I and some others continue to favor alectinib or brigatinib as we wait for [additional] results from the CROWN study. It’s something that must be thought about carefully. There are some AEs that must be factored in. Of course, the presence or absence of CNS metastases should be a critical factor since lorlatinib seems to have very good CNS penetration.

Sajjad Bhatti, MD of the University of Arkansas for Medical Sciences, spotlighted the phase 3 ADAURA trial in his presentation onEGFR. What did you find exciting about the primary results?

The use of adjuvant osimertinib [Tagrisso] demonstrated a statistically significant and clinically meaningful benefit for patients with stage IB, II, and IIIA EGFR-mutant lung cancer after complete tumor resection in the phase 3 ADAURA trial [NCT02511106]. The trial results were very impressive. They found that adjuvant therapy with osimertinib was associated with almost an 80% reduction in the risk of disease recurrence or death in patients with stage IB to IIIA EGFR-mutant lung cancer. The staging that was used in the trial was the 7th edition staging even though we currently use the 8th edition staging.

In the study, osimertinib was compared with placebo for a treatment duration of up to 3 years or until disease recurrence. The primary end point in this study was disease-free survival [DFS], and the key secondary end point was overall survival. The study was unblinded early under the recommendation of the independent data monitoring committee because of efficacy, and at the time of the unblinding, the randomized patients had been followed for at least 1 year, and the DFS curve separated early such that there was almost an 80% reduced risk of disease recurrence for the osimertinib arm, which is impressive. That benefit was seen across all stages, particularly stage II and III.

It’s very exciting that we have an adjuvant option for patients with EGFR-mutant disease, which, in the United States is about 15% of all patients with lung cancer and in Asia is about 30%. Adjuvant osimertinib is another option for a good chunk of patients with lung cancer. There is of course criticism about the fact that we don’t know yet about the survival benefit only the DFS, so that adds another point of conversation with patients, but a lot of oncologists are already discussing [adjuvant osimertinib] and testing patients with early-stage lung cancer for EGFR, because if you don’t test for it, you won’t know if they have an EGFR mutation.

A. Mazin Safar, MD, of the University of Arkansas for Medical Sciences – Veterans Affairs, discussed frontline immunotherapy regimens in advanced NSCLC. How does tolerability and disease burden influence your treatment recommendations between chemoimmunotherapy and immunotherapy alone?

We have a lot of new studies on frontline immunotherapy. CheckMate 227 [NCT02477826] and CheckMate 9LA [NCT03215706] are important studies. CheckMate 227 evaluated the combination of ipilimumab [Yervoy] and nivolumab [Opdivo] as frontline therapy. CheckMate 9LA employed 2 cycles of chemotherapy along with ipilimumab and nivolumab. These studies are important because they are adding to the information that we have from the KEYNOTE-189 [NCT02578680] and KEYNOTE-407 [NCT02775435] trials for patients with nonsquamous and squamous cell carcinoma.

We are in a fortunate position to be able to decide between different treatments; all these regimens are good, viable therapies. We must use our judgement to decide which regimen to use, considering how the patients can tolerate chemotherapy.

For example, if a patient is unable to tolerate cytotoxic chemotherapy, the CheckMate 227 regimen is a very reasonable approach for patients who have a PD-L1 expression of more than 1%. Also, some patients may have more aggressive disease where we want to incorporate cytotoxic chemotherapy up front. Of course, a discussion with the patient [that considers their] preferences is important because some patients are not interested in receiving chemotherapy, and that’s something that has to be factored in. It can be confusing for many thoracic oncologists about what the optimal regimen is in the front-line setting.