The Lung Cancer Master Protocol (Lung-MAP), a large precision medicine umbrella trial supported by the National Cancer Institute (NCI) and their partners, has opened the trial to include advanced-stage patients with all non–small cell lung cancers (NSCLCs). To accommodate these new trial patients, the NCI has also made further changes to the trial’s protocol. 

The updates to the study also included a new screening protocol that recommends the use of liquid biopsies as an alternative when tissue is not available. The investigators hope that this will also ease the process of registering new patients for the trial and allow for more trial sites to open up more quickly. A further change with Lung-MAP includes 2 new sub-studies assessing PARP inhibition and a PD-L1 and VEGF inhibitor combination that opened in early 2019.1

The rationale behind the expansion of the Lung-MAP trial is to provide alternative options for patients with advanced disease. In a press release, Vassiliki A. Papadimitrakopoulou, MD, chief of thoracic medical oncology and professor of medicine at The University of Texas MD Anderson Cancer Center, said, “when most people are diagnosed with non–small cell lung cancer, their cancer has already grown and spread to other organs. If standard therapies don’t work for these patients—and often they don’t—they need alternatives.”

During the 20th Annual International Lung Cancer Congress, Targeted Oncology spoke with another Lung-MAP investigator, Fred R. Hirsch, MD, PhD, about the status and importance of the trial and new recommendations for molecular testing and liquid biopsies working their way into practice in the lung cancer field.

As a result of new agents and combinations approved for patients with lung cancer, guidelines for molecular testing have been expanding their suggestions for gene alterations that should be tested for. The National Comprehensive Cancer Network (NCCN) guidelines and European Society of Medical Oncology (ESMO) now recommend testing for BRAF, NTRK, and RET alterations among patients with lung cancer in addition to EGFR, ROS1, and ALK. 

Hirsch, the Joe Lowe and Louis Price Professor of Medicine and executive director of the Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai, suggested that oncologists use a next-generation sequencing panel that incorporates these genes, and more, for a more comprehensive view of the patient’s tumor that could open new avenues for targeted therapies or clinical trials, such as some of the sub-studies in the Lung-MAP trial.

Hirsch discussed with Targeted Oncology how changes to molecular testing recommendations, liquid biopsy use, new agents and treatment regimens, and more are all coming together to improve precision medicine approaches to treating patients with lung cancer.

TARGETED ONCOLOGY: Are there any clinical trials happening with biomarkers that you find interesting?

Hirsch: I’m excited about many of the clinical trials that are happening. However, I’m [most excited about] The Lung Cancer Master Protocol, the Lung-MAP, which I have been a part of developing. This is a master protocol [which] started for patients with squamous lung cancer but has been adapted to also [include] nonsquamous lung cancer. Today, it is focusing on molecular targeted therapies but we also have immunotherapy involved in the Lung-MAP study, particularly looking into the immunotherapy-refractory space. Several of the arms of the [Lung-MAP] trial have been completed and the publications are on the way.

Lung-MAP also has several interesting sub-studies and I’m excited about that. There is the ALK Master Protocol trial initiated by NCI in the United States and it’s looking into different sequencing of ALK inhibitors based on [the patient’s] mutation profile. I think this is the right way to go in the future. [As we] get more drugs and drugs targeting resistant mutations, we need a collaborative approach among institutions to sequence all the new drugs. Master protocols are a good way to move forward. [It’s also important to give] opportunities to feed the concept with continuous new drugs coming into the scenario.

TARGETED ONCOLOGY: Can you provide an overview of revised guidelines for molecular testing in patients with NSCLC?

Hirsch: Fortunately, we see rapid progress in the treatment of NSCLC. Of course, guidelines have to follow the development and it goes very fast. [In my presentation] I talked about updates. The core of the guidelines here in the United States and many places globally is the CAP/IASLC/AMP guidelines [which were] published last year. At that time, we defined EGFRROS1ALK, as a minimum for molecular testing. However, later on, we got approvals for other targets. So, the NCCN guidelines and ESMO guidelines have [since been] updated. NCCN guidelines now include RETNRTK, and BRAF. All those new targets should be included.

In our guidelines, we recommend using a next-generation sequencing panel to get a broad picture of the molecular profile of the patient’s tumor. [This is] not because we have an approved drug for all abnormalities, but there are a lot of clinical trials going on and [we] believe it is important for the patient to know about the molecular profile so that if you don’t have an approved treatment for these patients, there are clinical trials to be offered that might match their molecular profiling. 

TARGETED ONCOLOGY: What should community oncologists take away from the CAP/IASLC/AMP guidelines?

Hirsch: You need to have a molecular characterization of the patient’s tumor. That sounds very simple, but believe me, not all patients with NSCLC undergo molecular testing. In the community [setting], molecular testing is not necessarily a natural thing and it should be. Lung cancer treatment today is mainly based on molecular profiling particularly when we’re talking about advanced disease. [That is my key message to community oncologists].

Another message is don’t ignore the rare mutations because if the patient happens to have it, [there are now drugs with amazing effects]. So, even if the abnormality is infrequent, it’s important to test for it because that patient might be the one who has this mutation or fusion. 

TARGETED ONCOLOGY: In your opinion, how do liquid biopsies compare with tissue biopsies?

Hirsch: We have seen evolving technology development for liquid biopsies. In the beginning, we had a very high specificity but relatively low sensitivity. This means that if the finding is negative in the blood, we cannot be sure that it’s a true negative finding. But with new technology, the sensitivity has also increased. 

I think liquid biopsy is a good alternative to tissue biopsies today. In the CAP/IASLC/AMP guidelines, we recommended liquid biopsy in cases where the tissue was insufficient for molecular testing or in a case where [there is no tissue]. This concept has been strengthened over time. 

TARGETED ONCOLOGY: What next steps in research should be taken to remove some of the restrictions with liquid biopsies?

Hirsch: We still need technology development. I think that liquid biopsies will have a specific role in monitoring molecular abnormalities during specific targeted treatments. [This will allow us to] see changes or resistance to the treatment at an earlier stage than we do today with imaging. Monitoring treatment with liquid biopsy will be an important approach in the future. 

TARGETED ONCOLOGY: What are some controversies in immunotherapy and how are they being addressed?

Hirsch: Immunotherapy is encouraging but we still need a lot of work to do to improve the long-term effects. Even if you have impressive 5-year survival data for monotherapy or better data with combination therapy, [the question is] what is the best combination and what is the sequencing of that combination? That is an area we need to work on in the future. 

We need solid clinical trials and we need to be sure we get biopsies from the patients before and after treatment to learn about sensitivities and resistance mechanisms. It is also important to have liquid biopsies during treatment to see if we can monitor the changes over time, as I’ve mentioned before. The immune system is very complex, so, even though we are very excited about immunotherapy, we need to learn more about the interaction between the tumor microenvironment and the tumor and how the different components are playing together. With a better understanding of that, we can design and combine treatment more optimally than we do today. 

TARGETED ONCOLOGY: We’re starting to see longer-term results on the duration of therapies that have been introduced in the last 5 years in patients with NSCLC. What are the data saying about the duration of immunotherapy versus targeted therapy?

Hirsch: In my opinion, the duration of immunotherapy is an open question. We need more studies to figure out what is the most optimal duration. Is it 2 years, 1 year, or longer? We actually don’t know. [At this point], we are lacking those clinical studies. 

TARGETED ONCOLOGY: Are there any studies ongoing that could change the standard of giving patients with actionable mutations a molecularly targeted therapy first versus immunotherapy?

Hirsch: Currently, in the paradigm, if you have a molecular driver, the patient gets molecular targeted therapy upfront. I think we all agree on that. What happens if the patient progresses after a specific targeted therapy is yet to be established. But there are studies now in that space too. 

The bottom line is, a patient with a molecular target for which we have an effective targeted therapy should be given a tyrosine kinase inhibitor upfront. 

Lung-MAP precision medicine trial expands to include more patients. Lung-MAP website. Posted January 29, 2019. Accessed August 16, 2019..

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