Patel Breaks Down the Meaning of Molecular Testing in Lung Cancer

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Partner | Cancer Centers | <b>UCSD Moores Cancer Center </b>

Paying particular attention to the specific type of gene mutation on a molecular testing report is critical in an era of increasing genomic complexity in non–small cell lung cancer.

Paying particular attention to the specific type of gene mutation on a molecular testing report is critical in an era of increasing genomic complexity in non–small cell lung cancer (NSCLC), explained Sandip P. Patel, MD.

“It’s not enough for us to name the street, so to speak, of EGFR, you have to get the address. Is it an exon 19 mutation, an L858R mutation, an exon 20 insertion, or an atypical mutation, perhaps in exon 18? It’s important that we understand what testing for EGFR means, because the treatments are going to be very different if you have an exon 19 mutation or L858R mutation vs an exon 20 insertion,” Patel said in an interview with OncLive® following an Institutional Perspectives in Cancer (IPC) webinar on lung cancer.

Patel, the chair of the IPC meeting, an associate professor of medicine at the University of California (UC) San Diego School of Medicine, and a medical oncologist at the Moores Cancer Center at UC San Diego Health in La Jolla, California, discussed frontline immunotherapy in advanced NSCLC, the treatment of patients with EGFR- and KRAS G12C–mutant and EGFR exon 20 insertion–positive disease, and the management of stage III disease.

OncLive®: You discussed the use of frontline immunotherapy in metastatic NSCLC. Why is it critical to evaluate for biomarkers other than oncogenic drivers like EGFR and ALK?

Patel: One of the biggest advances we have had in the management of NSCLC has been the advent of cancer immunotherapy. One of the main tenets of precision oncology is getting the right treatment to the right patient. We talked about the importance of molecular testing and ensuring that we have adequate tissue to test for EGFR, ALK, and other driver mutations because those patients are better candidates for targeted therapy.

We also went through the data for all the frontline immunotherapy combinations. For patients who have PD-L1–high tumors expressing greater than 50% [PD-L1] there are opportunities for combination immunotherapy either with chemotherapy or immunologics targeting other immune pathways. We’re all aware of anti–PD-1/PD-L1 approaches, but [there’s also the opportunity to] incorporate antiangiogenic agents and anti–CTLA-4 blockade in potential scenarios. Fundamentally, what we’re trying to do is get the right treatment to the right patient, and it’s rarely one size fits all. We also talked about the importance of appropriate biomarker testing to determine which treatment makes the most sense for a given patient.

The take-home message for frontline use of immunotherapy in NSCLC is really to understand the totality of the patient’s situation. This means not just the PD-L1 status, but also the burden of disease in which chemoimmunotherapy may be preferred for patients with higher burden tumors.

In the genomic landscape, [we should] ensure [that] patients don’t have an actionable mutation—for example, in EGFR and ALK—for which targeted therapy may be their preferred option. In lung cancer, making the radiographic diagnosis, the histologic diagnosis, and the molecular diagnosis is key to ensure that we give the best opportunity for immunotherapy to work in the proper patient population.

Your colleague, Lyudmila A. Bazhenova, MD, of UC San Diego Health Moores Cancer Center, spoke about treating patients with EGFR-mutant NSCLC. Why is it important to capture more than just the gene mutation with molecular testing?

Dr Bazhenova spoke very nicely about the importance of treatment in patients with EGFR-mutated NSCLC. It’s not enough for us to name the street, so to speak, of EGFR, you have to get the address. Is it an exon 19 mutation, an L858R mutation, an exon 20 insertion, or an atypical mutation, perhaps in exon 18? It’s important that we understand what testing for EGFR means, because the treatments are going to be very different if you have an exon 19 mutation or L858R mutation vs an exon 20 insertion. It’s important to have precision oncology, both in terms of testing but also in terms of treatment. It’s much more complicated than saying a patient has an EGFR mutation given the number of new options that we have, including 2 new options forEGFR exon 20 insertions, one of which is an IV [intravenous] therapy and the other of which is a pill. Molecular testing [is not just testing for a mutation like] EGFR. How did you test for EGFR, and what’s the specific mutation in EGFR? That’s key in getting the patients on appropriate treatment.

Kathryn Gold, MD, of UC San Diego Health Moores Cancer Center, shared insights on treatments for patients with KRAS G12C mutations and EGFR exon 20 insertion mutations. What specificity of molecular analysis is necessary for these mutations?

Dr Gold very nicely discussed the state of the art in other driver mutations, including KRAS G12C, for which we have one targeted therapy and likely one on deck. The key concept here is that these drugs are currently available for use in the second-line setting after, ideally, immunotherapy or chemoimmunotherapy. These drugs currently are mutation specific, so they only work for KRAS G12C mutations, so we can’t just say that the patient has a KRAS mutation. What is their KRAS mutation? What’s the street and the address? That’s how we get the patient to the right destination in terms of getting appropriate precision oncology therapeutics.

Jim Urbanic, MD, of UC San Diego Health Moores Cancer Center, spoke about the management of stage III NSCLC. Why is a multidisciplinary team critical to the care of patients with stage III disease?

Dr Urbanic nicely summarized the state of treatment in stage III NSCLC. Multidisciplinary teams that include the proceduralist, interventional pulmonologist, radiologist, radiation oncologists, surgeons, and medical oncologist are key, because this is one of the areas that we can cure patients, though it is an uphill battle for many. We can cure patients with [stage III] disease with a multitude of approaches, which will soon include neoadjuvant approaches, adjuvant approaches, and concurrent chemoradiation approaches, followed by consolidative immunotherapy. A multidisciplinary group can best understand the pathologic findings, radiographic findings, and biomarker findings to best give a patient their optimal therapy. Immunotherapy in the appropriate context, even in the curative-intent setting for NSCLC can have profound benefits, whether it be done after concurrent chemoradiation, or as part of an induction strategy prior to surgery. These drugs, especially immunotherapeutics, are finding a home not only in the frontline metastatic setting, but also in locally advanced disease and even earlier stages of disease, [where we are] potentially enhancing cure rates.

What approaches are you looking forward to in upcoming clinical trials?

A multitude of clinical trials are attempting to move the needle in favor of our patients with NSCLC. Some of them involve novel immunotherapy targets that are being investigated in the frontline space, such as TIGIT. Others are looking at unique scenarios for the utilization of drugs such as PD-1/PD-L1 inhibitors, such as after SBRT [stereotactic body radiation therapy], or in earlier-stage disease.

The best is yet to come for many of our patients, but [treatment] is very unlikely to be one size fits all. The importance of appropriate radiographic diagnosis, histologic diagnosis, and molecular and biomarker diagnosis will become increasingly important across all stages of disease to ensure that we give patients their best therapy.