Part 2: Rare Mutations and Non-Clinical Barriers for Molecular Testing in NSCLC

Ravi Salgia, MD, PhD

Chair and Professor, Department of Medical Oncology & Therapeutics Research

City of Hope Comprehensive Cancer Center

Duarte, California

DISCUSSION QUESTION

• What are some of the non-clinical barriers to testing (eg, access, insurance, insufficient tissue quantity)? ​

NIHAL ABDULLA, MD: When we have a newly diagnosed patient with lung cancer, I prefer to do next-generation sequencing [NGS], which includes a liquid biopsy at the same time. I usually end up using Tempus most of the time. There are restrictions on some insurances, they want us to add molecular analysis on the tissue only. That’s the only concern I have; first you have to wait for the tissue biopsy to see if that shows any positive results. In the case where it comes back after 7 to 10 days due to insufficient material, I’m stuck.

Then I try to see if they will allow liquid biopsy. But if I get a negative result, some more days have passed while the patient is waiting for treatment. Then, I do try to do another biopsy. I have a couple of patients who only have pleural effusions; and with pleural effusions they’re finally able to determine a few cells are adenocarcinomas, without a mass. Even after drainage of the fluid, we couldn’t see a mass in the lung. Now we are stuck; I keep on asking for liquid biopsies, keep on doing thoracentesis, but not getting enough sample. So, it just delays the time to initiate somebody on treatment.

[Since] there is a decrease in efficacy if you just have PD-L1, it is better to have all molecular analysis. As soon as we see [biomarker-positive] molecular results, it’s very exciting. Now we have a targeted treatment that we can offer.

RAVI SALGIA, MD, PHD: I’ve been in practice for over 30 years as a thoracic oncologist, and it’s an embarrassment for all of us as physicians that we’re depending on the payers to make decisions for us. But unfortunately, not every patient can pay for it out of pocket. I think we do have to follow the guidelines, but with the insurance companies, we have to fight for the cause. I have no vested interest in the liquid biopsy space, but I was in a meeting with Tempus recently, and Tempus said they will incur the cost. I think it’s an important [factor] for you all to discuss it with the various platforms, let’s say FoundationOne, or Tempus, or Guardant Health, to be able to say, “Can a liquid biopsy be done?” Will they absorb the cost, if and only if the insurance won’t pay? Those are important discussions to have.

It’s important to tell the patients, too. They signed this piece of paper that says we’re sending it to Guardant, but then they have to work together with the company to be able to pay. Again, it’s a tough issue, but we have to change that as a paradigm for all of us in medical oncology.

DISCUSSION QUESTIONS

• Do you read the entire molecular test report or look for specific results? ​
• Do you look for ALK, ROS1, BRAF, NTRK1/2/3, MET exon 14 skipping, RET, KRAS or other rare mutations at this time? ​

SWARNA CHANDURI, MD: In a case of mine, a patient had BRCA1 positivity, but without any breast cancer or ovarian cancer. Her twin had breast cancer, so she went and had bilateral ovariectomy, bilateral mastectomies, then presented with pleural effusion. Finally, the cell block was sent for Foundation CDx testing, that showed MET exon splice site positivity. She’s on capmatinib [Tabrecta], and for almost a year now she’s been doing well. But it took us almost 2 months before I could come to a molecular diagnosis on this case.

KAREN RECKAMP, MD, MS: I think that one of the important things that we found [in recent studies] were that BRCA, and especially BRCA2, can potentially be important as germline promoters of lung cancer [in general], and of lung cancer at an earlier age.¹ This was true for both smokers and non-smokers.

SALGIA: This is about a patient who has a MET exon 14 skipping mutation. So, what would your next step be? Capmatinib has been approved for MET exon 14 skipping.² Tepotinib [Tepmetko] has been approved; crizotinib [Xalkori] was one of the first ones to be utilized, so that could have been an option, and that would have been OK.^3,4 For chemotherapy, it depends—if you have a large tumor burden and you want to really reduce the tumor burden, you could do that. ICI [is likely] not [a reasonable option]; and other, [such as radiation, is an option if the patient has] let’s say, brain metastasis with severe edema that you needed to take care with radiation.

SALGIA: These are important therapeutic targeting [approaches] that have come to fruition. These are type 1B MET inhibitors, which [have] G1163 amino acid site interaction that’s independent of capmatinib and tepotinib, whereas crizotinib is G1163-dependent. Crizotinib doesn’t cross the blood-brain barrier as well as these drugs, so that’s an important one to keep in mind as well.

_REFERENCES:

_{1. Reckamp KL, Behrendt CE, Slavin TP, et al. Germline mutations and age at onset of lung adenocarcinoma. Cancer. 2021;127(15):2801-2806. doi:10.1002/cncr.33573}

_{2. FDA grants accelerated approval to capmatinib for metastatic non-small cell lung cancer. FDA. Published May 6, 2020. Accessed December 1, 2021. https://bit.ly/3rsymQI}

_{3. FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. FDA. Published February 3, 2021. Accessed December 1, 2021. https://bit.ly/3pbC2U8}

_{4. FDA expands use of Xalkori to treat rare form of advanced non-small cell lung cancer. FDA. Published March 11, 2021. Accessed December 1, 2021. https://bit.ly/3d7hbMf}