Evaluating the Uses of Genomic Testing in NSCLC Treatment

David P. Carbone, MD, PhD

For patients with non–small cell lung cancer (NSCLC), physicians need to determine the patient’s biomarker status to treat them, but every patient’s disease is unique. Physicians in 2 separate virtual live events considered this when discussing the case of a patient with nondriver-mutated NSCLC.

These 2 Case-Based Roundtable^TM events were led by David P. Carbone, MD, PhD, and Jonathan Wesley Riess, MD, MS, in the Ohio/Michigan region and Great Lakes region, respectively. They discussed with fellow physicians the same case of a 72-year-old White man with metastatic NSCLC. The diagnosis was made after a CT scan of the patient’s chest and abdomen showed a 9-cm spiculated mass in the left lower lobe, loculated pleural effusion in the left hemithorax, and a right adrenal metastasis.

The patient’s ECOG performance score was 1, with laboratory results showing normal organ function and blood counts. However, immunohistochemistry showed the patient had a PD-L1 tumor proportion score of 95%, with next-generation sequencing (NGS) results negative for molecular aberrations in EGFR, ROS1, BRAF, ALK, RET, MET, ERBB2, NTRK, and KRAS.

In both events, the group of physicians were polled. The majority responded that their preferred recommendation for a patient like this would be a regimen of platinum-based doublet chemotherapy with an anti–PD-L1 therapy; 58% of physicians in the group led by Riess and 67% of physicians in Carbone’s group preferred this approach. However, the patient in this case was strongly opposed to chemotherapy and ultimately opted for a single-agent immune checkpoint inhibitor (ICI).

To find the proper ICI and subsequent treatment for this patient with NSCLC, physicians in both groups discussed the use of genetic markers that help define treatment targets in this patient population. Although the patient had negative results for several different markers associated with lung cancer, both groups agreed on the importance of using techniques to discover whether the patient had negative or positive results for these markers is where physicians should start.

Starting With Genetic Markers in Lung Cancer

The groups led by Carbone and Riess separately established that to begin identifying the biomarkers the patient may or may not have, they should look at the National Comprehensive Cancer Network (NCCN) guidelines.¹

“In the NCCN guidelines and in practice, the first step when you’re dealing with [NSCLC], especially nonsquamous disease, is molecular testing,” Carbone, director of the James Thoracic Center and coleader of the Translational Therapeutics Program at the Ohio State University Comprehensive Cancer Center in Columbus, said to his fellow physicians. “In my practice, we would [perform] a core biopsy…and we would do a tissue-based analysis. At my institution, it’s all done in house, and we get EGFR, ALK, ROS1, RET, and MET results within 5 days and NGS results within 2 weeks for MET and BRAF.”

The second version of the 2023 NCCN guidelines for treating patients with NSCLC call for physicians to test for biomarkers when the patient has either adenocarcinoma or squamous cell carcinoma, especially when they already have advanced disease. Carbone referred to these guidelines because they provide a framework to make treatment decisions, with each biomarker leading to a different treatment that targets and inhibits the mutation present in the patient’s tumor.

For example, if the patient were to have a NTRK1/2/3 gene fusion, the guidelines recommend providing them with the preferred treatment of either larotrectinib (Vitrakvi) or entrectinib (Rozlytrek). Moreover, Riess explained that he distinguishes among KRAS G12C, BRAF, EGFR, ALK, and ROS1 mutations, despite EGFR and ALK biomarkers being excluded from earlier trials looking at the use of ICIs in this patient population.

Jonathan Wesley Riess, MD, MS

According to Riess, the director of thoracic oncology at the University of California Davis Health Medical Center, many never- and light-smoking patients with lung cancers and these oncogene drivers would likely not benefit from single-agent immunotherapy. However, because KRAS G12C is a smoking-associated mutation, patients with this specific mutation will do well with immunotherapy. Results ultimately reflected this with the approval of adagrasib (Krazati) by the FDA based on the KRYSTAL-1 trial (NCT03785249) for patients with KRAS G12C–mutated, locally advanced NSCLC^2,3. However, the patient in this case ultimately had nondriver-mutated NSCLC, which required a process of elimination using NGS to determine proper treatment.

Comparing NGS and Biomarker Testing Across Multiple Clinics

NGS has become an essential part of providing a diagnosis for and subsequently treating patients with lung cancer. Screening for these characteristics and mutations allows for a better diagnosis at an early stage of the disease but has mainly shown its potential in clarifying which treatments to use in later lines of therapy.

In a review of genetic markers in lung cancer from JCO Precision Oncology, investigators elaborated on how lung cancer is the most diagnosed cancer in the world and that these biomarkers can provide earlier and more accurate diagnoses and treatment plans for patients.⁴ This is due to the molecular basis of lung cancer being an accumulation of genetic and epigenetic changes in the cell nucleus, leading to the weakening of DNA structure and making it more susceptible to mutations. Morphological abnormalities such as hyperplasia, metaplasia, dysplasia, and carcinoma in situ can also precede invasive cancer, so mutations are an inherent part of a patient’s lung cancer diagnosis.

Performing a liquid and/or tissue biopsy for the patient becomes an essential part of care, but recent years have enabled a deeper understanding of genomic changes in a patient’s cancer, allowing for these biomarkers to emerge. However, most tumors do not have an identified molecular driver that can be used as a genetic biomarker, meaning the importance of using NGS to look at as many highly sensitive biomarkers as possible increases for these patients.

However, not every clinician has the same access to this method. “In my practice, we contract with a commercial lab [called] Integrated Oncology for NGS, and it takes about 3 to 4 weeks. So, when I see patients, my approach is a bit different because of the practice,” Mohamad Khasawneh, MD, an oncologist at the Lawson Cancer Center in Pikeville, Kentucky, explained in response to Carbone’s practice being able to do NGS in house. “I do both liquid and tissue biopsy, because to get the liquid faster I can use the FoundationOne CDx liquid biopsy and send tissue for NGS [while] waiting for the molecular markers to come. Whichever comes first with the answers that I’m looking for, I will use to make [treatment] decisions for the patient.”

This highlights the challenges and different approaches that certain treatment centers have to define the patient’s disease and then provide targeted treatment. Not every center can afford to work in house, and many community oncologists don’t have this type of testing on hand. According to the recent research in JCO Precision Oncology, data from the National Survey of Precision Medicine in Cancer Treatment, a nationally representative sample of practicing United States oncologists, showed that although 69.9% of oncologists reported that their primary practice had onsite pathology, oncologists at multispecialty group academic practices were significantly more likely to have onsite pathology.⁴

For instance, nonacademic single-specialty groups had an adjusted odds ratio (OR) of 0.1 (95% CI, 0.07-0.15) for onsite pathology compared with an OR of 0.23 (95% CI, 0.14-0.38) for oncologists who were part of a nonacademic multi-specialty group.5 Moreover, most oncologists reported their practice had contracts with outside laboratories, but nonacademic single-specialty practices (adjusted OR [aOR], 0.58; 95% CI, 0.40-0.90) and solo nonacademic practices (aOR, 0.29; 95% CI, 0.13-0.65) were still less likely to have these contracts. Protocols for such genomic testing and molecular tumor boards also decreased outside the academic setting.

Reflecting the use of outside testing, Tareq Al Baghdadi, MD, a hematologist/oncologist at the Trinity Health IHA Medical Group in Ypsilanti, Michigan, explained in Carbone’s group that he uses FoundationOne CDx in his practice if there are sufficient tissue samples from the patient but that it takes approximately 2.5 weeks for the results to come back. Moreover, at his practice, they don’t do concomitant liquid biopsies unless the tissue is inadequate, but their pathologist would rather not run any testing on these patients. However, if the patient required immediate treatment, then Al Baghdadi would give 1 cycle of carboplatin- or cisplatin-based doublet treatment without the ICI.

The Role of a Patient’s PD-L1 Status

In comparison to Carbone’s group, Riess’ group chose to focus on the importance of the patient’s PD-L1 status to identify a proper treatment outside of the NGS results. Because the patient in the discussed case showed highly positive results for PD-L1, most of the physicians in Riess’ group recommended the tandem use of the ICI and chemotherapy, even though the use of single-agent PD-L1 inhibitors is FDA approved. However, not every clinician in Riess’ group wanted to leave out chemotherapy.

“I gave a patient pembrolizumab [Keytruda] alone, and she had a nice response for 3 months, but a repeat CT scan showed that it was a mixed response and some of her metastatic lesions were growing,” Michael A. Harris, MD, an oncologist with MultiCare Regional Cancer Center in Puyallup, Washington, explained when discussing the role of monotherapy. “[At the time] I didn’t have a lot of data about what to do. Do I continue the pembrolizumab and add chemotherapy or give chemotherapy alone? I ended up [adding chemotherapy] to pembrolizumab, and she experienced a complete clinical remission.”

Riess agreed that the approach was rational because both the single-agent and combination therapy had been approved by the FDA. Moreover, layering chemotherapy on immunotherapy could be beneficial because there is evidence the patient Harris described was experiencing progression on single-agent therapy. But for patients with a high level of PD-L1, such as the patient with a 95% PD-L1 score, Riess would still recommend the single agent PD-1 or PD-L1 therapy.

Other physicians pointed out the importance of layering in chemotherapy if the response to therapy is not everything they had hoped for. A meta-analysis of 14 studies with 3448 patients combined showed that chemotherapy in addition to ICIs for patients with NSCLC with a PD-L1 status of 50% or more improved the patient’s survival benefits over chemotherapy alone.⁶

Overall, for patients on this combination of chemotherapy and ICI there was a significant improvement in progression-free survival (PFS) and objective response rate (ORR) compared with chemotherapy alone and sintilimab plus chemotherapy (HR, 0.31; 95% CI, 0.20-0.49). The addition of pembrolizumab to chemotherapy ranked first in PFS and ORR benefit (OR, 4.2; 95% CI, 2.6-6.7), but in terms of overall survival, the addition of cemiplimab outranked the combinations of atezolizumab and pembrolizumab with chemotherapy (HR, 0.57; 95% CI, 0.43-0.77). According to the meta-analysis, chemotherapy in addition to ICIs might improve PFS. For Riess, this is part of why he sees it as a valid approach in certain cases.

While Carbone’s group did not discuss the role of the patient’s PD-L1 status as extensively, they also wanted to know about similar alternatives for the role of pembrolizumab like cemiplimab. “Cemiplimab is only approved for patients with greater than 50% PD-L1 expression, same [as] atezolizumab. But pembrolizumab has the greater than 1% approval, even though the subset analysis showed no benefit,” Carbone explained when they asked. “They have different dosing, as I’ve said, pembrolizumab has an every-6-week [dosage].”

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 2.2023. Accessed April 7, 2023. https://bit.ly/40NC5XK}

_{2. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. FDA. December 12, 2022. Accessed April 7, 2023. https://bit.ly/40RgQnV}

_{3. Palma G, Khurshid F, Lu K, Woodward B, Husain H. Selective KRAS G12C inhibitors in non-small cell lung cancer: chemistry, concurrent pathway alterations, and clinical outcomes. NPJ Precis Oncol. 2021;5(1):98. doi:10.1038/s41698-021-00237-5}

_{4. Wadowska K, Bil-Lula I, Trembecki Ł, Śliwińska-Mossoń M. Genetic markers in lung cancer diagnosis: a review. Int J Mol Sci. 2020;21(13):4569. doi:10.3390/ijms21134569}

_{5. Gardner B, Doose M, Sanchez JI, Freedman AN, de Moor JS. Distribution of genomic testing resources by oncology practice and rurality: a nationally representative study. JCO Precis Oncol. 2021;5:PO.21.00109. doi:10.1200/PO.21.00109}

_{6. He M, Zheng T, Zhang X, et al. First-line treatment options for advanced non-small cell lung cancer patients with PD-L1 ≥ 50%: a systematic review and network meta-analysis. Cancer Immunol Immunother. 2022;71(6):1345-1355. doi:10.1007/s00262-021-03089-x}