Should You Wait for NGS Results Before Initiating NSCLC Treatment?

New updates in the treatment of non–small cell lung cancer (NSCLC) have underscored the importance of preexisting recommendations for molecular testing, according to Beth Sandy, MSN, CRNP, and Tajuana Bradley, MSN, APRN-BC.¹

Beth Sandy, MSN, CRNP

Sandy, who is a nurse practitioner at the Abramson Cancer Center with the Hospital of the University of Pennsylvania, and Bradley, who is a nurse practitioner with Georgia Cancer Specialists, which is affiliated with Northside Hospital Cancer Institute, recently presented on precision medicine in NSCLC during the 2023 JADPRO Live Annual Meeting.

Tajuana Bradley, MSN, APRN-BC

To begin their presentation, they posited a hypothetical to the audience: suppose you are caring for a 65-year-old man with advanced NSCLC. PD-L1 immunohistochemistry testing reveals that his tumor has high PD-L1 expression, but you are still waiting for the results from the next generation sequencing (NGS). This patient is anxious to begin treatment right away.

What do you do? Should you immediately begin therapy with chemotherapy plus immunotherapy? Should you wait 1 more week to see if the NGS results come in and then start the immunotherapy if not? Delay treatment until the molecular testing results arrive and teach the patient about the importance of biomarker testing? Order a liquid biopsy?

“It is a loaded question,” Sandy admitted to listeners.

Wait for Results Before Initiating Treatment

For patients with NSCLC and actionable driver mutations, targeted therapy directed to their mutation is associated with much better outcomes than standard chemotherapy. In a study conducted in 2019, the median overall survival (OS) with driver mutation–directed targeted therapy was 18.6 months vs 11.4 months with standard chemotherapy (P < .001).²

“It really goes to show the importance of waiting until we get all of our information,” Bradley said.

Further, data has demonstrated that patients with EGFR mutations who began PD-L1 immunotherapy before switching to EGFR-directed osimertinib (Tagrisso) experienced very high rates of immune-related toxicity with osimertinib in those first 3 months. Over 15% of patients assessed in this study developed severe or life-threatening immune-mediated toxicities, including pneumonitis, colitis, or hepatitis, with this approach. Emerging data suggest a similar reality with patients with ALK mutations.³

Although this does not appear to be a significant problem for patients with KRAS mutations, BRAF mutations, or HER2 expression, it is something that providers should be aware of, according to Bradley.

Notably, the rate of NGS is improving. Between 2015 and 2020, the percentage of patients with advanced or metastatic NSCLC who underwent NGS testing improved from 28% to 68%. However, as of 2020, a third of patients with advanced/metastatic nonsquamous NSCLC still had not received broad-based genomic testing.⁴

The median turnaround time is approximately 10 days for NGS, although Bradley shared that in her practice, it often takes 3 to 4 weeks before those results come back. She acknowledged that it can be hard to tell patients they need to wait that long, but she encouraged nurses to really impress on patients the importance of these biomarkers and the impact they can have on OS.

Predictive vs Prognostic Biomarkers

As Bradley explained, a predictive biomarker indicates whether a certain therapy will be effective. A predictive biomarker helps clinicians gauge whether a specific therapy will interact with the tumor, which ultimately impacts patient outcomes.

So, for example, EGFR is a predictive biomarker. This biomarker helps clinicians gauge how well the disease may respond to EGFR-directed therapy. Similarly, PD-L1 expression indicates how effective single-agent immunotherapy may be for some patients.

“If the person has, for instance, an EGFR mutation, they get EGFR targeted therapy. We know that, predictably speaking, these patients will have better outcomes based on getting that targeted therapy,” Bradley explained.

A prognostic biomarker indicates what a patient’s overall prognosis will be; a prognostic biomarker shows how the tumor is expected to behave, regardless of treatment.

KRAS is a prognostic biomarker because, regardless of therapy choice, patients with KRAS mutations have poorer outcomes overall. Similarly, TP53, STK11, and KEAP1 are emerging a prognostic biomarker as they indicate poorer prognosis overall.

“TP53 is a tumor suppressor gene, and if that thing is not working properly, whether in breast [cancer], ovarian [cancer], or a malignant hematology, it will indicate a poor prognosis overall,” she said.

Neoadjuvant Treatments Spark New Testing Recommendations

The National Comprehensive Cancer Network recommends conducting a broad panel-based molecular test, which is most typically done by NGS testing. If no biomarkers are uncovered, then providers should consider performing an RNA sequencing panel, if one hasn’t been conducted yet, to identify any possible RNA fusions.

All patients with advanced or metastatic NSCLC should be tested for 9 different molecular targets: EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, METex14 skipping mutation, RET, ERBB2 exon 20 insertions, and PD-L1 positivity.

Of note, testing should now be conducted in the perioperative setting. As Sandy explained, based on findings from the phase 3 ADUARA trial (NCT02511106), providers should be testing for at least EGFR in the postoperative setting because osimertinib is approved for patients with EGFR mutations in that setting.

Further, as many providers now offer their patients neoadjuvant immunotherapy, testing is actually needed to determine treatment ineligibility.

“We are actually testing for at least EGFR and ALK perioperatively not because there is a drug approved, but because you should not give neoadjuvant immunotherapy if they have one of those driver mutations, because they are unlikely to respond to it,” Sandy explained.

“We are testing in so many different settings,” she continued, emphasizing that “In the preoperative setting, or the neoadjuvant setting, now it is an exclusionary criterion because we should not be giving neoadjuvant immunotherapy if there is EGFR or ALK. We are really moving NGS testing into an earlier setting."

Revisiting the Patient Case

To return to the question about the 65-year-old man, the correct answer is to wait for those results come back, the nurse practitioners explained.

“The correct answer is to delay treatment until you have those results back,” Sandy concluded. “And I know this is hard.”

“For many of our patients, when they are diagnosed with lung cancer, they are ready to start treatment like last week,” Bradley remarked, emphasizing that most individuals are eager to start therapy as soon as possible. Bradley likes to use breast cancer as a tangible example that patients may already be familiar with when she explains why waiting for testing results is so important.

“Everyone knows about breast cancer,” she said. “I frame that in their minds, [explaining] that we don’t make a move in breast cancer until we have all of our information, and we need to apply those same practices in lung cancer because we know that when we get the right biomarker with the right, treatment, these patients do better.”

References

1. Bradley T, Sandy B. Advancing precision-targeted treatment for patients with metastatic non–small cell lung cancer. Presented at: 2023 JADPROLive. November 9-12, 2023; Orlando, FL.
2. Singal G, Miller PG, Agarwala V, et al. Association of patient characteristics and tumor genomics with clinical outcomes among patients with non-small cell lung cancer using a clinicogenomic catabase JAMA. 2019;321(14):1391-1399. doi:10.1001/jama.2019.3241
3. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib. Ann Oncol. 2019;30(5):839-844. doi:10.1093/annonc/mdz077
4. Hess LM, Krein PM, Haldane D, Han Y, Sireci AN. Biomarker Testing for Patients With Advanced/Metastatic Nonsquamous NSCLC in the United States of America, 2015 to 2021. JTO Clin Res Rep. 2022;3(6):100336. Published 2022 May 7. doi:10.1016/j.jtocrr.2022.100336
5. National Comprehensive Cancer Network® (NCCN®). Non-Small Cell Lung Cancer (Version 5.2023). https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf Accessed November 15, 2023