Role of Biomarkers in Deciding Neoadjuvant/Adjuvant Approach in NSCLC

Balazs Halmos, MD

Associate Director

Professor of Medicine

Clinical Science Montefiore Einstein Comprehensive Cancer Center

New York, NY

CASE SUMMARY

An otherwise healthy 60-year-old White woman presented with a nonproductive cough. She is a former smoker with a 45 pack-year history. She had an ECOG performance status of 0, blood pressure 120/93, heart rate of 74 bpm, body mass index of 22, and lungs were clear to auscultation bilaterally. All laboratory results were within normal limits. A chest X-ray revealed a 5.5-cm right mass in the right upper lobe of the lung, and a CT chest/abdomen scan showed a lobulated 5.5 × 5.1-cm mass in the right upper lobe.

A biopsy of the right upper lobe revealed thyroid transcription factor-1–positive adenocarcinoma consistent with non–small cell lung cancer (NSCLC). PET imaging was negative for any spread to lymph nodes or distant metastasis. A brain MRI was negative and pulmonary function tests were normal.

The patient underwent a mediastinoscopy with negative lymph nodes on frozen section, followed by right upper lobectomy without complications. Her histopathology was a 5.5-cm tumor with negative margins, 0 nodes positive for malignancy, and a pathologic stage IIB* (pT3N0M0) lung adenocarcinoma. Molecular testing showed an EGFR exon 19 deletion and 40% PD-L1 tumor proportion score. Her performance status was now 1.

DISCUSSION QUESTIONS

• Upon histopathologic confirmation of primary NSCLC, when do you test for genetic mutation ​biomarkers?​
• Which biomarkers do you select for genomic assay from resected surgical tissue or biopsy?​

ILMANA FULGER, MD: For a case of T3N0 lung cancer in a nonsmoker or [less heavy] smoker, I definitely want to know the EGFR status and the PD-L1 status. If the PD-L1 expression is positive, I could offer her neoadjuvant chemotherapy based on the CheckMate 816 trial [NCT02998528]…. I’ve had patients who we were able to downstage significantly and make the surgery much easier. And now…if there is an EGFR mutation, we can consider incorporating osimertinib [Tagrisso] or EGFR-targeted treatments for a patient like this even in the neoadjuvant setting for this large tumor.

BALAZS HALMOS, MD: Terrific answer. This patient has a 45 pack-year smoking history…would you not do an EGFR test [for this patient]?

FULGER: No, I would still test for EGFR.

HALMOS: Absolutely.That’s definitely important to remember, just because somebody smoked heavily doesn’t protect you from getting an EGFR mutated or translocated lung cancer. Using clinical parameters for guiding molecular testing is not a great idea. The best [approach] is to comprehensively test. Maybe test even more for a nonsmoker, but do not leave out anyone from appropriate testing. Because just because somebody smoked, they still have perfectly fine risk of getting a non-smoker’s cancer.

DISCUSSION QUESTIONS

• What is the role of neoadjuvant, adjuvant, and perioperative therapy in your practice? ​
• How do you decide on whether to employ a neoadjuvant, adjuvant, or peri-operative strategy?​
• What are your treatment goals?​
• Which agents or regimens do you typically employ?​

HALMOS: Do you want to comment on how do you define a patient for one vs the other [based on] tumor size, nodal status, biomarker status, etc? Dr Belenkov, in your practice when it comes to this, it seems like you use mostly adjuvant therapy; is that right?

ELLIOT BELENKOV, MD: I do neoadjuvant therapy as well. We do NGS [next-generation sequencing] on biopsy, we do [PD-L1] staining, and we determine in essence—if there is EGFR mutation as an example, we’re not going to do neoadjuvant chemotherapy on a resectable tumor right away. We’re not going to do a neoadjuvant therapy incorporating immune checkpoint inhibitors because of the toxicity and such. In those cases, we go directly to surgery and then do adjuvant therapy. If there is an EGFR mutation, we follow up with adjuvant osimertinib for a year. It’s also an open [question] right now whether it’s a year or 2 years or maybe prolonged depending on the stage.

HALMOS: You raise a very good point in terms of toxic interactions [between] immunotherapy and targeted therapy. It’s even more important to get the biomarker status right before committing somebody to an immunotherapy-based approach because if you have to switch to targeted therapy because you didn’t realize the patient had an EGFR mutation, there is added toxicity afterwards.

YIWU HUANG, MD: Then there are also efficacy [concerns]; in terms of immunotherapy, for patients with EGFR mutations, they are not effective.

HALMOS: True; we know very well now from a long series of studies that there’s added toxicity and no benefit.¹ It’s very important to get the patient on the right path. Any other comments on clinical parameters? Is it only the node-positive disease whom you currently offer neoadjuvant therapy? Or do you have for it for node-negative disease as well?

BELENKOV: I do it for node-negative disease, depending on the size of the tumor. But if it’s stage 2, size-wise and such, I would do it.

HALMOS: The National Comprehensive Cancer Network guidelines for neoadjuvant therapy [show] the list of combinations that you can add, [including] CheckMate 816 and KEYNOTE-671 [NCT03425643] regimens, which are currently approved. There’s likely a lineup of other choices that will be available at one point.² The clinical studies that led to these approvals were fairly restrictive, so do they always apply to the real-world patient that you see in practice? We need to learn, we need to always be cautious in terms of not overreaching, but hopefully, they are applicable to at least a large spectrum of patients.

_References:

_{1. Gainor JF, Shaw AT, Sequist LV, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis. Clin Cancer Res. 2016;22(18):4585-4593. doi:10.1158/1078-0432.CCR-15-3101}

_{2. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 1.2024. Accessed December 20, 2023. https://tinyurl.com/ydsfxfaz}