Experts Delve into Case-Based Discussions of Locally Advanced Lung Cancer Management

Sarah Goldberg, MD, MPH

Expert oncologists engaged in a case-based discussion regarding the management of locally advanced lung cancer at the 25th Annual International Lung Cancer Congress. The panel discussed 2 complex case studies of a 77-year-old woman with a significant smoking history presenting with a left hilar mass and a 73-year-old never-smoker with a cough and a lung mass.

During the discussion, oncologists answered questions about appropriate diagnostic procedures, noting the importance of thorough mediastinal staging with endobronchial ultrasound or mediastinoscopy. Optimal treatment options, including chemoradiation followed by durvalumab and neoadjuvant chemoimmunotherapy followed by surgical resection, were also debated based on patient-specific factors such as resectability and preference. The optimal use of molecular testing and the integration of targeted therapies into practice, particularly in oncogene-driven cases, was also discussed.

Panelists included:

• Sarah Goldberg, MD, MPH, associate professor, Internal Medicine, Yale School of Medicine; associate director, Medical Oncology-Hematology Program; Research Director, Center for Thoracic Cancers; chief, Thoracic Oncology, Yale Cancer Center, New Haven, Connecticut
• Megan E. Daly, MD, professor, Clinical Radiation Oncology; associate director, Clinical Research; Jennifer Rene Harmon Tegley and Elizabeth Erica Harmon Endowed Chair in Cancer Clinical Research, University of California (UC) Davis Comprehensive Cancer Center, Sacramento, California
• Percy Lee, MD, FASTRO, professor, vice chair, Clinical Research; medical director, Orange County; medical director, Coastal Regions, Lennar Foundation Cancer Center, Department of Radiation Oncology, City of Hope, Duarte, California
• Meghan Ramsey, MD, clinical associate professor, the Division of Pulmonary, Allergy, and Critical Care Medicine, Stanford Healthcare, Stanford, California
• Anjali Sibley MD, MPH, director, Stanford Emeryville Cancer Center; clinical associate professor of medicine (Oncology), Stanford University School of Medicine, Hematology & Medical Oncology, Stanford Healthcare, Stanford, California
• Millie Das, MD, clinical associate professor; chief, Oncology, VA Palo Alto Health Care System, Palo Alto, California
• Harvey I. Pass, MD, Stephen E. Banner Professor of Thoracic Oncology, Department of Cardiothoracic Surgery; professor, Department of Surgery, NYU Grossman School of Medicine, New York, New York.

Below is a recap of key questions, controversies, and conclusions from this panel discussion.

Case 1

A 77-year-old woman with an 80 pack per-year smoking history who quit 10 years ago presents with shortness of breath. Her chest X-ray reveals a left hilar mass, and a PET-CT scan shows an FDG-avid 10 cm left hilar mass along with a bulky FDG-avid anterior mediastinal lymph node measuring 3.2 cm in the short axis. An MRI of the brain is negative. A CT-guided biopsy confirms squamous non–small cell lung cancer (NSCLC). Immunohistochemistry shows 85% PD-L1 expression, tumor mutational burden is high, and next-generation sequencing identifies a PIK3CA mutation. The patient’s ECOG performance status is 1.

Question 1: Do you stage additional lymph nodes in the mediastinum to determine single- vs multi-station N2 disease prior to selecting treatment options?

Ramsey: I would agree with the majority of the audience [and say] that I would [perform an] endobronchial ultrasound with transbronchial needle aspiration of mediastinal lymph nodes. It is important for staging these patients [to have that option]. Certain [scans] can have false negatives.

As far as transbronchial needle aspiration of mediastinal lymph nodes vs mediastinoscopy, we're getting more and more data with this; there's noninferiority to doing either [option] and one is much less invasive [than the other] for the patients. Therefore, it comes down to the thoroughness of the procedure you're doing rather than the procedure itself.

How thorough are you during transbronchial needle aspiration of mediastinal lymph nodes vs how thorough are you during mediastinoscopy? That's part of what we're doing

Question 2: What is your general treatment approach? Chemoradiation followed by consolidation durvalumab (Imfinzi), or neoadjuvant chemotherapy followed by surgical resection?

Goldberg: As I have mentioned, these are the types of cases we talk about during tumor boards, because neither [option] is wrong. They're both reasonable strategies, assuming you follow [them correctly], and it really comes down to [whether] the patient is resectable from a surgical standpoint. That [is when] the surgeon looks at the imaging and decides if they can, as was mentioned, do an R0 resection.

[Sometimes], the patient wishes to undergo surgery and sometimes people feel strongly [about that], which may push us one way or the other. [However], a couple of years ago, this would have been more straightforward: it would have been chemoradiation followed by durvalumab. Now, [patients with] stage III cancer or even bulky lymph nodes are still considered [strong candidates] for surgical resection with neoadjuvant chemoimmunotherapy.

Pass: I agree with you. I think that this is a surgically resectable patient. The word needs to get out not only to medical oncologists but to surgeons [about] the [idea of the] phase 3 PACIFIC [NCT02125461] trial, which really did not have a surgeon evaluating these patients. If you look at the protocol and see how they staged these patients, there was controversy as to whether there were resectable patients, though it was still a great trial.

Das: The treatment radiation field is quite large. This is the exact patient [to whom] we are excited to administer neoadjuvant chemotherapy/immuno-oncology. We know that the patients with stage III disease benefited most and we know that this patient's PD-L1 expression level is 85%. [They] are likely to benefit and to have downstaging. I would try to get that patient to go for surgery if considered a surgical candidate.

Lee: I agree with that. If it's a bulky primary tumor in the lower lobe, it's challenging to go through chemoradiation in safe manner. We don't know the answer here, as there is no head-to-head comparison as far as this treatment algorithm. Patient preference is really, really important, as is a multidisciplinary approach.

Sibley: Patient preference is important here. A lot of people don't want radiation, and I would have chosen neoadjuvant chemotherapy per the phase 3 KEYNOTE-671 trial [NCT03425643] just because KEYNOTE-671 did include patients with stage IIIB disease. That is an option now without radiation, and it did include many patients with squamous disease as well. Plus, it gives us the opportunity for adjuvant treatment when we're done. We saw major pathological rates in patients who were on KEYNOTE-671, so there are a lot of factors here.

Question 3: You decide on neoadjuvant chemoimmunotherapy followed by surgical resection for this patient with stage IIIB NSCLC with squamous histology and a single station bulky anterior-posterior window N2 lymph node, PD-L1 IHC at 85%, high tumor mutational burden, and a PIK3CA mutation. Do you choose carboplatin, paclitaxel, and nivolumab (Opdivo) followed by surgical resection or cisplatin, gemcitabine, and pembrolizumab (Keytruda) followed by surgical resection and adjuvant pembrolizumab?

Goldberg: I try to give cisplatin in the curative setting whenever possible, so when patients are eligible for cisplatin, I prefer a cisplatin-based regimen. I also like giving a perioperative regimen because then I can have the option of giving adjuvant therapy. I like to have the option to potentially give additional immunotherapy after resection. Therefore, I probably would have done the same.

Das: I personally like the carboplatin, paclitaxel, and nivolumab approach per the phase 3 CheckMate 816 trial [NCT02998528]. Te phase 3 CheckMate 77T trial [NCT04025879], which also shows us that we can give out additional adjuvant nivolumab afterward. There weren't enough choices for this question. It would be reasonable to go with the CheckMate 816 regimen and potentially continue nivolumab as an adjuvant treatment per the CheckMate 77T trial for patients who don't achieve a pathologic complete response, pending approval.

Case 2

A 73-year-old man with no history of smoking presents with a cough. A chest X-ray reveals a mass in his left lower lobe. A PET-CT scan shows an FDG-avid mass in the right lower lobe measuring 2 cm with a standard uptake value of 6, along with additional FDG-avid hilar lymph nodes measuring 1.5 cm with a maximum standard uptake value of 5.1, and a subcarinal lymph node measuring 1.6 cm with a maximum standard uptake value of 6. MRI of the brain is negative. A CT-guided biopsy of the right lower lobe confirms lung adenocarcinoma with thyroid transcription factor 1 positivity. His ECOG performance status is 1.

Question 1: Do you stage the mediastinum prior to determining treatment options?

Ramsey: No, we wait to confirm the diagnosis. Although this pattern is quite suspicious, we do have cases of [changes] that can cause false positives. I think it's such a crucial determination. I will add, it is not uncommon that we're seeing these. I highly encourage patients to get to the pulmonologist rather than going more of an interventional radiology route; at the same time, it's the most efficient way to get patients to the doctors.

Question 2: What molecular testing would you order for this patient?

Goldberg: We do in-house testing for broad panel next-generation sequencing [NGS], as well as PD-L1. We don't have rapid EGFR testing, although we'll be getting it very soon.

Here, the most important thing is broad genomic profiling. You can even question the value of PD-L1 in this patient who is a never-smoker. PCR is also helpful. Decisions are needed on these patients quickly and [it can take] a couple of weeks for NGS [results] to come back. Though rapid testing in these small panels where we are just getting 1 or 2 genes has fallen out of favor, in some cases [it can be helpful].

Sibley: Many of us in the audience work in community centers. It's very important to ensure that we do have this available and, if not, figure out a way to work with pathology and ensure that there is good communication to test for these things as well, as we just mentioned, immunotherapy regimens. We need to make sure that we have a team in place everywhere that can provide and support multidisciplinary care.

That goes back to the relationships between providers and oncologists, as well as between providers and community hospitals. Of course, genomic profiling is a necessity, but we need to make sure everybody can do this.

Goldberg: For a while, EGFR [mutations were] important in this setting, but now ALK mutations are also important. Those are the 2 [targets] that we have the most data for… but you may want to think about targeted therapies for patients with ROS1 or RET mutations, completely extrapolating from other studies.

It's helpful to get the broad test it's just a matter of timing and if you are pressed to get testing results back. In an ideal world [you do all], but otherwise, a broader panel where you're getting all of all your actionable alterations, is important in this setting.

We're definitely in need of more novel assays, whether it be blood or otherwise, so we can get these results quickly and not have to get these big biopsies.

Question 3: What general treatment approach would you utilize for this never-smoking 73-year-old patient with stage IIIA, NSCLC-adenocarcinoma?

Lee: The choice of chemoradiation followed by osimertinib [Tagrisso] is a very reasonable choice. Now, we have 2 good options for patients. Chemoradiation followed by osimertinib, looks very good and promising; however, we want to see the long-term outcomes as far as survival. The indefinite use of osimertinib troubles some people, [from] oncologists and physicians [to] patients. What we will see is other subsets that don't need them for the entire duration in their life. However, again, it's patient choice.

Ramsey: The question here is, you know, obviously for a surgeon to decide whether the patient is still considered resectable and if they are, I think that the approach of neoadjuvant chemotherapy followed by surgery followed by adjuvant osimertinib is reasonable. These are the cases [we bring to the] tumor board. Overall, chemoradiation followed by osimertinib [for life] is a very reasonable option because we know that these patients are at high risk of recurrence and progression…Either one of these options is fine, although anything with immunotherapy should be out.

Question 5: Among patients with oncogene driven mutations, which genotypes and treatments would you consider for patients with unresectable stage III disease after completion of chemoradiation?

Goldberg: The data for osimertinib in the EGFR-mutated setting is so strong. We see how terribly these patients do with chemoradiation alone. It's tempting to administer it beyond those with EGFR mutations, although we don't have data [to support this]. Extrapolating [data] from the phase 3 LAURA [NCT03521154] and ALINA [NCT03456076] trials, I would probably give alectinib [Alecensa] to patients with ALK-positive lung cancer after chemoradiation, despite the lack of data. I might discuss it with patients; I think it's something to consider. However, I don't know that we're going to get many trials of all these subsets, so I think this extrapolation is going to be going on for a long time.

Reference

Case-Based Panel Discussion: Locally Advanced Disease. Presented at: 25th Annual International Lung Cancer Congress; July 25-27, 2024; Huntington Beach, CA.