Fox Chase Cancer Center Experts Highlight the Growing Treatment Landscapes in Lung Cancer

Hossein Borghaei, DO, MS

Multiple FDA-approved frontline immunotherapy options have continued to shape the treatment paradigm in non–small cell lung cancer (NSCLC). Additionally, more knowledge regarding the effects of immunotherapy on certain driver mutations has helped drive therapy decisions across lines of treatment, according to faculty from an OncLive^® Institutional Perspectives in Cancer webinar on lung cancer.

The event, chaired by Hossein Borghaei, DO, MS, chief, Division of Thoracic Medical Oncology, professor, Department of Hematology/Oncology, co-director, Immune Monitoring Facility, Gloria and Edmund M. Dunn chair in Thoracic Oncology, Fox Chase Cancer Center, Temple Health, covered updates across the landscapes of NSCLC and small cell lung cancer (SCLC).

Borghaei was joined by the following colleagues:

• J. Nicholas Bodor, MD, PhD, MPH, assistant professor, Thoracic Oncology Program, Department of Hematology/Oncology, Fox Chase Cancer Center, Temple Health
• Joseph Treat, MD, professor, Department of Hematology/Oncology, vice chair, Education, medical director, Ambulatory Care, Fox Chase Cancer Center, Temple Health
• Martin J. Edelman, MD, chair, Department of Hematology/Oncology, professor, Department of Hematology/Oncology, Deputy Cancer Center director for Clinical Research, Fox Chase Cancer Center, Temple Health
• Christopher J. Manley, MD, director, Interventional Pulmonology, Section of Pulmonary Medicine, associate professor, Department of Medicine, Fox Chase Cancer Center, Temple Health
• Sameera Kumar, MD, assistant professor, Department of Radiation Oncology, Fox Chase Cancer Center, Temple Health

Below, Bodor, Treat, Edelman, Manley, and Kumar summarize the main messages from their presentations.

Frontline Immunotherapy in NSCLC

Bodor: The treatment landscape is rapidly changing for NSCLC. There are multiple approved frontline immunotherapy options that we have for patients. I can’t emphasize enough the importance of up-front molecular profiling and PD-L1 testing. How about patients with driver-mutated tumors? Immunotherapy would not be the option for these patients in the frontline setting, especially those with targets such as EGFR, ALK, or ROS1. But [immunotherapy] could potentially be considered in subsequent lines of therapy.

What we know from retrospective studies, as well as the second-line registration trials, is that immunotherapy by itself as a subsequent-line treatment tends to not work in many of these driver-mutated tumors, [although] tumors [harboring mutations] such as KRAS and BRAF may be the exception. However, for patients with EGFR-, ALK-, or ROS1-mutated tumors, the ones that we frequently see in never smokers, I would look for an immunotherapy-based clinical trial for these patients, rather than giving immunotherapy alone to them.

Lastly, how about immunotherapy in never smokers without a molecular target? This is a true orphan subgroup. Unfortunately, these patients don’t have a target. Additionally, what we know about never smokers with lung cancer is that they generally don’t respond well to immunotherapy, especially immunotherapy alone. Even in cases where these patients may have a high level of PD-L1 expression, I generally try not to be fooled by that. I would favor giving immunotherapy with chemotherapy in those patients.

EGFR Exon 20 Mutations in NSCLC

Treat: The [data seen with amivantamab-vmjw (Rybrevant) in the phase 1 CHRYSALIS trial (NCT02609776)] are good, but when you put these data in context, say with osimertinib [Tagrisso], these response rates are not as robust in EGRF exon 20 mutations as one sees in EGFR exon 19 or exon 21 [L858R] mutations. However, [these response rates] certainly appear to be better [compared with how] other EGFR tyrosine kinase inhibitors [TKIs] have performed in patients with EGFR exon 20 mutations.

[In CHRYSALIS] the median duration of response with amivantamab was 11 months, which is quite good. It mimics the findings with first-generation gefitinib [Iressa] and erlotinib [Tarceva] in EGFR exon 19 and L858R mutations, which was about 10 or 11 months. These responses are respectable, although they are not as robust as the 17- or 18-month responses seen with osimertinib in the EGFR exon19 and L858R mutations.

[In May 2021, results from CHRYSALIS] led to the FDA approval [of amivantamab for adult patients with NSCLC harboring EGFR exon 20 insertion mutations]. However, because this antibody [doesn’t have] central nervous system [penetration], the ongoing phase 3 MARIPOSA trial [NCT04487080] is looking at amivantamab plus lazertinib [Leclaza] vs osimertinib as first-line therapy. This is an interesting and potentially important trial. It offers an opportunity perhaps to do better than osimertinib, but we will see.

The Current Management of SCLC

Edelman: SCLC tends to get ignored a lot. It represents between 10% and 15% of all of lung cancer, making up about 20,000 to 25,000 incident cases a year, which would make it, if it were by itself, the seventh most common malignancy. I discussed some recent developments in biology, mentioned a bit about the staging, went over limited and extensive disease, and mentioned some recent [developments] with prophylactic cranial irradiation.

The biology of SCLC has evolved a great deal in past few years. There’s a nearly universal inactivation of TP53 and RB1. One of the methods of resistance for EGFR-mutated disease is evolution to SCLC. You can detect this if you have full next-generation sequencing and see that there are p53 and RB mutations, along with an activated EGFR mutation. You should be aware that there is likely a small cell clone [about to be] activated.

In the past few years, there have been several studies that have defined 4 subsets of SCLC, and they have a remarkably different susceptibility to immunotherapy. This has not yet been prospectively tested, but it raises the possibility that we will be able to enrich our population for those who will respond to immunotherapy. What’s very different about SCLC from NSCLC is that the biology is not defined by gene mutations or translocation but rather by gene expression or a transcriptional aspect.

Pulmonary Intervention

Manley: When we think about diagnosis and staging, starting around 2003, the introduction of linear ultrasound on the bronchoscope gave pulmonologists a role in the diagnosis and staging of lung cancer. Using endobronchial ultrasound, you can reach multiple lymph node stations, far further than with mediastinoscopy. It has become the preferred method of staging, and newer scopes allow us to get further into the lung parenchyma. Often, we can avoid traditional needle biopsies and can biopsy around great vessels up to about the fourth-generation bronchus, just with linear ultrasound. We also use radial ultrasound to confirm location of nodules in the periphery, and then we try to biopsy them in real time.

Pulmonologists have a role from the initial diagnosis and staging [of lung cancer] to re-biopsy to get adequate tissue and for palliation of symptoms. We are having a larger and larger role in the complete arc of cancer care, and we’re here to support our colleagues to keep patients out of the hospital, feeling well, and on treatment.

Treating Oligoprogressive NSCLC

Kumar: Currently, for patients with metastatic NSCLC, the standard of care is either palliation or locally ablative therapy for oligometastatic disease. Oligometastatic disease is disease where patients present with anywhere from less than 3 to less than 5 lesions. This can be at the time of diagnosis, after the first 4 to 6 cycles of systemic therapy, or a short time after receiving targeted therapy.

Something similar [to oligometastatic disease] is oligoprogressive disease. The rationale for treating patients who have oligometastatic disease is that many of these patients fail locally at the sites of their original disease, and then this uncontrolled disease growth can seed distant sites and lead to further complications for the patient and worse survival.

If oligometastatic disease is where patients have only a few areas of metastases, oligoprogressive disease is where a patient is currently under therapy, and they are overall responding to the therapy, but they only have a few sites of progression. The rationale for treating these patients includes providing local benefits of preventing ill effects of growing metastases. For example, if a patient has a growing tumor in the lung, you save them shortness of breath, or if they have growing tumor in the bone, you save them some pain. You can control the resistance subpopulation.