Tailored Treatment Improves Outcomes Across Lung Cancer

Shirish M. Gadgeel, MD

The hallmarks of lung cancer diagnosis and treatment are evolving, evidenced by increases in minimally invasive surgery, and immunotherapy combinations, as well as targeted therapies for rare molecular subsets, according to faculty from an OncLive^® Institutional Perspectives in Cancer webinar on lung cancer.

The event, chaired by Shirish M. Gadgeel, MD, head of the Division of Hematology/Oncology and associate director of Patient Experience and Clinical Care at the Henry Ford Cancer Institute, focused on the benefits of sublobar resection, frontline immunotherapy, novel targeted therapies, and gene alteration inhibition in non–small cell lung cancer (NSCLC), as well as future advances in small cell lung cancer (SCLC).

Gadgeel was joined by his colleagues:

• Andrew Popoff, MD, FACS, thoracic surgeon, Henry Ford Cancer Institute
• Balazs Halmos, MD, MS, professor, Department of Medicine, Albert Einstein College of Medicine, director, Section of Thoracic Medical Oncology, Montefiore Medical Center
• Gregory Kalemkerian, MD, clinical professor, University of Michigan
• Amy M. Weise, DO, medical oncologist, Henry Ford Cancer Institute

Below, Gadgeel, Popoff, Halmos, Kalemkerian, and Weise summarize the main messages from their presentations.

Surgical Updates for NSCLC

Popoff: As screening penetrants increases, we will hopefully find many more early-stage lung cancers. Sublobar resection does appear to be an oncologically sound resection strategy in select patients.

Sublobar resection can offer durable results in early-stage disease. Resection after neoadjuvant immunotherapy or chemoimmunotherapy is effective but may have much higher rates of conversions.

Minimally invasive surgery is safe and effective, and the trends favor robotics. In 2022 or 2023, robotic lobectomy is projected to exceed [video-assisted thoracoscopic surgery (VATS)] lobectomy for the first time. The percentages of VATS lobectomies are falling [compared with those of] robotic lobectomies.

Frontline Immunotherapy in NSCLC

Gadgeel: Immunotherapy in frontline NSCLC has changed patient outcomes. In patients with high PD-L1 expression, my preferred therapy is pembrolizumab [Keytruda], although I do consider chemotherapy plus pembrolizumab in patients who have high-volume disease.

In patients with low or no PD-L1 expression, I use either chemotherapy plus [an immuno-oncology (IO) drug] or the [dual] IO/IO combination, particularly in patients with PD-L1–negative squamous cell lung cancer.

Chemotherapy plus nivolumab [Opdivo] has also been recently approved as a neoadjuvant therapy for patients with stage II to III NSCLC.

Molecular Targeting in NSCLC

Halmos: Recognizing the molecular drivers in certain cancer types, especially certain lung cancers, can drive proper treatment. EGFR-targeted therapy has led to a dramatic improvement in outcomes compared with standard chemotherapy. It’s one thing to understand how patients respond, but as cancers become resistant to therapy, we can also use our molecular understanding through biopsies and, as of late, liquid biopsy technology, to learn about the change the cancer has had to undergo, the dynamic evolution that has taken place in the cancer to disallow the original drug to work.

Multiple generations of agents for EGFR-mutated lung cancer have become the poster children of precision medicine. Novel molecules must be redesigned to be able to work in patients with EGFR exon 20 insertions. We have new agents, different molecules, and specific antibodies such as amivantamab-vmjw [Rybrevant] and mobocertinib (Exkivity), which are now FDA-approved. Osimertinib [Tagrisso] is used for the more actionable and classic EGFR-mutated cases, as it has great [central nervous system (CNS)] activity and excellent tolerance, although with limited activity in high doses. There will be some need for improvement in this context.

We also have many new compounds and ideas now as to how to target KRAS. By creating chemicals that bind to KRAS, we can put a leash on it and bind it to a common protein, so it doesn’t have the ability to run after BRAF.

We have all these great options now to offer our patients for the best outcomes. But it’s not just the medical oncologists that ultimately help our patients; it is multidisciplinary care. It takes a village, from the pulmonologists, molecular pathologists, and our pharmaceutical partners as well, to pull this to the forefront. We’re happy that in this age, hopefully we can work on the next model for better patient outcomes.

Current Management of SCLC

Kalemkerian: SCLC is divided into limited stage (LS) and extensive stage (ES). In LS-SCLC, the goal is to cure the disease. The standard therapy for LS-SCLC is chemoradiotherapy with either cisplatin or carboplatin plus etoposide for 4 cycles, with the radiotherapy administered early and concurrently with chemotherapy. Radiation can be given twice daily or once daily up to 60 Gy to 70 Gy. [Prophylactic cranial irradiation (PCI)] is standard for responders.

Future advances for LS-SCLC [include investigating the role of immunotherapy through ongoing trials]. Currently, immunotherapy is not part of the therapy for LS-SCLC, but hopefully in the next couple of years, we’ll get some studies out that will demonstrate clinical benefit.

The goal in ES-SCLC is to prolong survival and optimize quality of life for as long as possible. The latest advance is thefirst advance in the past 40 years in this stage of disease, which is the addition of immunotherapy to chemotherapy.

Standard therapy in ES-SCLC is with carboplatin, etoposide, and either atezolizumab [Tecentriq] or durvalumab [Imfinzi] followed by maintenance with immunotherapy. You can also consider thoracic radiation for patients who have had excellent response in extra-thoracic sites or inadequate intra-thoracic response, whose airways you would want to try to protect from further compromise when they progress.

PCI use in ES-SCLC is controversial. The PRIMALung study [NCT04790253] did demonstrate an improvement in overall survival [OS] with PCI, but there were several problems with this study, including not imaging patients’ heads before PCI. At this time, my preference is to do surveillance imaging rather than PCI to spare patients from getting whole-brain radiation if it’s not needed. However, PCI is still a potential option.

Regarding subsequent therapy for SCLC, in June 2020, [we saw the FDA approval of] lurbinectedin [Zepzelca] [as] single-agent therapy. We prefer single-agent therapy because of toxicity and [the] unclear potential benefits of [combination therapy]. The use of immunotherapy in subsequent treatment is no longer standard.

[Patients with] relapsed SCLC now receive single-agent chemotherapy with lurbinectedin in the second line and potentially topotecan or paclitaxel down the line.

New Trials and Targets in Lung Cancer

Weise: In my presentation, I discussed MET, HER2, and RET alterations in lung cancer, which when combined account for approximately 5% of molecular abnormalities [in lung cancer]. These are not very common but are still present and significant.

The first study I discussed, GEOMETRY mono-1 trial [NCT02414139], evaluated capmatinib [Tabrecta]. This included patients with either stage IIIB or IV NSCLC with either the exon 14 skipping mutation or MET amplification. We saw responses across all lines, independent of molecular alteration.

Tepotinib [Tepmetko] is an FDA-approved MET inhibitor that was studied in the VISION trial [NCT02864992]. Comparing several MET inhibitors, crizotinib [Xalkori] is no longer the standard of care after the FDA approval of capmatinib and tepotinib. Those two drugs have activity in the first line, second line, and beyond, with a median duration of response of roughly 1 year and [progression-free survival (PFS)] of 9 months to 1 year.

Currently, clinical trials looking at MET inhibitors include the phase 2 Geometry-N study [NCT04926831] looking at capmatinib in the neoadjuvant and adjuvant settings. There’s also a multikinase MET inhibitor ningetinib that is being studied in patients with MET exon 14 skipping mutations.

Multiple TKIs have also been evaluated in patients with RET-positive NSCLC, with varying degrees of success. [One FDA-approved agent is] selpercatinib [Retevmo], which demonstrated a median PFS of 18 and a half months. Patients responded [regardless of immunotherapy or TKI exposure history].

Pralsetinib [Gavreto] is another FDA-approved agent with [an overall response rate] of 61% and a median PFS of 17 months. Both selpercatinib and pralsetinib demonstrate activity in frontline and post-chemotherapy settings and have good CNS penetration with similar adverse effect profiles.