Targeted Therapies Continue to Expand the Treatment Paradigm in NSCLC

Christine Bestvina, MD

The treatment landscape continues to expand across non–small cell lung cancer (NSCLC), with the FDA approvals of multiple agents, including targeted therapies such as sotorasib (Lumakras) and lorlatinib (Lorbrena), according to faculty from an OncLive^® State of the Science Summit^™ on lung cancer.

The event, chaired by Christine Bestvina, MD, assistant professor of medicine, hematology and oncology (cancer), University of Chicago Medicine Comprehensive Cancer Center, highlighted updates across the lung cancer landscape, including the use of frontline immunotherapy in NSCLC, plus the role CTLA-4 inhibitors could play in this patient population.

Bestvina was joined by her colleagues:

• Mary J. Fidler,MD, medical oncology section chief, associate professor, Department of Internal Medicine, Division of Hematology, Oncology and Cell Therapy, Rush Medical College
• Frank Weinberg, MD, PhD, physician, researcher, Division of Hematology & Oncology, University of Illinois Health
• Lawrence E. Feldman, MD, professor of medicine, University of Illinois College of Medicine, Translational Oncology Program, University of Illinois Health
• Everett E. Vokes, MD, John E. Ultmann Professor, physician-in-chief, biological sciences chair, Department of Medicine, University of Chicago Medicine

Below, Fidler, Weinberg, Bestvina, Feldman, and Vokes summarize the main messages from their presentations.

Biomarker Testing in Lung Cancer

Fidler: Comprehensive next-generation sequencing [NGS] is essential for [patients with] stage IV adenocarcinoma. [NGS] should include RNA sequencing and circulating tumor DNA [ctDNA] assays, [which] can maximally capture targeted alterations. We saw that with a [2018 report by Charu Aggarwal, MD, MPH, of Penn Medicine,] where some of the alterations were only captured in the ctDNA assays.

Perioperative PD-L1 [testing] could be useful to guide multimodality therapy, and EGFR testing should be performed on resectable patients that may pursue a neoadjuvant chemotherapy [plus] immunotherapy approach, given the overwhelming disease-free survival benefit with osimertinib [Tagrisso] for [patients with EGFR mutations].

New Updates on Targeted Therapy for NSCLC

Weinberg: Sotorasib received [FDA] approval in May 2021 for patients with KRAS G12C–[mutated] metastatic NSCLC in the second-line setting or later. Adagrasib is a KRAS G12C inhibitor, but it is not yet approved.

In general, [KRAS G12C inhibitors] are tolerated well. Gastrointestinal [adverse] effects [AEs] and liver abnormalities are the largest treatment-related AEs. There is emerging data in studies that we should keep an eye on in terms of combination treatment that’s ongoing.

Lorlatinib was approved in March 2021 for the treatment of patients with ALK fusion–positive metastatic NSCLC. Alectinib [Alecensa], for most [clinicians], is still our go-to first-line [treatment] for patients with ALK fusion–positive metastatic NSCLC. But I would consider lorlatinib in the first line if the patient has significant central nervous system metastasis. [It is important to] be aware of the unique [AE] profile of lorlatinib.

Selpercatinib [Retevmo] was FDA approved in May 2020 [for the treatment of patients with RET alteration–positive NSCLC]. Pralsetinib [Gavreto] was approved in September 2020 for the first-line treatment of patients with metastatic NSCLC with RET fusions. [Notably], selpercatinib has less myelosuppressive [AEs].

Larotrectinib [Vitrakvi] was approved in November 2018 [for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment]. Entrectinib [Rozlytrek] was approved in August 2019 for the first-line treatment of solid tumors harboring NTRK fusions without resistance mutations. [Additionally], there are emerging second-generation inhibitors to overcome on-target resistance.

Frontline Immunotherapy in NSCLC

Bestvina: Immune monotherapy is what’s preferred for patients [with NSCLC] who have high PD-L1 [expression], although chemotherapy [plus] immunotherapy may be preferred in never smokers or patient [who present with more aggressive disease]. Chemotherapy [plus] immunotherapy is what’s recommended to for [patients with] a [PD-L1 tumor proportion score of] less than 50%.

The addition of a CTLA-4 [inhibitor] may be helpful for certain patient subgroups. But stay tuned, because lots of combination trials [are expected] to read out soon.

Current Management of Small Cell Lung Cancer (SCLC)

Feldman: In the paradigm of treatment for extensive-stage SCLC, we want to consider clinical trials. In the first-line setting, [treatment options include] etoposide [and] platinum [chemotherapy combined with] either atezolizumab [Tecentriq] or durvalumab [Imfinzi]. In the second-line setting, we have an FDA approval for topotecan and lurbinectedin [Zepzelca]. Many investigators prefer [liposomal] irinotecan instead of topotecan, although that is an off-label usage.

In the third-line setting for patients who haven’t had a checkpoint inhibitor, one can consider pembrolizumab [Keytruda] or nivolumab [Opdivo]. Otherwise, we still have agents such as paclitaxel and temozolomide [Temodar] to consider in the third-line setting.

Treatments Options for Resectable NCSLC

Vokes: Survival [rates] in resectable lung cancer are still too low. Although we should be happy with the [current] results, we shouldn’t be content and say we don’t have to look any further. Targeted therapies and immune checkpoint inhibitors have significantly improved treatment outcomes, and resection is the key. [Treatment can be given before or after surgery], but the key is to cut [the disease] out, [if possible].

[The use of] adjuvant and neoadjuvant chemotherapies are evidence based. Osimertinib is [FDA] approved [as an adjuvant treatment following tumor resection in EGFR-mutated NSCLC], and atezolizumab [is approved for use as an adjuvant treatment following resection and platinum-based chemotherapy in patients with stage II to IIIA NSCLC with a PD-L1 expression on 1% or more of tumor cells]. Moreover, neoadjuvant nivolumab and [platinum-doublet chemotherapy was recently approved for adult patients with resectable NSCLC].