Biomarker Identification Drives Research and Drug Development in NSCLC and SCLC

Ranee Mehra, MD

Ongoing efforts to integrate immunotherapy approaches into treatment and improve biomarker identification remains crucial for refining the navigation and development of emerging therapeutic approaches in both non–small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), according to faculty from an OncLive State of the Science Summit™ on Lung Cancer.

The event was chaired by Ranee Mehra, MD, the director of Head and Neck Medical Oncology and a professor of medical oncology at the Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland Medical System, in Baltimore, Maryland.

Presentations highlighted treatment updates across lung cancer subtypes, including navigating the array of available ALK inhibitors in NSCLC, key topics of debate regarding the management of KRAS G12C–mutated NSCLC, and current treatment approaches in SCLC. Other topics covered the evolving role of immunotherapy in NSCLC and the perioperative management of metastatic EGFR-mutated disease as well as locally advanced disease.

Mehra was joined by her colleagues at the University of Maryland:

• Katherine A. Scilla, MD, FACP, medical oncologist, assistant professor of medicine, and associate program director of the Hematology Medical Oncology Fellowship Program
• Samuel Rosner, MD, assistant professor of medicine and thoracic oncologist

Below, Mehra, Scilla, and Rosner highlight some of the main messages from their presentations.

Mehra Discusses Considerations For Sequencing Next-Generation ALK Inhibitors in First-Line NSCLC Paradigm

Mehra: Looking through history, it’s remarkable how the treatments for ALK-positive NSCLC have evolved since [this subset was first characterized]. The National Comprehensive Cancer Network guidelines now list several [ALK inhibitor] options in the first-line setting, including alectinib [Alecensa], brigatinib [Alunbrig], and lorlatinib [Lorbrena]. There are other options as well, in some circumstances, including ceritinib [Zykadia] and crizotinib [Xalkori].

With 3 active next-generation agents, [careful] consideration [is essential regarding] which one to use in the first-line setting. [These agents have] different toxicity profiles, and that is a factor to consider. The degree of baseline central nervous system [CNS] disease and CNS activity of the drugs are important to consider as well. All [these drugs] have CNS penetration, but if a patient has a high CNS burden of disease, physicians may consider lorlatinib in certain situations. One caveat to that to consider is the sequencing options for therapy. We have data for lorlatinib in patients who had [previously received] other ALK inhibitors. When [considering] sequencing in the reverse fashion, we don’t know the efficacy of alectinib or brigatinib after lorlatinib. We want to give patients potent agents up front, but we also want to have next-line options [available]. Those are the things to consider between all the different treatment groups.

[To summarize the current efficacy data with these agents, according to previously reported data], the CNS response rate for alectinib was either 81% or 59%, [depending on whether patients had] measurable or nonmeasurable disease. With brigatinib it was 78%, and with lorlatinib it was 66% to 82%, depending on whether [patients with] nonmeasurable disease [were included]. Overall response rates in general were in the 70% to 80% [range for all 3 options]. Intracranial duration of response was a median of 17.3 months with alectinib, and 12-month [intracranial duration of response rates] were 78% and 96% with brigatinib and lorlatinib, [respectively].

Overall, brigatinib, alectinib, and lorlatinib are all options for the first-line treatment of patients with metastatic NSCLC. [Additionally], resistance and response to therapy is associated with comutation status, such as TP53 mutations and ALK variants. Patterns of [ALK inhibitor] resistance are [also] influenced by the choice of first-line agent, and phase 3 data have shown a benefit in disease-free survival with the use of adjuvant alectinib after surgical resection of ALK-positive NSCLC.

KRAS Inhibition Displays Mixed Results in NSCLC, Though Interest and Optimism Remain

Rosner: KRAS is a key and now targetable oncogene in NSCLC, and responses to therapy are heterogeneous with some correlation based on comutation status. That also applies to targeted therapies. Not all KRAS mutations are the same, or at least that’s what we’re starting to learn in terms of characterizing these both from both a demographic and histopathologic perspective. We often associate KRAS with smoking exposure, which certainly it is, but that’s not uniformly true. We can see variation based on the specific KRAS mutation with KRAS G12C mutations [occurring more commonly] in patients who were never smokers. We also have seen that KRAS mutations tend to be associated with a higher expression of PD-L1 as well as tumor mutational burden, but this is not uniformly true. KRAS G12C is perhaps associated with a lower tumor mutational burden level.

Given the fact that historically KRAS was associated with smoking, there was this thought that [patients with KRAS mutations] would have superior outcomes with immunotherapy as well as chemo-immunotherapy. [However], the data have been fairly mixed, particularly when you compare it with other smoking-related oncogenic drivers such as BRAF. [We’re seeing a] slight, but not statistically significant, trend toward improvement for [patients with] KRAS-mutated disease. There’s a lot we’re learning about what drives that heterogeneity in terms of response.

Early KRAS inhibitors have shown modest but meaningful benefit for patients [with NSCLC] and offer an opportunity for us where we didn’t have targetable options before. However, newer agents are also being studied, [such as] pan-RAS inhibitors. [These are exciting for] patients with KRAS G12C mutations as well as those without. Future questions remain regarding whether there’s a role for these agents in the frontline setting, either in combination with immune checkpoint blockade or as monotherapy.

Novel Immunotherapy Approaches Are Under Investigation in Both Extensive-Stage (ES)-SCLC and Limited-Stage (LS)-SCLC

Scilla: Platinum-etoposide plus immunotherapy is the standard of care for the first-line treatment of ES-SCLC. Concurrent chemoradiation with cisplatin and etoposide remains our standard therapy for limited-stage patients. [However,] there [are a few] novel approaches being considered in LS-SCLC. Given the benefit of the addition of immunotherapy in the extensive-stage setting, there’s a lot of interest in potentially bringing immunotherapy into the limited-stage treatment paradigm as well. In the [phase 3] LU005 study [NCT03811002], patients in the experimental arm will receive atezolizumab [Tecentriq] as a component of treatment with concurrent chemoradiation and then continue that after [for 1 year]. In the [phase 3] ADRIATIC study [NCT03703297], patients are receiving chemoradiation therapy [followed by either durvalumab (Imfinzi) plus placebo, durvalumab plus tremelimumab (Imjudo), or placebo].

Further studies are ongoing looking at novel agents for patients that have relapsed or refractory disease. [Lastly], there’s a need for further biomarker identification so that we can try to figure out which patient subsets are going to benefit most from therapies.