Authors: Daniel A. Saez, MSc, Treatment and Trials Navigator, GO2 for Lung Cancer and Jacinta R. Wiens, PhD, Director of Lung Cancer Registry, GO2 for Lung Cancer

The World Conference on Lung Cancer (WCLC) highlighted many up-and-coming treatments for patients with different mutations, while also shedding light on proven existing drugs. Many talks at WCLC reinforced previously presented data for already approved targeted therapies. GO2 for Lung Cancer has amassed an overview of the talks at WCLC which highlighted either ongoing trials or very newly approved drugs for common mutations in non-small cell lung cancer (NSCLC) below.

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ALK

Patients with ALK+ non-small cell lung cancer (NSCLC) that has spread outside of the lungs (metastatic) have had several different options approved for their treatment. WCLC reminded patients and caregivers that there is a trial underway called the ALCHEMIST trial for early stage ALK+ patients to identify whether or not the drug Xalkori improves outcomes. This trial is similar to the AUDURA trial and it or another like it would lead to the first approval of a targeted therapy for patients diagnosed with early-stage ALK+ NSCLC. In addition, a poster at WCLC presented data on the combination of the already approved ALK targeted therapy Zykadia with a drug approved for BRAF mutated NSCLC called Mekinist. This combination could add another line of targeted therapy to patients with ALK+ NSCLC and potentially extend their time on treatment.

EGFR

It is common knowledge in the EGFR community that one of the biggest concerns for patients with EGFR mutated NSCLC and their loved ones is progression on Tagrisso. Tagrisso resistance is not yet completely understood and there is no clear next line of treatment for when it happens. However, several studies at WCLC were highlighted which focus on combining Tagrisso with other drugs in effort to keep patients on treatment longer. These combinations range from HER2 inhibitors, previously approved EGFR inhibitors (like Gilotrif), and drugs meant to support Tagrisso by encouraging cell death through a process called apoptosis. While none of these combinations provide a direct solution to Tagrisso resistance, it demonstrates the broad array of research being done in the area.

In addition to Tagrisso combinations, WCLC featured talks highlighting two more topics of high importance in the EGFR treatment landscape: treatment for those with exon 20 insertion, and EGF vaccination treatment. In the short time since WCLC ‘21, a second approval for treatment of EGFR exon 20 insertion mutations occurred. The trial which led to the approval of Exkivity was featured at the conference prominently and brought attention to the apparent clinical benefit for patients taking Exkivity that have an EGFR exon 20 insertion. Talks at WCLC also shed light on early phase clinical trials for drugs intended for EGFR exon 20 insertion mutated NSCLC. Data from the highly anticipated EGF vaccine trials was discussed at WCLC which suggested that combining these vaccines with the previously approved drug, Gilotrif, may delay resistance to targeted therapy and improve outcomes. More research is necessary to determine if this will impact the standard of care.

KRAS

For many years the most common mutation in NSCLC, KRAS, was considered undruggable. However, in 2021 the first FDA approved targeted therapy for patients with the specific KRAS G12C mutation came to light. One of the main topics discussed at WCLC pertaining to KRAS targeted therapies included combinational treatment of either already approved KRAS G12C inhibitors (Lumakras) or of KRAS G12C inhibitors not yet approved but in clinical trials. These combinations ranged from immunotherapy drugs to other targeted therapies and even included drugs meant to affect tumor cell cycle. The broad nature of the combination therapy clinical trials, underway by multiple companies, marks the immense amount of research being done in the space and that physicians and scientists are not content with the approval of Lumakras in 2021, but instead want patients to have access to more options. Work in the field of drug resistance for KRAS mutated NSCLC was also highlighted. Researchers attempted to identify if patients with mutations other than KRAS G12C experienced progression differently than other patients. Researchers were unable to identify if any one singular mutation had dominant effects on resistance and more research is needed in this space.

MET

There are currently two FDA approved treatments for patients with NSCLC that has the MET exon 14 skipping mutation, Tabrecta and Tepmetko. However, at WCLC two main points of interest about MET mutated NSCLC were discussed. The first being data on a possible third drug for the MET exon 14 skipping mutation and the second being very early data for a drug that would target a second type of change in the MET gene that some patients with NSCLC experience called overexpression. Data from a phase 2 trial showed that a drug already approved to treat NSCLC with the EGFR exon 20 insertion mutation, Rybrevant, may be a possible third option for the MET exon 14 skipping mutation. A drug that is currently names ABBV-399 shows clinically meaningful responses for patients with high or intermediate MET expression. This would fill a currently unmet need for patients diagnosed with NSCLC that have this change in the MET gene. Studies for this drug, and others like it, must continue before there is an approval, but this demonstrates a great step towards more patients receiving targeted therapies.

RET

Patients with RET rearranged NSCLC, like those with other targetable mutations, have better outcomes on targeted therapies than on chemotherapy or immunotherapy. Like any other patient treated with a targeted therapy, those with RET rearranged NSCLC must receive a biomarker test that shows their mutation. WCLC highlighted that a type of test called RNA based NGS is the gold standard for detecting RET rearrangements. A commonly used test called FISH still gives excellent results which are mostly in line with RNA based NGS. However, an outdated form of biomarker testing called immunohistochemistry (IHC) has a high rate of false positives and should only be used as a last resort. However, even only receiving IHC is better than not receiving biomarker testing at all. In addition to identifying the most appropriate type of biomarker testing for RET rearrangement, WCLC also highlighted the phase 3 trial, LIBRETTO-432, to identify if a drug approved for metastatic RET rearranged NSCLC (Retevmo) would provide better outcomes for early-stage patients with RET rearranged NSCLC. This would mark the first RET targeted therapy approved for patients with early-stage NSCLC.

ROS1

Based on the ability for Xalkori, an already approved ROS1 and ALK targeted therapy, to work on multiple mutated genes, WCLC shed light on a clinical trial that seeks to determine if the drug Alunbrig, which has already been approved to treat ALK+ NSCLC, has clinically significant activity for patients with ROS1 mutations. There are currently only two drugs approved for patients with NSCLC that has a mutation in ROS1. More research in this area would give these patients more options and hope for treatment.