Targeted Therapy Treatment Updates from ASCO 2022

Author: Andrew Ciupek, PhD, Associate Director, Clinical Research

Targeted therapy research was front and center at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting. Data was presented from several studies detailing new targeted therapies and better understanding of how to treat non-small cell lung cancer (NSCLC) with various driver mutations. Following are some highlights from targeted therapy information presented at the meeting.

KRAS

The first targeted therapy for NSCLC with a KRAS G12C mutation, Lumakras (sotorasib), was approved last year as an option for NSCLC that had already been treated with another therapy, such as chemotherapy. Although this was a breakthrough in making targeted therapy available for one of the most common NSCLC mutations, only a portion of KRAS G12C-positive NSCLC responded well to Lumakras (sotorasib) and identifying new treatment options will be beneficial to many patients.

• Data from the KRYSTAL-1 trial showed that the newer KRAS G12C targeted therapy, adagrasib, led to promising rates and lengths of response when given as a treatment after other previous therapies. A larger clinical trial, KRYSTAL-12, is in progress to compare adagrasib to standard therapies. Positive results may lead to adabrasib being an additional targeted therapy option for KRAS G12C-positive NSCLC.
• Data presented from the KRYSTAL-1 trial showed that adagrasib had promising results when treating brain metastasis. Importantly, data on the effectiveness of adagrasib for active and untreated brain metastasis was shared. This research is important since patients with this type of brain metastasis are often prevented from participating in clinical trials.

EGFR

Tagrisso (osimertinib)’s effectiveness has made it the standard of care first treatment for EGFR-positive NSCLC. But for many patients, resistance (where the cancer starts to grow or spread again while still being treated) is an issue. More treatment options are needed for EGFR-positive patients to help when Tagrisso (osimertinib) resistance happens.

• Updated data was shared from the CHRYSALIS-2 trial, confirming that a combination of amivantamab and azertinib produced promising results in treating EGFR-positive NSCLC, even after progression on multiple other lines of therapy including Tagrisso (osimertinib). This combination is being compared to other therapies in larger clinical trials and may have promise as a future option.
• Data from an early phase trial showed that telisotuzumab vedotin (Teliso-V), showed initial positive results in treating NSCLC that had c-MET overexpression after developing Tagrisso (osimertinib) resistance. Repeat biomarker testing (after resistance to targeted therapies occurs) may help identify new changes such as c-MET overexpression for which clinical trials may be an option.

EGFR-positive NSCLC with an exon 20 mutation does not respond as well to standard targeted therapies approved to treat NSCLC with the most common EGFR mutations. Specific targeted therapies for EGFR exon 20-positive NSCLC, Exkivity (mobocertinib) and Rybrevant (amivantamab-vmjw), were approved in 2021, but these drugs do not produce responses to the same degree as the other EGFR targeted therapies. Many people living with EGFR exon 20-positive NSCLC would benefit from additional treatment options.

• A clinical trial of CLN-081 showed promising responses that occurred when it was used to treat NSCLC with an EGFR exon 20 mutation that had already been treated previously with multiple other therapies, including other EGFR targeted therapies. It may represent a future additional option for patients with NSCLC with an EGFR exon 20 mutation.

MET

Since 2020, two different targeted therapies have been approved for initial treatment of NSCLC with a MET exon 14 skipping mutation—Tabrecta (capmatinib) and Tepmetko (tepotinib). However, as with many targeted therapies, some tumors may not respond well to these drugs and resistance can develop. This underscores the need to continue researching new treatments for NSCLC with these mutations.

• Data from the CHRYSALIS-2 trial revealed that amivantimab may be a future addition treatment option for NSCLC with a MET exon 14 skipping mutation. It showed promising rates and durations of responses, however the effectiveness may be higher for cancer that has not yet been treated with other MET exon 14 targeted therapies.

NTRK

Vitrakvi (larotrectinib) and Rozlytrek (entrectinib) are both approved initial targeted therapy options for cancers that have an NTRK fusion, including NSCLC. Understanding how well these drugs work long term for patients and under which situations they are most effective could help determine the best options for NTRK fusion-positive NSCLC.

• Combined long-term follow-up data from two different clinical trials confirmed that Vitrakivi (larotrectinib) produces high rates of lasting response to treatment in NTRK fusion-positive NSCLC, even in patients with brain metastasis. Weight gain was noted as a physical side effect for a group of patients.

Biomarker Testing

Receiving comprehensive biomarker testing is important at diagnosis to determine if a NSCLC tumor has a mutation that would benefit from a targeted therapy. It is also beneficial at progression after being on targeted therapy to help pick the next best treatment option. Biomarker testing is often done using a tumor biopsy, however a liquid biopsy (simple blood sample) can be helpful when getting a tumor biopsy is difficult or does not work well. Understanding how biomarker testing using tissue biopsies and liquid biopsies compare can help inform treatment decisions-based on these different types of tests.

• Data from the BFAST trial, a study looking to see if using only liquid biopsy biomarker testing would help identify ROS1-positive NSCLC that would benefit from the ROS-1 targeted therapy Rozlytrek (entrectinib), was shared. Researchers observed that overall, patients had slightly lower benefit from Rozlytrek (entrectinib) in this trial than expected. However, researchers believe that liquid biopsy is more likely to detect a mutation when the cancer is at a more advanced stage and thus patients in this trial had less benefit from therapy since they had more advanced cancer growth. This may indicate that tumor biopsy-based testing is better at diagnosis or with lower stage cancer and liquid biopsy may be best for repeat testing at progression or with higher stage cancer.