Key Advances Showcase the Potential of Precision Medicine in NSCLC

Christian Rolfo, MD, PhD, MBA

Next-generation sequencing (NGS) is a necessity in driving progress in lung cancer, according to a panel of experts from Fox Chase Cancer Center who presented during an OncLive® Institutional Perspectives in Cancer webinar on precision medicine. However, its sustainability will be dependent on the implementation of thorough informatics and infrastructure that can support the integration of genomic results into electronic medical records, said Christian Rolfo, MD, PhD, MBA.

During the meeting, the panelists provided key take-away messages from their presentations on biomarker testing, molecular testing results, and EGFR-, RET-and KRAS-targeted therapies.

The chair of the event, Hossein Borghaei, DO, MS, chief, Division of Thoracic Medical Oncology, director, Lung Cancer Risk Assessment, professor, Department of Hematology/Oncology, co-director, Immune Monitoring Facility, Lung Cancer and Mesothelioma TRDG member, and Gloria and Edmund M. Dunn Chair in Thoracic Oncology, of Fox Chase Cancer Center, highlighted the current sphere of EGFR-directed therapy in NSCLC.

Borghaei was joined by fellow Fox Chase Cancer Center faculty:

• Balazs Halmos, MD, MS, director of Thoracic Oncology, and director of Clinical Cancer Genomics at Montefiore Medical Center
• Christian Rolfo, MD, PhD, MBA, professor of medicine and director of Early Phase Clinical Trials in the Department of Medicine at the University of Maryland School of Medicine
• Stephen Liu, MD, an associate professor of medicine, director of thoracic oncology, and director of developmental therapeutics at Georgetown Lombardi Comprehensive Cancer Center

Testing for Biomarkers

Halmos: In thoracic oncology, NGS is here to stay, so that we leave no gene stranded and no patient’s tumor unturned, so that we can find the optimal treatment course for our patients up front as well as throughout their treatment continuum.

Interpreting Molecular Testing Result Reports: Challenges and Barriers

Rolfo: There’s a lack of familiarity and understanding by patients and clinicians, as well as poor access to genomic medicine expertise and testing. There is a high cost and lack of reimbursement for genetic or genomic tests and services. Additionally, there’s the potentially overwhelming and rapidly evolving nature of genomic information. There’s a need for extensive informatics and infrastructure to integrate genomic results into electronic medical records. There’s also non-acceptance of genomic medicine by institutions and clinicians.

Evidence-based scales for grading oncogenic drivers are useful tools for guiding oncologists. The adoption of tumor mutational burden is advisable and can help with interpreting NGS results and treatment decision making. Enrollment on clinical trials is preferred over the off-label use, increasing evidence for new targets and mechanisms of resistance. Integration of NGS results in the EMR increase opportunities for patients and improve understanding of every case. Education is crucial for interpretation and implementation of precision medicine.

RET- and KRAS-Targeted Therapies

Liu: There have been multiple FDA approvals across NSCLC. Precision is required for the best possible outcomes, so that we can deliver the right treatment and avoid the wrong treatment. It’s important to choose correctly from the start, and biomarker testing is a necessity.

Pralsetinib [Gavreto] is highly effective in RET fusion–positive NSCLC and was FDA approved on September 4, 2020. In the phase 1/2 ARROW trial [NCT03037385], after platinum-doublet chemotherapy, we saw a response rate of 66% and a median duration of response [DOR] of 22 months. In the first-line setting, we saw a response rate of 88% and a median DOR that was not yet reached. The median time to response was 1.8 months. It was also well tolerated, with a less than 6% rate of treatment discontinuation because of treatment-related adverse effects.

Selpercatinib [Retevmo] is another selective RET inhibitor that was evaluated in the phase 1/2 LIBRETTO-001 trial [NCT03157128]. In 218 patients previously treated with platinum-based chemotherapy, the response rate was 57%, the median DOR was 17.5 months, and efficacy was seen across genotypes and fusion partners.

Pralsetinib and selpercatinib are highly active in the frontline setting, well tolerated, and approved, and both agents have central nervous system efficacy. Resistance is expected, but next-generation agents are in development.

In the CodeBreak100 trial [NCT03600883], 960 mg of sotorasib [Lumakras] monotherapy daily led to a response rate of 37%, with a median DOR of 11.1 months, a median progression-free survival of 6.8 months, and a median overall survival of 12.5 months. Sotorasib was granted an FDA accelerated approval on May 28, 2021. The CodeBreak200 trial [NCT04303780] is now evaluating sotorasib vs docetaxel in patients with KRAS G12C–mutated NSCLC, and first-line trials are underway.

EGFR-Targeted Therapies

Borghaei: Osimertinib [Tagrisso] is the current, established frontline treatment option for patients with advanced EGFR-mutated NSCLC. In the adjuvant setting, osimertinib is associated with an improvement in disease-free survival for patients with EGFR-mutated early-stage NSCLC. Other potential options such as combinations with chemotherapy or VEGF inhibition are under investigation. For patients with recurrent EGFR exon 20 insertion [mutations], amivantamab[-vmjw (Rybrevant)] is now an approved treatment option, with other options being evaluated.