NSCLC Therapy is Increasingly Targeted

Targeted therapies that zero in on cancer with particular genetic anomalies are playing an increasingly important role in the treatment of lung cancers as researchers gain a clearer understanding about the specific “driver mutations” involved in cancer cell growth, down to the level of mutations in certain genes.

This kind of mutation-specific targeted therapy has come on especially strong as a strategy for treating patients with non-small cell lung cancer (NSCLC), which accounts for between 80% and 85% of lung cancer cases. The incidence of lung cancer in the United States has been declining, but lung cancer is still the leading cause of cancer death in the country, accounting for about 25% of cancer deaths each year.

Targeted therapies are the cornerstone of this kind of precision medicine. They can be either small molecules or monoclonal antibodies. When the FDA approves a targeted therapy, it typically approves a companion diagnostic test that identifies the biomarkers that determine whether the targeted therapy is appropriate.

Researchers have determined several genes play a key role in lung cancer, including EGFR, KRAS, MET, LKB1, BRAF, PIK3CA, ALK, RET and ROS1. Research of therapies that target the mutations of these genes has expanded over the past decade, leading to the approval of several important therapies targeting EGFR, KRAS and MET mutations.

The KRAS gene has been particularly challenging to develop a therapy against. The KRAS protein doesn’t have “deep pockets” for drugs to bind to, making it difficult to block activated KRAS. But investigators have begun exploiting a specific point on the gene,
KRAS G12C.

A therapy approved in May 2021 forms an irreversible bond with cysteine residue of KRAS G12C, holding the protein in its inactive form. The therapy, Amgen’s Lumakras (sotorasib), was granted accelerated approval from the FDA, making it the very first therapy to address a KRAS mutation in any cancer. Lumakras is used to treat adult patients with NSCLC whose tumors have a KRAS G12C mutation and who have received at least one prior therapy. KRAS mutations are present in about 13% of NSCLC cases. Regulators also approved two companion diagnostics: QIAGEN therascreen KRAS RGQ PCR kit and the Guardant360 CDx.

Research continues on Lumakras. A trial assessing Lumakras alone and in combination continues. A phase 2 trial of the drug as a first-line treatment for NSCLC was scheduled to start last month. Amgen is also studying Lumakras in the treatment of KRAS G12C-mutated advanced colorectal cancer in the CodeBreak 101 clinical trial.

KRAS G12C is the target of another NSCLC therapy in development, Mirati Therapeutics’ adagrasib. The company announced in June 2021 that adagrasib has received breakthrough therapy designation for this indication. Data were presented at the European Lung Cancer Virtual Congress in March 2021 from an early-stage trial that showed 45% of the 51 patients evaluable had a partial response to treatment with adagrasib.

A couple of leading therapies are designed to home in on EGFR and MET receptors. In May 2021, the FDA approved Rybrevant (amivantamab-vmjw), a bispecific antibody directed against EGFR and MET receptors. Developed by Janssen, the drug is used to treat adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutation who have progressed with chemotherapy. Rybrevant, administered intravenously, had previously received the FDA’s priority review and breakthrough therapy designation.

At the same time, the FDA approved Guardant Health’s Guardant360 CDx liquid biopsy as a companion diagnostic. The test will be used for tumor mutation profiling to identify patients with locally advanced or metastatic NSCLC who harbor the EGFR exon 20 insertion.

A first

Rybrevant is the first drug the FDA has approved for patients with NSCLC who have the EGFR exon 20 mutation. About 2% to 3% of patients with NSCLC have these mutations, and they are the third most common type of EGFR mutation. Patients with this mutation have a worse prognosis because it causes rapid cell growth and spread of cancer. Five other targeted therapies to treat EGFR mutations in NSCLC are available, but they target EGFR genes that have exon 19 deletion and exon 21 substitution mutations. Janssen is also testing Rybrevant as a treatment for patients with those mutations. At the 2021 annual meeting of the American Society of Clinical Oncology, the company released data about a phase 1 trial of Rybrevant in combination with lazertinib, an experimental therapy that Janssen licensed from Yuhan Corp., a South Korean company. The combination led to a median duration of response of 9.6 months in chemotherapy-naive patients. Rybrevant is also being studied in a phase 3 trial in combination with carboplatin-pemetrexed, a chemotherapy combination, in NSCLC patients with exon 20 mutations. A separate trial, which has not yet started recruiting patients, will evaluate Rybrevant and the chemotherapy combination in patients with exon 19 deletion and exon 21 substitution mutations.

Targeting MET

Over the past year, two therapies targeting a different mutation, the MET exon 14 skipping alteration, have been approved, providing the first options for this mutation. The MET gene encodes for a tyrosine kinase receptor that activates signaling pathways involved in cell proliferation, survival and growth. The MET exon 14 skipping alteration is seen in about 3% to 4% of cases of NSCLC. Patients with MET-positive lung cancers are most likely to have a smoking history.

In February 2021, the FDA approved EMD Serono’s Tepmetko (tepotinib) for the treatment of adult patients with metastatic NSCLC with MET exon 14 skipping alterations. Tepmetko is a once-daily oral therapy administered as two 225-milligram tablets (450 milligrams in total) and is the first oral MET inhibitor approved as a treatment for NSCLC.

Applications for Tepmetko have been submitted to other regulatory agencies, including the European Medicines Agency and in Australia, Switzerland and Canada under the FDA’s Project Orbis initiative, which provides a framework for concurrent submission and review of oncology medicines among international partners.

EMD Serono is continuing to study Tepmetko. The company presented updated data from a phase 2 trial at the 2021 Annual Meeting of the American Society of Clinical Oncology. In one analysis, a biomarker response detected in liquid biopsy was measured. A reduction in variant allele frequency following Tepmetko treatment was related to an improved treatment outcome. That result indicates a liquid biopsy may provide a reliable means for monitoring response to treatment and understanding resistance
mechanisms.

In another analysis, Tepmetko demonstrated efficacy in patients with MET exon 14 skipping NSCLC with brain metastases. Brain metastases are reported in 20% to 40% of these patients and are associated with poor prognosis.

A third analysis from this study was with a cohort of patients with NSCLC with MET amplification. In this group, Tepmetko showed potential, especially in patients who had not been previously treated.

Novartis’ Tabrecta (capmatinib) is another MET inhibitor therapy. It was approved in May 2020 for patients whose tumors have a mutation that leads to MET exon 14 skipping. Tabrecta is given twice daily as 400-milligram oral medication. Foundation Medicine’s FoundationOne CDx has been approved as a companion diagnostic.

Denise Myshko is senior editor of Formulary Watch®, a website affiliated with Managed Healthcare Executive®.