Chasing the Target: MET Gene Abnormalities Open New Doors in NSCLC
Capmatinib and tepotinib are highly selective kinase inhibitors targeting MET.
Approximately 70% of patients with non– small cell lung cancer (NSCLC) have a genomic mutation. For 3% to 4% of these patients, this genomic mutation is a MET exon skipping mutation.1
MET exon mutations occur when MET messenger RNA splices and causes abnormal MET receptors with enhanced stability to develop. This causes MET signaling to increase as a result, which prompts further cancer cell proliferation and survival.1
“An abnormal change in the MET gene can cause their cancer to grow and spread faster,” Carmi Fazio, MSN, RN, explained to Oncology Nursing News. “That exon 14 skipping refers to the mesenchymal-epithelial transition vector gene, what MET stands for. [MET] is a receptor kinase coded by the MET gene and is expressed on the surfaces of epithelial cells. MET is important to cell signaling, cell proliferation, and cell survival. If you dysregulate that signaling, you unleash all the cellular processes that embody and propel metastasis.”
Fazio is director of oncology nursing services at ICAN, International Cancer Advocacy Network, a 501(c)(3) charitable organization specializing in direct patient navigation. The MET Crusaders, under the ICAN umbrella, is a multistakeholder biomarker support organization for patients with MET exon 14 skipping, amplification, overexpression, and fusion in the United States and abroad. In an interview with Oncology Nursing News, Fazio discussed the science behind this mechanism of action and how nurses can best support this patient population.
As Fazio explained, patients who have MET exon 14 skipping mutations are usually older and have historically received a poor prognosis. However, in recent years, selective MET tyrosine kinase inhibitors have entered the treatment landscape, offering these patients targeted treatment options.
“Patients [with] MET exon 14 skipping are fortunate to have 2 approved drugs in a standard arsenal, and both are highly selective, oral, and well tolerated,” Fazio said. “Many clinicians view these drugs as interchangeable.”
In February 2021, the FDA granted accelerated approval to tepotinib (Tepmetko) as a treatment for adults with metastatic NSCLC with MET exon 14 skipping alterations. The regulatory decision came on the heels of published data from the phase 2 VISION trial (NCT02864992), which was a multicenter, nonrandomized, open-label, multicohort trial that enrolled 152 patients with advanced or metastatic NSCLC and MET exon 14 skipping alterations. In the trial, cohort A included patients with MET exon 14 skipping mutations and cohort B included patients whose disease harbored MET amplifications.2
Patients in the VISION trial received 450 mg of tepotinib daily. Among the 69 patients who were treatment naïve, the overall response rate (ORR) was 43% and the median duration of response (DOR) was 10.8 months. Among the 83 previously treated patients, the ORR was 43% and the median DOR was 11.1 months.
Comparatively, in August 2022, the FDA granted capmatinib (Tabrecta) regular approval as a treatment for patients with metastatic NSCLC whose disease harbors a MET exon 14 skipping mutation, as detected by an FDA-approved test.3
The agent had previously been granted accelerated approval in May 2020, supported by findings from the phase 2 Geometry Mono-1 trial (NCT02414139). This multicenter, nonrandomized, open-label, multicohort study revealed that the MET exon 14 skipping inhibitor led to a 68% ORR (95% CI, 55%-80%) among treatment-naïve patients (n = 60). In the subgroup of pretreated patients (n = 100), the ORR was 44% (95% CI, 34%-54%). The DOR was 16.6 months (95% CI, 8.4-22.1) and 9.7 months (95% CI, 5.6-13.0), respectively. “As our 2 anchor drugs for MET exon skipping, capmatinib and tepotinib are well ensconced in the treatment landscape of patients [with] exon 14 skipping, both as single agents and in drug combinations,” Fazio said.
Managing Common AEs
In the VISION trial findings, tepotinib was associated with an 86% rate of treatment-related adverse events (TRAEs) of any grade; 24% of these events were grade 3 or higher. The most common TRAEs to emerge were peripheral edema (54%), nausea (20%), diarrhea (20%), increased creatinine level (18%), and hypoalbuminemia (15%).1
The most common grade 3 or 4 TRAEs were peripheral edema (7%), pleural effusion (3%), and increased lipase level (3%). A total of 11% of patients needed to discontinue treatment because of TRAEs.
In the Geometry Mono-1 trial findings, the most common TRAEs of any grade associated with capmatinib were edema (59%), nausea (46%), musculoskeletal pain (40%), fatigue (34%), vomiting (28%), dyspnea (25%), cough (21%), and decreased appetite (21%).2 The most common grade 3 or 4 TRAEs were edema (13%), musculoskeletal pain (4.3%), fatigue (8%), dyspnea (7%), and pneumonia (6%).
Peripheral Edema
For both capmatinib and tepotinib, peripheral edema is recognized to be one of the most common AEs. “Edema seems to be the most challenging adverse effect to manage,” Fazio said.
Despite this, there is no unified management for this AE, although some reports suggest that by switching between the MET inhibitors, the AE can be managed without stopping treatment.4
"We had a particular patient who was experiencing lower extremity edema,” Terri Alexander, MSN-HCSM, said in an interview with Oncology Nursing News. Alexander is a research nurse supervisor at The University of Texas MD Anderson Cancer Center in Houston. Alexander also coauthored an article on managing AEs for patients with MET exon 14 skipping NSCLC.5 “Our nursing recommendations included compression stockings and elevating his legs. When he would do both, his edema would improve, but it did not resolve. Unfortunately, Texas heat in the summer kept him from being consistently adherent with the compression stockings. He felt better when he wore them, but they were too hot to wear in the summer,” Alexander said.
Patients who experience peripheral edema may have impaired quality of life and physical function. As such, Alexander urged nurses to educate patients about preventive strategies, including limb elevation, physical activity, and exercise. In addition, nurses and providers can help proactively monitor patients by measuring their weight and limb circumference at baseline and throughout treatment in addition to inspecting the patient for swelling or skin erosions.
For patients who develop edema, the Common Terminology Criteria for Adverse Events Version 5.0 should be used to assess and grade the toxicity. Management strategies can include compression garments, lymphatic massage, and kinesiotherapy. According to Alexander, daily or as-needed diuretics may be considered. Treatment interruptions and dose reductions may also be appropriate. “[Teach patients] to be proactive,” Fazio advised, stating that patients should “start wearing compression stockings right away, keep their feet up whenever possible, and wear loose-fitting clothes when the edema or the swelling starts to occur.”
Fazio added that patients should make a plan with their oncologist regarding dose reduction. “Should the edema become an issue that becomes intolerable and interferes with the patient’s quality of life, there are organizations such as Connie Cares, a nonprofit organization that helps patients control their lymphedema,” she said.
Because edema is an expected AE with MET inhibitors, Alexander agreed with Fazio that patients who are aware of this AE before treatment are better equipped to tolerate it. “Patients need to let the clinical team know when they start having the edema so that management can start early,” she said. “Nurses can recommend that patients elevate their limbs, increase their activity, and [try] compression stockings.”
Gastrointestinal Adverse Events
Along with peripheral edema, gastrointestinal AEs are some of the most common events reported with these anticancer therapies. For tepotinib, it is recommended to take the tablets with food, increase hydration, and eat smaller meals with bland foods.
“For tepotinib-[induced] gastrointestinal AEs, our physicians often place the patient on antiemetics,” Alexander said. “From the nursing standpoint, I would recommend patients keep crackers at hand or eating smaller meals more frequently to decrease the nausea and vomiting, which can enable patients to continue receiving treatment.”
“The main objective for patients is to always remember that, regardless of their treatment, they still have a life to live and that has to come first,” Fazio said about managing AEs during treatment. “The adverse effect monitoring and management that I [recommend] is to take their medications with foods to lessen the stomach discomfort and to anticipate the common adverse effects and plan for them,” she said. “Being prepared gives them confidence that they can weather whatever comes their way when they start treatment.”
Supporting the Patients
According to Fazio, nurses can best support patients by promoting good communication between patients and oncologists. “Don’t be afraid to ask questions about the dose reductions when the adverse effects become intolerable,” she encouraged. “Oncology is supposed to be patient centered, [with] treatment directed by the patient.” Fazio also advises nurses to encourage their patients to join the MET Crusaders Facebook page, an online space for patients to boost each other and share their experiences. “They know they’re not alone,” she said about the page. “It helps them to know that I am available to them on the page to answer any question or concerns they might have. I am there for them—not only on that format, but also privately—to discuss [concerns they have], whether they be physical or psychosocial.”
Fazio also stressed the importance of goal setting in supporting patients with MET alterations. She said it is important for nurses to recognize that there will be highs and lows that accompany treatment but that goals allow patients to have a reason to continue. “A goal will give them direction,” she said.
“Other common AEs associated with MET inhibitors include increased creatinine [level], increased liver enzymes [measured via liver function tests (LFTs)], and pleural effusions,” Alexander said, noting that in her clinical experience, she has yet to see patients develop pleural effusion but has cared for patients with increased creatinine level and LFTs. “We recommend that patients increase their fluid intake for their creatinine and, if needed, the physician can hold the drug and we would repeat weekly until the creatinine levels have improved. With increased LFTs, we watch their levels and are prepared to hold the drug or possibly to reduce the dose if needed.”
Alexander’s advice to nurses is to provide them with reassurance. In her experience, patients can sometimes become disheartened after being on treatment for a long time. She recalled that her one patient lived more than 2 hours away from The University of Texas MD Anderson Cancer Center who initially experienced a 50% tumor burden reduction through treatment with tepotinib. “In the beginning, he was so adherent with his visits and letting me know what was going on—and the drug worked,” she said. “We were all so excited with the news.”
However, Alexander noted that for patients who are on these therapies for a long time, the treatment can become monotonous, and it can become easier to let other aspects of life interfere. That was especially true for her this patient, who was experiencing peripheral edema and found compression sleeves uncomfortable to wear in the Texas heat. “I would get the phone call: ‘Ms Terri, I can’t make it to my appointment tomorrow.’ And the treatment would be delayed until he could make it back to Houston,” Alexander said.
According to Alexander, the nurse can help a patient through this experience by reminding them they are there for them. “Let the patient know that you hear them and their frustration with the AEs that they are experiencing,” she said, noting that for a population of patients, these drugs have proven effective.
“As nurses, we want to do everything in our power to be able to encourage patients to be adherent with [the] drug, but we must remind our patients that they have to communicate with us,” Alexander said. “I often tell my patients that I am not a mind reader. I need them to tell me what is going on so I can offer the best advice for them. If we know about the AE when they are starting, then we can better help the patient control them.”
Treatment Landscape
As Fazio pointed out during the 2020 American Society of Clinical Oncology Virtual Scientific Program, Mark Awad, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, announced that more than 500 mutations at the DNA level cause MET exon 14 skipping.6 “If that isn’t genetic complexity, I don’t know what is,” she said, noting that in addition to exon 14 skipping mutation, there is also MET amplification, which is an increase in the number of genes. Approximately 4% of patients with non–small cell lung cancer have MET amplification. Patients may also develop MET overexpression, which is when there are too many copies of the MET receptor.
Finally, a very rare MET fusion or rearrangement is when a chromosomal rearrangement leads to the gene fusion, which results in chimera MET protein.6
Because of the genetic complexity, Fazio stressed how important it is to order a tissue or liquid biopsy to identify patients with MET alterations. MET Crusaders helps provide support for patients with MET exon skipping mutations, amplifications, overexpression, and fusions. Therefore, Fazio and her coworkers tell patients with newly diagnosed solid tumors to ask their oncologists to “profile, profile, profile.”
“Every patient [with] newly diagnosed non– small cell lung cancer should get next-generation sequencing,” Fazio said. She noted that in the VISION trial, 58% of patients were profiled via a tissue biopsy and that 65% of patients underwent plasma testing.
Furthermore, because patients with MET mutations tend to be older, reimbursement from Medicare is typically available for next-generation sequencing because of a pivotal Centers for Medicare & Medicaid Services decision in 2018. “With next-generation sequencing having a 2-week turnaround time, there is no excuse not to order such profiling to detect the mutation or fusion that is driving your patient’s lung cancer or any other cancer type,” Fazio said.
Fazio concluded by strongly encouraging patients to seek community in the form of the MET Crusaders Facebook page, because it is a space specifically designed to help support these patients. “It’s a tight community that really comes together for each other; they share beautiful moments of their lives and every success. In spite of the disease, beautiful moments do occur. We are there to support their every need, every bump in the road, and celebrate every success,” she said.
References
- Hong L, Zhang J, Heymach JV, Le X. Current and future treatment options for MET exon 14 skipping alterations in non-small cell lung cancer. Ther Adv Med Oncol. 2021;13:1758835921992976. doi:10.1177/1758835921992976
- Tepmetko. Prescribing information. EMD Serono Inc; 2021. Accessed September 5, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214096s000lbl.pdf
- Tabrecta. Prescribing information. Novartis; 2022. Accessed September 5, 2023. https://bit.ly/3JLN2kQ
- Kunimasa K, Kawamura T, Tamiya M, et al. Capmatinib successfully overcomes tepotinib-induced intolerable peripheral edema. Thorac Cancer. 2021;12(24):3426-3428. doi:10.1111/1759-7714.14205
- Ahn L, Alexander T, Vlassak S, Berghoff K, Lemmens L. Tepotinib: management of adverse events in patients with MET exon 14 skipping non-small cell lung cancer. Clin J Oncol Nurs. 2022;26(5):543-551. doi:10.1188/22.CJON.543-551
- Awad MM, Lee JK. JKL. Characterization of 1387 NSCLCs with MET exon 14 (METex14) skipping alterations (SA) and potential acquired resistance (AR) mechanisms. Presented at: 2020 American Society of Clinical Oncology Virtual Scientific Program. 29-31, 2020.
