Targeted Therapy Approvals Improve Outcomes, Expand Options for Patients With NSCLC

Beth Sandy, MSN, CRNP

Many patients with non–small cell lung cancer (NSCLC) achieve much better outcomes with targeted therapy compared with chemotherapy, according to Beth Sandy, MSN, CRNP.¹

For example, findings from Singal G et al found that the median overall survival (OS) was 18.6 months for patients with NSCLC who received targeted therapy for their driver mutation.² In comparison, among those who received standard-of-care chemotherapy when they had a driver mutation, the median OS was 11.4 months.

However, with many new targeted therapies receiving FDA approval, it can be difficult to stay up to date on the various options.

As part of 6th Annual School of Nursing Oncology Annual Meeting, Sandy, who is a thoracic oncology nurse practitioner at the Abramson Cancer Center with the University of Pennsylvania, gave a brief overview on the treatment landscape for patients with NSCLC who have actionable driver mutations. She highlighted which agents were approved for which mutations, compared their efficacy and safety profiles, and noted if any promising new generation agents were under investigation for the driver mutation.
Throughout the presentation Sandy noted that patients are only eligible for targeted treatments if have been tested for mutations or fusions, and have documented evidence.

“Biomarker testing was never more important than it is now in NSCLC,” Sandy noted. “Up to 40% to 50% of patients with adenocarcinoma are going to have some kind of actionable mutation, where we can give them a targeted therapy instead of chemotherapy or immunotherapy, to manage their disease—usually with better outcomes and less toxicity.”

EGFR-Mutated NSCLC

There are 5 drugs approved to treat EGFR-mutated NSCLC, including the first-generation agents gefitinib (Iressa), and erlotinib (Tarceva), and the second-generation agents afatninib (Gilotrif), osimertinib (Tagrisso), and dacomitinib (Vizimpro).

Osimertinib is the preferred agent recommended by the National Comprehensive Cancer Network guidelines based on its superiority over the first generation agents, and its favorable toxicity profile.³

In the first-line metastatic setting, osimertinib was associated with a 38.6-month median OS (95% CI, 34.5-41.8), compared with 31.8 months with a comparator EGFR tyrosine kinase inhibitor (95% CI, 26.6-36.). The hazard ratio was 0.80 (95.05% CI, 0.64-1.00; P = .046)^.4,5

Moreover, in light of recent data showcasing the agent’s value in the adjuvant setting, osimertinib is now an option for patients following surgery and chemotherapy.⁶

Exon 20 insertions Mutations

There are 2 approved agents for patients with exon 20 insertions: amivantanib (Rybrevant) and mobocertinib (Exkivity).

Amivantitanib is given intravenously (IV) once per week for 4 weeks, and then once every other week. Relevant adverse effects (AEs) include infusion reaction with the first dose (66%) and rash (74%).⁷

Mobocertinib is an oral agent and patients take 4 tablets a day. Major reported AEs included diarrhea (93%), 20% of which was grade 3 or greater, and heart rate corrected prolongation or cardiomyopathy, which is rare.⁸

Both agents can cause interstitial lung disease, which was reported among 3.1 % and 4.3% of patients, respectively.

KRAS Mutations

KRAS mutations are the most common oncogenic drivers in NSCLC and present in approximately 25% of nonsquamous and 3% of squamous cases. Patients who are likely to have a KRAS mutation include younger, female, and Caucasian patients, as well as those with a smoking history. Among KRAS mutations, G12C is the most common variant representing approximately 40%-50% of KRAS mutations and is evident in about 13% of adenocarcinomas.

In 2021, the first targeted therapy for patients with a KRAS G12C mutation, sotorasib (Lumakras), was approved for locally advanced or metastatic disease which had progressed after at least 1 prior platinum-based regimen and/or immunotherapy based on findings from CodeBreaK 100 (NCT03600883).

Sotorasib is administered at 960 mg once daily either with or without food.⁹ The tablets are sold as 120 mg and patients will take 8 tablets. The most common laboratory abnormalities associated with this targeted treatment are decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

Patients taking sotorasib should avoid the concomitant use of proton pump inhibitors and H2 blockers. Over the counter acid reducing mutation, such as TUMS, are OK.¹⁰

Adagrasib, another oral therapy targeting KRAS mutations, is under investigation. The agent has shown encouraging clinical activity; however, as of August 2022, it is not approved.¹¹

MET Exon 14 Skipping Mutations

Patients with MET exon 14 skipping mutations have 2 approved treatment options: capmatinib (Tabrecta) or tepotinib (Tepmetko).

Among 100 pretreated patients with MET exon skipping–mutated NSCLC treated with capmatinib, the overall response rate (ORR) was 44.0%, the median duration of response (DOR) was 9.7 months, and the median progression-free survival (PFS) was 5.5 months. In the treatment naïve cohort (n = 60), the median ORR was 66.7%, the median DOR was 12.6 months, and the median PFS was 12.3 months.¹²

Oral doses of capmatinib can be given at 400 mg twice daily with or without food.¹³ Commercially available doses are sold at 150 mg and 200 mg. The most common AEs associated with this treatment include peripheral edema, fatigue, nausea, vomiting, dyspnea, and decreased appetite. The most common laboratory abnormalities (greater than 20%) include decreased albumin, increased creatinine, alanine transaminase increase (ALT), alkaline phosphatase, amylase, gamma-glutamyl transferase, lipase, and aspartate transaminase increase (AST).

The agent includes a box warning for interstitial lung disease/pneumonitis, hepatotoxicity, photosensitivity, and embryo-fetal toxicity. Nurses prescribing this drug to patients should ensure that patients are avoiding strong to moderate CYP3A inducers.

Among 83 pretreated patients with MET exon skipping–mutated NSCLC who were treated with tepotinib, the ORR was 44.6%, the median DOR was 11.1 months, and the median PFS was 10.9 months. In the treatment-naïve cohort (n = 69), the median ORR was 44.9%, the median DOR was 10.8 months, and the median PFS was 8.5 months.¹⁴

Tepotinib should be taken with food once daily at 450 mg.¹⁵ Tablets are 225 mg. The most common AEs associated with this agent include edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. Common laboratory abnormalities include decreased albumin and sodium, as well as increased creatinine, alkaline phosphatase, ALT, AST, potassium, amylase, and gamma-glutamyltransferase.

This agent shares the same warnings as capmatinib, except it is not associated with photosensitivity. Patients taking this drug should avoid strong CYP3A and P-glycoprotein inhibitors as well as strong CYP3A inducers.

BRAF Mutations

The percentage of patients with BRAF-mutated NSCLC is 2%, making it an uncommon mutation with this disease, Sandy noted. This mutation is more common among smokers.

The combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) was approved for patients with BRAF V600E–mutant NSCLC. According to data from the 2022 International Association for the Study of Lung Cancer (IASLC) Targeted Therapies conference, 20% to 50% of patients with a BRAF mutation have V600E-positive disease.¹⁶ It is slightly more common among female nonsmokers. The most common toxicity associated with this treatment is a noninfectious fever.

Other drugs under investigation for this setting include encorafenib (Braftovi) plus binimetinib (Mektovi), as well as vemurafenib (Zelboraf) and cobimetinib (Cotellic). These agents are not approved.

ALK, ROS1, RET, and NTRK

An RNA-fusion panel is the most sensitive test for identifying fusions and gene arrangements, Sandy said. However, next-generation sequencing, immunohistochemistry (IHC), and fluorescence in situ hybridization testing, can be useful as well.

There are 5 approved drugs for patients with ALK fusions in NSCLC, all of which have different toxicity profiles, administration, and schedules, she noted.

For example, crizotinib (Xalkori) is taken at 250 mg twice a day and is available in 250-mg and 200-mg capsules;¹⁷ ceritinib (Zykadia) is taken at 450 mg daily and is available in 150-mg capsules;¹⁸ alectinib (Alecensa) is taken at 600 mg twice a day, and is available in 150-mg capsules;¹⁹ brigatinib (Alunbrig) is taken at 90 mg daily for the first week, and then at 18 mg daily for the following, and is available at 30-mg, 90-mg, and 180-mg capsules;²⁰ and lorlatinib (Lorbrena) is taken at 100 mg daily and is available at 25-mg and 100-mg tablets.²¹

Of these, alectinib, brigatinib, and lorlatinib, have demonstrated excellent intracranial penetration.

For patients with evidence of ROS1, there are 2 approved drugs: crizotinib and entrectinib (Rozyltrek). The 2 agents have demonstrated similar response rates, although entrectinib has considerably better intracranial penetration. Both drugs are associated with excellent and durable responses. Patients are often able to live a long time with these treatments.

Patients with RET gene rearrangements have 2 treatment options available to them, selpercatinib (Retevmo) and pralsetinib (Gavreto). Both drugs have similar efficacy data, including excellent response rates and long durable responses for 1 to 3 years. Selpercatinib may be given to patients who weigh 50 or more kg at a dosage of 160 mg twice daily. Associated AEs include elevated transaminase, hypersensitivity reactions, hepatotoxicity, hypertension, skin rash, electrolyte abnormalities, abdominal pain, constipation, diarrhea, nausea, vomiting, xerostomia, and fatigue.²²

Pralsetinib must be given on an empty stomach. This drug is given at a dose of 400 mg and its associated toxicities include elevated transaminases, neutropenia, anemia, thrombocytopenia, hypertension, dysgeusia, diarrhea, constipation, increased creatinine, pneumonitis, and hyponatremia.²³

NTRK gene fusions are best found on a fusion panel. These are rare, and among the gene fusions, NTRK 1 and NTRK 3 represent the most common expressions. There are 2 first generation agents available: entrectinib and larotrectinib (Vitraki). The response rate with these agents was 70%.

Another agent, repotrectinib (TPX-005), is under investigation.²⁴

HER2-mutated NSCLC

The important thing to recognize with HER2-mutated NSCLC is not to confuse it with IHC+, or overexpression, or amplification, Sandy stressed. As of 2022, antibody-drug conjugates have demonstrated the most clinical activity with this biomarker, with fam-trastuzumab deruxtecan-nxki (Enhertu) leading the way in terms of clinical activity, but no agents are approved.

Data from the DESTINY-Lung01(NCT03505710) trial showed that among 85 patients the best percentage change of tumor size was 54.9% (95% CI, 44.2%-65.4%).²⁵

Targeted treatments for HER2-mutated NSCLC is an emerging field, Sandy noted.

References

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