Targeted Therapy Options

Elizabeth Waxman

It seems as though this year has seen a number of new targeted therapies approved in the non–small cell lung cancer (NSCLC) space: amivantamab, sotorasib, capmatinib, tepotinib, selpercatinib, and pralsetinib. With the exception of amivantamab, all of these are oral therapies, which has gotten my patients really excited.  

Whitney Lewis

Yes! It’s been an exciting year for NSCLC with regard to FDA approvals for targeted therapies, and I’ve been having some trouble keeping up. I can’t remember a time where there were six new approvals in almost as many months. These new targeted therapies open up a great opportunity for patients with rare mutations, which really highlights the importance of broad molecular and genomic profiling for this disease. Before we go through these new drugs, I want to point out that the average 5-year overall survival for stage IV NSCLC is only about 6%.¹

Sotorasib is perhaps the most impactful approval, since KRAS is the most common mutation in lung cancer, and lung cancer is the most common cancer worldwide.² As you know, KRAS mutations historically confers a poorer survival relative to patients without a KRAS mutation, independent of treatments.³ So to see an effective drug approved in this space is very exciting. It’s also an easy drug to take in terms of toxicity, which is the best of both worlds for our patients. It’s currently approved for second-line therapy after patients fail chemotherapy or immunotherapy, or the combination, specifically for the KRAS G12C mutation, and it still achieved a 37% response rate with a duration of response of 11 months in the CodeBreaK100 trial.⁴ One area to note though is that the central nervous system (CNS) penetration of this drug isn’t well understood, as patients with active, untreated brain metastases were excluded.⁴

Elizabeth Waxman

Patients with RET rearrangements, found in only about 1% to 2% of NSCLC,⁵ also have a new generation of targeted therapies to explore. What sets pralsetinib and selpercatinib apart from vandetanib and cabozantinib, which have historically been used for this population, is the extreme potency and specificity for RET fusion protein versus multi-targeted kinase activity. The response rates to these new-generation RET inhibitors are 55% to 60%, including patients who were previously treated, and the median duration of response was almost 18 months with selpercatinib and not yet reached for pralsetinib at a median follow up of 12 months.^5,6 The drugs also have promising CNS activity for intracranial metastases.^5,6 So they’re certainly making an impact on survival in this small subset of NSCLC patients.

What we don’t know yet are patterns of resistance and if there might be cross-sensitivity of resistance between these agents to know if changing targeted therapies after progression would have additional yield. There is some anti-VEGF activity with these drugs, so side effects such as hypertension, bleeding, and potentially holding for surgery and other procedures should be taken into account when prescribing.^5,6 Although there are no head-to-head comparisons, it appears there is more myelosuppression with pralsetinib and more GI toxicity with selpercatinib, so the toxicity profiles should be reviewed to help select which agent to start for individual patients.^5,6 

Whitney Lewis

Another new targeted therapy group breaking into the NSCLC arena are the MET inhibitors tepotinib and capmatinib. MET exon 14 skipping mutations are found in around 3% to 4% and MET amplifications occur in 1% to 6% of NSCLC cases.⁷ Both capmatinib and tepotinib are approved for either front-line or subsequent therapy for patients with metastatic NSCLC with MET exon 14 skipping mutations, which can be seen in both adenocarcinoma and squamous cell carcinoma. Capmatinib has a response rate of 68% when used first-line, with a duration of response of 12 to 13 months, and in the second-line or greater setting, a response of ~40% and duration almost 10 months in the GEOMETRY trial.⁷ Tepotinib has a response of 46% and a duration of 11 months⁸; the VISION trial did not break down responses by treatment-naïve or previously treated population, so direct comparison between these numbers should be done so with caution. Crizotinib has long been used in this space, but with the approval of these new MET inhibitors, it’s now only recommended in certain circumstances, for example, when dealing with financial burden or intolerance to capmatinib or tepotinib.

Capmatinib and tepotinib are generally well tolerated, with the most common side effects being nausea/vomiting, peripheral edema, and an increase in serum creatinine.^7,8 I want to highlight the creatinine increase for a moment because I think this can be a really alarming change to both providers and patients when they see it. Capmatinib and tepotinib are inhibitors of MATE1 and MATEK-2, which are renal transporters, and creatinine is a substrate, so the increase in creatinine may not reflect a true change in renal function and rather be a reflection of inhibition of tubular secretion.

Elizabeth Waxman

Whitney, one question regarding hypertension and increased creatinine: Is there any contraindication to using ACE inhibitors or ARBs for patients on either capmatinib or tepotinib due to the blocking of tubular secretion? 

Whitney Lewis

I wouldn’t consider that a contraindication to these antihypertensive classes, but I would recommend initiating at a low dose and titrating slowly since ACEi/ARBs can independently cause an elevation in serum creatinine and can result in some acute kidney injury themselves, so it might be a little difficult to tell if the patient is experiencing this based on the serum creatinine alone. I would recommend checking potassium as well as assessing renal function more holistically with BUN, urinalysis, etc., to rule out other causes of AKI. Also of note, the increase in creatinine quickly resolves to baseline upon discontinuation of the drug.

Capmatinib also has some activity for MET amplifications (tepotinib also had about a 40% response rate, but duration of response was not estimable) with a 40% response rate and a median duration of response of 7.5 months.^7,8 Crizotinib can also be considered in this space, but due to tolerability, capmatinib is still preferred.

Elizabeth Waxman

One other exciting development we need to mention is amivantamab. It’s the first FDA-approved drug for EGFR exon 20 insertion mutations, which are typically resistant to other available EGFR therapies. It’s important also to note that exon 20 mutations can occur in both the EGFR and the HER2 domains, but amivantamab is only indicated for patients with EGFR mutations. However, there are some recommended (albeit not yet FDA approved) therapies with phase I/II data to support their use if you do have a patient with an exon 20 HER2 mutation or HER2 overexpression.

Whitney Lewis

Yes, amivantamab was an exciting approval. Amivantamab has a response rate of 40%, with a median duration of response of about 11 months.⁹ It is generally well tolerated with typical EGFR inhibitor side effects, with the addition of edema, arthralgias/myalgias, neuropathy, and a very high incidence of infusion reactions (66%), which should be discussed with the patient, and pre-medications are recommended before every dose of amivantamab.⁹

Elizabeth Waxman

It’s also important for clinicians to know that amivantamab is given intravenously and has frequent treatments scheduled: every week for four infusions, then twice monthly (days 1 and 15 of a 4-week cycle). The infusion times are lengthy at first, with day 1 and day 2 given over 5 and 7 hours, respectively, because the first dose is broken up over 2 days and given with an escalating infusion rate. Eventually it can be given over 3 hours if tolerated. Amivantamab is given as a flat dose, with two doses currently FDA approved depending on the patient’s weight.¹⁰

Whitney Lewis

There is also data evaluating the combination of amivantamab plus lazertinib for patients with classical EGFR-mutated NSCLC that has progressed on osimertinib. This was a really exciting cohort from the CHRYSALIS trial: Patients had progressed on osimertinib but could have had up to four prior lines of therapy and were started on amivantamab plus lazertinib.¹¹ The response rate was 36%, but clinical benefit was found in almost two-thirds of patients, and the duration of response was almost 10 months. This is a marked improvement over what we might expect from traditional chemotherapy and even chemoimmunotherapy. The data from the clinical trial also showed benefit for other mutations, although the numbers are small.

Elizabeth Waxman

I think clinicians should know that these new targeted therapies, when prescribed, will require prior authorization. Clinicians, patients, and families should be aware there may be a delay in starting treatment until that is completed. Insurance companies may have preferred agents or may not have updated formularies (many only do this once a year) and require molecular profiling results as well as a copy of the published clinical trial data that got these drugs approved. Most of these new drugs also require frequent lab monitoring at treatment initiation, so it is important to ensure we regularly follow up with patients once they start therapy to make sure monitoring guidelines can be followed.