Exkivity FDA Approval a ‘Compelling’ Solution as First Oral Therapy for Lung Cancer Subset


Here’s what patients should know about the recent FDA approval of Exkivity, the first oral therapy for patients with non-small cell lung cancer who have EFGR exon 20 insertion mutations.

The recent Food and Drug Administration (FDA) approval of Exkivity (mobocertinib) will provide an effective treatment option for a subset of patients with non-small cell lung cancer (NSCLC) who previously did not receive any benefit from other targeted drugs. It also has distinct significance as it is the first oral therapy approved in this subset.

Exkivity is intended to treat adult patients with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EFGR) exon 20 insertion mutations whose disease progressed during or after platinum-based chemotherapy.

“The EGFR exon 20 insertion mutant lung cancer group has always been a challenging group to treat, because their tumors are uniquely resistant to most of the oral therapies that we've given historically,” Dr. Joel Neal said in an interview with CURE®. “One or two of them may work for a couple of months very modestly with low response rates, but mobocertinib is much more specific for the exon 20 mutation, and the response rates and duration of response are significantly higher than with any other oral therapies that have been tested off-label.”

Neal, who is an associate professor of medicine in oncology at Stanford Cancer Institute and Stanford University, was a coinvestigator on the Exkivity trial that led to the approval.

Opening a New Door for Patients With EFGR Exon 20 Insertion Mutations

“We've known about this mutation, and we've been trying to figure out what to do with this group of patients; we haven't had many options for them,” said Dr. Andrea McKee, chief of the division of radiation oncology at the Lahey Hospital and Medical Center Sophia Gordon Cancer Center in Burlington, MA and a national spokesperson for the American Lung Association, in an interview with CURE®. “And now we have this option. (The FDA) simultaneously also approved the test that looks for this specific mutation. So, if a patient comes in, and especially if they fit that sort of profile, they will be tested to see if they carry that deletion and can then benefit from the drug.”

The next-generation sequencing test is called the Thermo Fisher Scientific’s Oncomine Dx Target Test, and it determines whether patients with NSCLC have EGFR exon 20 insertion mutations, as McKee explained.

Patients who have the EGFR exon 20 insertion mutation can experience more rapid cancer growth. Although it doesn’t represent a huge population of patients, McKee said, it does represent a higher proportion of female patients, Asian patients and nonsmokers. These patients previously did not respond well to EGFR-targeted drugs and did poorly with standard chemotherapy.

“Historically, most of these patients would have received platinum-based doublet chemotherapy in the first line setting if they had metastatic disease, with or without antiangiogenic therapy or immunotherapy,” Neal said. “But in our experience, immunotherapy wasn't very effective in this patient population. After platinum-based therapy, the only approved option was other chemotherapies or immunotherapy, but again, the effects were modest.”

Oral Therapy Can Improve Quality of Life

In May 2021, an intravenous (IV) therapy called Rybrevant (amivantamab) was granted accelerated approval for this patient population.

“So they had that as an option, but as a bispecific EGFR and MET antibody it has a very different mechanism of action than this oral therapy,” Neal explained.

As the first oral therapy, Exkivity will make it easier for these patients to manage the balance between treatment and everyday life, McKee said.

“(A drug) given through an IV is more difficult (than) having an oral drug. Think about it from a patient perspective – you can be at home and take your cancer treatment, you can still go to work and do all of your sort of normal activities and take an oral medication not bound to an infusion center,” McKee explained.

Effectiveness, Potential Side Effects and What to Say to Your Provider

Data from phase 1/2 trial that the FDA based its decision on were compelling, McKee said. The 114 patients who were treated with Exkivity in the trial had a median duration of response (DoR) of 17.5 months, meaning that, on average, tumors responded to treatment without growing or spreading for that amount of time. They also had an overall response rate (ORR), or proportion of patients whose disease responded to therapy, of 28%; a median overall survival (OS) of 24 months; and a median progression-free survival (PFS) of 7.3 months.

Side effects experienced by the patients in the trial were minimal, McKee said. The most frequently reported events were diarrhea, rash, nausea, stomatitis (inflamed and sore mouth), vomiting, decreased appetite, paronychia (infection surrounding the fingernail), fatigue, dry skin and musculoskeletal pain.

“Somewhat uniquely, this drug does have more of a warning for QT prolongation… and a small risk of heart arrhythmias,” Neal said. “So we monitor with EKGs, and also treat patients for side effects with what we call supportive care – preventing diarrhea, preventing rash. Somewhere around 20%-30% of patients may have to undergo dose reduction to make it more tolerable from the FDA-approved dose… But on the trials, we encouraged intensive management of diarrhea and continuing the highest tolerated dose for better brain penetration and better efficacy overall.”

Looking Ahead

McKee emphasized that patients should speak with their providers to learn about the treatment, or even just whether or not they are EGFR-positive, so they can properly advocate for themselves.

“I think it's important for people to know about this because their provider may not necessarily be aware, it can be challenging for providers to stay up to date with everything that's going on,” she urged.

As for Exkivity, Neal explained that it has accelerated approval so it has been deemed safe and effective to use, but has not yet been compared with standardized therapy in a trial to determine whether it is a better option.

“I'm not sure that's critical to show superiority to chemotherapy, because mobocertinib shouldn't prevent with the efficacy of chemotherapy,” he said. “If it's equal to chemo in a randomized trial, then it still represents an additional option beyond chemotherapy, and could even be potentially combined with chemotherapy in the future.”

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