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The majority of people with advanced EGFR-mutant non-small cell lung cancer (NSCLC) receiving first-line osimertinib (Tagrisso) will respond to therapy. But acquired resistance to the tyrosine kinase inhibitor (TKI) is almost inevitable.

"Acquired resistance, as opposed to de novo resistance, is when a patient initially had at least some response, and then at some point -- usually between 6 months [and] up to a year or years later -- disease starts growing again," said Timothy F. Burns, MD, PhD, of the University of Pittsburgh and UPMC Hillman Cancer Center. "Across the board at the time of resistance, the first thing that should be done is liquid or tissue biopsy to find out what the resistance mechanism is."

Mechanisms of resistance to third-generation EGFR TKIs like osimertinib are very heterogeneic, explained Vamsidhar Velcheti, MD, of NYU Langone's Perlmutter Cancer Center in New York City.

Patients can develop secondary mutations in EGFR (on-target mutations) that cause osimertinib to not work as effectively or mutations outside of EGFR (off-target mutations), like MET amplifications.

"It is hard to predict what kind of resistance mechanisms these tumors may have," Velcheti said. "That is what makes it challenging in terms of figuring out the best upfront therapeutic strategy for a patient."

Resistance Mechanisms

One of the most commonly found mechanisms of resistance to osimertinib is the C797S mutation. data showed about mutation in plasma samples compared with 2% of patients having acquired L718Q and 1% with S768L mutations.

In vitro studies have shown that as many as one-third of patients may have EGFR amplification, with with other EGFR-resistant mutations.

"The majority of osimertinib resistance mechanisms are going to be on other pathways [that] we call bypass pathways," Burns said.

are the most common resistance mechanism; others include HER2 amplification and KRAS mutations.

Finally, other tumors that develop resistance may be those undergoing histologic transformation to either small cell lung cancer or squamous cell NSCLC.

"If the liquid biopsy does not find something, a tissue biopsy should be done," Burns advised. "One mechanism of resistance that cannot be detected by liquid biopsy is histologic transformation."

Treatment Options

If a patient is resistant to osimertinib and sequencing does not reveal MET or RET amplification or other targetable alterations, the next line of standard care is to give another EGFR-targeting agent in combination with chemotherapy, Burns said: "In this case, amivantamab [Rybrevant] is an obvious choice for the second-line setting."

Amivantamab is a bispecific antibody that targets both EGFR and MET. The agent recently received in combination with carboplatin and pemetrexed for patients whose disease progressed on or after an EGFR inhibitor. Approval was based on the MARIPOSA-2 trial that showed significantly improved progression-free survival (PFS) with amivantamab-chemotherapy compared with chemotherapy alone.

"Generally in those cases, there was a 64% response rate in those patients after progression on osimertinib," Burns noted. "Although it was not approved this way, you can also give amivantamab alone after osimertinib and that has about a 30% response rate, studies showed."

In addition, Burns said that patients can continue on an EGFR inhibitor – either lazertinib (Lazcluze) plus amivantamab or osimertinib plus amivantamab.

Future Options

The antibody-drug conjugate (ADC) patritumab deruxtecan (HER3-DXd) is a promising treatment for EGFR inhibitor-resistant disease.

"The hypothesis is that tumors that have resistance to EGFR TKIs tend to increase expression of HER3," Velcheti explained.

In the trial, patients with metastatic EGFR-mutated NSCLC with prior receipt of an EGFR inhibitor were randomly assigned to HER3-DXd or pemetrexed and platinum chemotherapy. HER3-DXd treatment significantly improved median PFS versus chemotherapy, co-developer .

Burns explained that HER3-DXd is "a drug that many in the clinic were waiting for as another option, and it was expected to be approved by the FDA on June 26, but there was an issue with a ," Burns said. "This is something the field is excited about, but it is likely delayed until early next year."

The ADC datopotamab deruxtecan (Dato-DXd), which targets TROP2, is also under investigation. In the phase II trial, Dato-DXd elicited a confirmed objective response rate (ORR) of 35.8% in patients with actionable genomic alterations. Among those patients with EGFR mutations, the ORR was 43.6%. Median duration of response was 7 months.

More to Learn

Velcheti said that more data are needed to fully understand when to continue targeting EGFR and when to switch to other classes of drugs. To that end, the phase II will test different agents in combination with osimertinib based on the identified TKI resistance mechanisms. These include savolitinib, gefitinib (Iressa), Dato-DXd, necitumumab (Portrazza), and other drugs specific to MET alterations, C797X mutations, or no identified biomarker.

"Fortunately, the treatment course of EGFR-mutant NSCLC is long," Burns said. "We are going to be able to go through multiple lines of therapy so the more options we have the better."

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