Acquisition of acquired resistance in EGFR-mutant NSCLC

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

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

Mechanisms of resistance to third-generation EGFR TKIs, such as osimertinib, are very heterogeneous, explained Vamsidhar Velcheti, MD, of the Perlmutter Cancer Center in New York City.

Patients may develop secondary mutations in EGFR (on-target mutations) that make osimertinib not work as effectively or off-target mutations EGFR (off-target mutations) such as meth amplifications.

“It’s hard to predict what kind of resistance mechanisms these tumors may have,” Velcheti said. “That’s what makes it difficult in terms of finding the best initial therapeutic strategy for a patient.”

Resistance mechanisms

One of the most common resistance mechanisms to osimertinib is the C797S mutation. The FLAURA process the data showed about 7% of patients acquired a C797S mutation in plasma samples compared to 2% of patients who acquired L718Q and 1% with S768L mutations.

In vitro studies have shown that up to a third of patients may have EGFR amplification, with about half of these appear with another EGFR– resistant mutations.

“Most of the mechanisms of resistance to osimertinib will be through other pathways (which we call bypass pathways),” Burns said.

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

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

“If the liquid biopsy doesn’t find something, a tissue biopsy should be done,” Burns advised. “One resistance mechanism that cannot be detected by liquid biopsy is histological transformation.”

Treatment options

Whether a patient is resistant to osimertinib and sequencing does not reveal meth or RET amplification or other targetable changes, the standard next line of 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 setting of second line”.

Amivantamab is a bispecific antibody that targets both EGFR and MET. The agent recently received FDA approval in combination with carboplatin and pemetrexed for patients whose disease has progressed on or after an EGFR inhibitor. Approval was based on BUTTERFLY-2 study that showed a significant improvement in progression-free survival (PFS) with amivantamab chemotherapy compared with chemotherapy alone.

“Overall, in those cases, there was a 64 percent response rate in those patients after progression on osimertinib,” Burns noted. “Although it hasn’t been approved that way, you can also give amivantamab alone after osimertinib and that has about a 30% response rate, studies have shown.”

Additionally, Burns said patients can continue to take 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 disease resistant to EGFR inhibitors.

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

In HERTHENA-Lung02 trial, metastatic patients EGFR-mutated NSCLC with prior receipt of an EGFR inhibitor were randomized to HER3-DXd or pemetrexed and platinum chemotherapy. HER3-DXd treatment significantly improved median PFS over co-developer chemotherapy Merck reported.

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 a problem with a third party manufacturer” said Burns. “That’s something the field is excited about, but it’s probably delayed until early next year.”

The ADC datopotamab deruxtecan (Dato-DXd), which targets TROP2, is also under investigation. In phase II TROPION-Long05 In the study, Dato-DXd resulted in 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%. The median duration of response was 7 months.

More to learn

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

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