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ASCO Studies Highlight Potential of Antibodies in Overcoming Anti-EGFR Rx Resistance in NSCLC

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CHICAGO (Precision Oncology News) – Researchers are investigating whether antibody-based treatments can be a more broadly effective and practical approach to battling resistance to EGFR-targeting tyrosine kinase inhibitors in non-small cell lung cancer.

Advanced NSCLC patients with EGFR mutations have access to multiple first-, second-, and third-generation tyrosine kinase inhibitors (TKIs) that stave off disease for a time, but cancer cells eventually find a way to proliferate by acquiring a complex landscape of resistance mutations and through unknown mechanisms.

Instead of trying to tackle this problem with tyrosine kinase inhibitors that target individual, often rare, resistance mutations, and carve up the lung cancer population into smaller and smaller molecularly defined subsets, researchers at the American Society of Clinical Oncology's annual meeting presented early data exploring whether therapeutic antibodies can be more broadly effective options. In separate Phase I studies featured here this week, several antibody-based therapies in development — Daiichi Sankyo's U3-1402, AbbVie's ABBV-399, and Janssen's JNJ-372 — demonstrated activity in patients who had stopped responding to anti-EGFR treatments via a variety of resistance mechanisms.

Currently, NSCLC patients with EGFR mutations receive first-line treatment with either first-generation TKIs, erlotinib (Tarceva) or gefitinib (Iressa); a second generation drug, such as afatinib (Gilotrif); or the third-generation drug osimertinib (Tagrisso). Patients experience progression-free survival with first-and second generation drugs for 10 to 15 months, and around 70 percent of EGFR-mutant lung cancer patients see their tumors shrink. But around 60 percent stop responding when they develop a T790M resistance mutation, at which point they get on osimertinib as a second-line therapy, or receive immunotherapy or chemotherapy if they don't have a T790M mutation.

Regardless of whether patients receive osimertinib as a first- or second-line therapy, they eventually become resistant to this third-generation drug as well, but through a different landscape EGFR mutations, such as C797S mutations, via MET amplification, as well as other known and unknown molecular mechanisms. "In each of these instances [of resistance], there are mechanisms that are undiscovered, or yet undetected, at least based on our current understanding and methodologies," said Pasi Jänne from the Dana-Farber Cancer Institute at the meeting. "Developing therapies to combat all individual resistance mechanisms is likely impractical, if not impossible."

As cancers progress and spread, patients can develop multiple mechanisms of resistance at the same time that occur in the same tumor or at different metastatic sites, making it even more challenging to devise a targeted treatment strategy. "Hence an alternative strategy would be to develop an approach that would be broadly active against all forms of resistance and be agnostic to the specific mechanism itself," Jänne said.

HER3, for example, is expressed in up to 67 percent of EGFR-mutant NSCLC, and Jänne led a Phase I trial that showed that the antibody drug conjugate, U3-1402, could be an alternative to TKIs in overcoming resistance in this setting. U3-1402 links a HER3 antibody to a DNA damaging agent. The antibody latches onto HER3 receptors on the cell surface and delivers the cytotoxic "payload" inside the cell that kills it.

The Phase I study enrolled 23 patients with advanced EGFR-mutant NSCLC who had progressed on erlotinib, gefitinib, afatinib, or osimertinib, but did not have a T790M resistance mutation. Before receiving treatment, patients had to have a biopsy for molecular analysis, and 19 patients were determined by immunohistochemistry testing to have HER3 expression. Patients also had a variety of EGFR resistance mutations.

All 16 patients evaluable for treatment response to U3-1402 saw their tumors shrink, with four patients to date having confirmed partial responses. The drug was broadly active in patients with known resistance mutations to osimertinib, such as an EGFR C797S mutation or HER2 and CDK4 amplification, as well as unknown resistance mechanisms.

Jänne highlighted the experience of a 65-year-old male patient with EGFR-mutated NSCLC who received erlotinib for five years and developed a T790M resistance mutation. He received osimertinib next, but eventually developed resistance through MET amplification and was prescribed osimertinib and the MET inhibitor crizotinib (Xalkori). When he became resistant to this regimen, it was due to a more complex mechanism that included a G724S mutation and an EGFR C797S mutation. Ultimately, he got on the Phase I study and received U3-1402, which shrank his metastatic tumors in the adrenal glands, as well as lesions that had affected his shoulder.

Patients in this Phase I dose finding study experienced treatment-related adverse events that were mostly manageable. They commonly experienced gastrointestinal side effects and platelet count decreases. One patient discontinued the study as a result of adverse events and seven required dose reductions.

Researchers are still evaluating the dose of U3-1402 and a dose expansion is planned for the third quarter of this year. "Based on these findings we believe that targeting HER3 with U3-1402 may be a practical approach to treat EGFR mutation non-small cell lung cancer that has developed diverse mechanisms of resistance," Jänne concluded at the meeting.

Despite these encouraging early results, according to Katerina Politi from Yale School of Medicine, the field still has a way to go to understand resistance mechanisms to EGFR inhibitors, particularly when it comes to newer third-generation TKIs, such as osimertinib. She highlighted several approaches that are being explored to address resistance in this setting. For example, some studies are combining first-and second-generation EGFR inhibitors with osimertinib to prevent the emergence of resistance mechanisms to the third-generation drug in the first place. In cases where existing TKIs don't work, researchers are combining TKIs with antibody-based drugs to try to boost their efficacy.

This is the approach taken by the team led by Ross Camidge from the University of Colorado Cancer Center, in combining AbbVie's antibody drug conjugate ABBV-399 with the first-generation EGFR inhibitor erlotinib in patients with cMET-amplified NSCLC cancer who had become resistant to anti-EGFR therapy. Patients had to have MET amplification as determined via IHC testing in a central lab or a MET exon 14-skipping mutation detected by a local lab.

Out of 29 patients evaluated in this study, nearly 35 percent saw their tumors shrink. Although the findings need to be validated in larger cohorts of patients, the early data are encouraging, researchers said, because cMET amplification is one of the main ways patients become resistant to EGFR TKIs. Up to 15 percent of tumors resistant to first-or second-generation TKIs and up to 25 percent resistant to third-generation drugs have cMET amplification.

Eric Haura from Moffitt Cancer Center presented another strategy at the meeting for tackling resistance to anti-EGFR therapy by using an antibody that binds to both EGFR and cMET. His team evaluated Janssen's JNJ-372 in around 100 patients and showed that 30 percent experienced tumor shrinkage.

In the study, there were 58 patients who had become resistant to the third-generation TKI osimertinib via an EGFR C790S resistance mutation, cMet amplification, or had resistance without an identified EGFR or cMET mechanism, and 16 patients, or 28 percent, saw their tumors shrink with JNJ-372. Importantly, eight patients out of 27 with EGFR exon 20insertions, which historically have been resistant to anti-EGFR therapy, responded to Janssen drug.

When JNJ-372 binds to the extracellular domains of the EGFR and cMET receptors, it can do three things: block the growth factor that activates the receptors, degrade the receptors, and recruit natural killer cells. The drug's ability to degrade the receptors is the mechanism that's most likely driving the broad activity seen in the trial, Haura suspects, because the antibody is designed to recognize the wild-type EGFR and cMET domains of the receptors on the cell surface, and isn't being inhibited by the resistance mutations in the intercellular domain.

"This may be a way to re-lump patients [into bigger groups] because you don't have to care about the specific resistance mechanisms so much if the antibody is able to come in and degrade the receptor," Haura said.

But the response rate in the study was 30 percent, and future studies will have to account for other factors that may be keeping more patients from responding. The Phase I study is still exploring higher doses of the drug, Haura noted, and more patients may see tumor shrinkage as they experience greater degradation of the receptor at these higher doses.

Reviewing the data from this study, Jessica Bauman from Fox Chase Cancer Center said that more work needs to be done to understand the role of EGFR expression and other resistance mechanisms in mediating response to the drug. Additionally, combining this antibody-based drug with EGFR TKIs could increase efficacy, she noted, and given JNJ-372's ability to recruit natural killer cells, combining it with a compound that stimulates natural killer cells may be worth exploring.

"While the complexity and heterogeneity of lung cancer are likely contributing factors for non-response, we are continuing to study and understand the genetic profile of patients to determine why some don't respond to certain treatments," said Matt Lorenzi, Janssen's VP of the Solid Tumor Targeted Therapy Area. "We are focused on the further development of novel therapies such as JNJ-6372, and potential combination approaches to increase effectiveness and response."

The Phase I study is continuing to explore the activity of Janssen's drug in different EGFR inhibitor resistant populations. The Phase I study has to accrue patients to a cohort looking specifically at how well JNJ-372 works in those who have become resistant to front-line osimertinib. A cohort of patients who have become resistant through EGFR exon 20 insertions hasn't finished enrolling.

Haura noted that now that there are investigational EGFR inhibitors, such as Spectrum Pharmaceuticals' poziotinib, being studied in NSCLC patients with exon 20 mutations, there is also the possibility of opening an arm that enrolls patients that have become resistant to these therapies. Additionally, because JNJ-372 targets cMET, it's worth considering opening an arm with patients with MET exon 14-skipping mutations, he added.  

Early approaches in precision oncology focused on tyrosine kinase inhibitors because 10 or 15 years ago, TKIs yielded much more dramatic initial responses against genomically driven tumors. By comparison, "most of us didn't think much of antibodies," Haura recalled. But the field now has greater understanding and appreciation of the complexity of tumor heterogeneity, and it makes sense to rethink the use of antibody-based drugs, he said.