New Approaches Target Overcoming Resistance to TKIs in EGFR+ NSCLC

Katerina A. Politi, PhD

Katerina A. Politi, PhD

The treatment ofEGFR-mutant non—small cell lung cancer (NSCLC) has experienced significant improvements with the development of tyrosine kinase inhibitors (TKIs), but resistance mechanisms that promote disease recurrence have tampered the runaway success of these revolutionary agents, said Katerina A. Politi, PhD, during the 2019 ASCO Annual Meeting.¹

Much remains unknown about the nature and evolution of aberrations inEGFR-mutant disease, Politi, associate professor of pathology at Yale School of Medicine, said to the audience. She noted that T790M is the most prevalent acquiredEGFRresistance mutation in patients who receive first- and second-generation TKIs. That picture is changing now that osimertinib (Tagrisso), which targets T790M, has moved into the frontline setting.

“We’re really in the initial stages of beginning to understand the mechanisms of resistance to third-generation tyrosine kinase inhibitors when these are used in the first-line setting and in the second-line setting,” Politi said. “Even with all these improvements in the treatment ofEGFR-mutant lung cancer, resistance is a major impediment to cures.”

She said osimertinib represents an important step forward in the treatment paradigm. The drug was initially approved in 2015 for patients with metastatic T790M mutation—positive NSCLC. In April 2018, the FDA expanded its indication to include first-line therapy for patients with metastatic disease whose tumors harborEFGRexon 19 deletions or exon 21 L858R mutations.

The use of first- or second-generation TKIs in the frontline setting has resulted in progression-free survival (PFS) of 10 to 15 months and response rates of approximately 70%, Politi said. With frontline osimertinib, a third-generation TKI, the PFS has been extended to 19 months and the response rate has grown to approximately 80%.

Besides acquired T790M mutations, resistance mechanisms to TKI therapy includeMETorHER2amplifications,MAPK/PI3Kpathway alterations, histologic transformation to small cell lung cancer or epithelial—mesenchymal transition, and oncogenic fusions. With osimertinib therapy, new resistance mutations have been identified. These include C797X, L718Q, and G724S after both first- and second-line osimertinib; additional mutations in G796X and L792X have been found after second-line therapy.

However, Politi noted that knowledge about TKI resistance mutations is incomplete. “One of the first things that we have to do is really identify all the mutations and mechanisms that are on-target mechanisms that can confer resistance to osimertinib,” she said. “We need to understand the relationship between the baselineEGFRmutation and resistance mechanisms.”

Politi described 2 central thrusts of ongoing research: countering on-targetEGFR-dependent mechanisms of resistance to TKIs and finding ways to attack TKI-resistant tumors without on-targetEGFRresistance mutations.

In the realm of known genetic targets, researchers are focusing onMETamplification, which is found in 5% to 10% of tumors resistant to first- and second-generation TKIs and may be present in 15% to 20% of tumors resistant to third-generation TKIs.¹

Early Findings for 2 Novel Therapies

JNJ-61186372

One novel antibody that is showing early signs of efficacy in this arena is JNJ-61186372, a bispecific antibody that targetsEGFRandcMETreceptors. Following Politi’s presentation, Eric B. Haura, MD, reported the latest findings from an ongoing first-in-human phase I study (NCT02609776).²

The study, which seeks to enroll 345 participants, is being conducted in 2 stages. Part 1, which sought to establish the appropriate dosage, recruited patients with metastatic or unresectable NSCLC who have progressed after receiving prior therapy or are ineligible for or unwilling to undergo other therapeutic options.

In Part 2, patients are required to have anEGFRactivating mutation. They are being channeled into 4 cohorts depending on whether they have received prior EGFR TKI therapy and on their mutations. Patients are receiving either 1050 mg or 1400 mg of JNJ-61186372 administered intravenously once a week during the first 28-day cycle and once every 2 weeks during subsequent cycles. JNJ-61186372 elicited a response rate in 30% of 108 participants with diverse primary and secondaryEGFRmutations who received the therapy in doses ranging from 700 mg to 1400 mg, said Haura, a senior member in the Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute. All responses were partial responses (PRs).

In 58 patients with progression after a third-generation TKI, the response rate was 28%, all PRs. This group comprised 8 patients with C797S mutations, 3 withMETamplifications, and 5 without identifiedEGFR- orMET-based resistance. These patients had received a median of 2.5 prior lines of therapy (range, 1-6). The median duration of treatment was 3 months (range, 0.03-17) and 39% were still receiving therapy.

In terms of adverse events (AEs), infusion-related reactions were most common; occurring in 62% of participants. These reactions typically occurred on the first day of treatment exposure and then grew less frequent as therapy continued, Haura said. Only 1 of the infusion-related reactions was of grade 3 severity; the rest were less than grade 3.

Other treatment-related AEs included rash (56%), paronychia (26%), constipation (22%), dyspnea (19%), fatigue (19%), and nausea (18%). These were all less than grade 3 severity. Grade 3 AEs included 1 each for impetigo, myalgia, peripheral edema, pericardial effusion, and pustular rash. There was 1 patient with grade 4 elevated lipase.

U3-1402

With so many mechanisms of resistance to anti-EGFR TKI therapies in first- and second-line settings, a drug that targetsHER3expression offers the potential to address multiple mutations, according to Pasi A. Jänne, MD, PhD.

Jänne presented early findings for U3-1402, an antibody—drug conjugate aimed atHER3expression inEGFR-mutant NSCLC. The drug is comprised of an anti-HER3 antibody attached to a novel topoisomerase I inhibitor.

U3-1402 inhibited tumor growth in patient-derived xenograft models ofHER3-expressing NSCLC withEGFRmutations that had grown resistant to EGFR-targeting therapy. It is now being tested in a phase I dose escalation and expansion study in patients with metastatic or unresectableEGFR-mutant NSCLC who are T790M-negative after progressing on TKI therapy or who have progressed after osimertinib (NCT03260491).

So far, 23 patients have received ≥1 dose of U3-1402, which is administered intravenously once every 3 weeks at doses ranging from 3.2 mg/kg to 6.4 mg/kg. Sixteen patients remain on treatment, while 7 have discontinued therapy, mostly because of progressive disease (n = 5).³

At a median follow-up of 4.2 months, U3-1402 therapy resulted in tumor shrinkage for all 16 evaluable patients, including 4 who had a PR, said Jänne, who is director of the Lowe Center for Thoracic Oncology and the Belfer Center for Applied Cancer Science at Dana-Farber Cancer Institute. Additionally, 6 patients still receiving therapy have achieved clinical benefit through stable disease.³

The most frequently reported AEs included nausea, which affected approximately 60% of participants, and fatigue, vomiting, and decreased appetite, each reported in about 40% of patients. Grade ≥3 toxicities included nausea, hypokalemia, and decreased platelet count. For dose-limiting toxicities, there were 3 occurrences of grade 4 platelet count decrease at the 6.4-mg/kg dose. One patient experienced grade 3 febrile neutropenia and grade 4 platelet count decrease at the 5.6-mg/kg dose.

Jänne said the trial is continuing with the 5.6-mg/kg cohort with a dose expansion planned for later this year. He said the strategy of targetingHER3may prove more practical than seeking to target individual mutations.

“Developing therapies to combat all individual resistance mechanisms is likely impractical if not impossible. Similarly, in patients with multiple mechanisms of resistance,” Jänne said. “An alternative strategy is to develop an approach that would be broadly active against all forms of resistance and be agnostic to the resistance mechanism itself.”

References:

1. Politi K. How can we overcome TKI resistance inEGFR-mutant NSCLC? Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. meetinglibrary.asco.org/record/175039/slide.
2. Haura EB, Cho BC, Lee JS, et al. JNJ-61186372 (JNJ-372), anEGFR-cMet bispecific antibody, inEGFR-driven advanced non-small cell lung cancer (NSCLC). Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9009. meetinglibrary.asco.org/record/174459/abstract.
3. Jänne PA, Yu HA, Johnson ML, et al. Safety and preliminary antitumor activity of U3-1402: a HER3-targeted antibody drug conjugate in EGFR TKI-resistant,EGFRm NSCLC. Presented at: 2019 American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 9010. meetinglibrary.asco.org/record/174523/abstract.