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Novel EGFR inhibitor safe, effective in EGFR-resistant NSCLC
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The third-generation EGFR tyrosine kinase inhibitor AZD9291 appeared effective and well tolerated in patients with EGFR-mutated, resistant non–small cell lung cancer, according to study results.
Patients with mutated T790M — which is associated with EGFR TKI resistance — were particularly responsive to the therapy. Researchers suggested this is especially promising because of the high levels of toxicity associated with the combination of afatinib (Gilotrif, Boehringer Ingelheim) and cetuximab (Erbitux, ImClone) typically used to treat patients with T790M mutations.
“Most patients, unfortunately, develop acquired resistance to EGFR inhibitors, and in 60% of the time, resistance is associated with a secondary EGFR mutation, known as EGFR T790M,” Pasi A. Jänne, MD, PhD, professor of medicine at Dana-Farber Cancer Institute and Harvard Medical School, said during a press conference. “There are no approved treatments for patients who develop this form of resistant, T790M-positive NSCLC.”
Jänne and colleagues evaluated data from 205 patients (median age, 60 years). The majority of patients (62%) were female; 65% of patients were Asian and 32% were non-Hispanic white.
Fifty-seven percent of patients had undergone immediate prior EGFR TKI therapy, and the median number of prior EGFR therapies was one (range, 1-5).
Researchers included 31 patients in dose escalation cohorts, which evaluated AZD9291 doses ranging from 20 mg to 240 mg. Dose expansion cohorts included 168 patients.
Overall, 109 patients (53%) demonstrated a confirmed or unconfirmed response to treatment. Researchers observed RECIST-defined response among patients assigned each dosage, and in patients with brain metastases.
Researchers evaluated T790M data in 157 patients; of them, 107 had a T790M mutation and 50 did not. Researchers observed responses in 64% (95% CI, 55-73) of patients with a T790M mutation and 22% (95% CI, 12-36) of those without the mutation. The overall disease control rate — including complete responses, partial responses and stable disease — among patients with T790M mutations was 94% (n=101).
Sixty-five of 69 patients who achieved a complete response were still receiving study treatment at the data cutoff, and the longest response lasted more than 7.5 months.
The most common adverse events — which researchers noted were primarily grade 1 — were diarrhea (30%), rash (24%) and nausea (17%). Twenty-four percent of patients experienced a grade 3 or grade 4 adverse event, and 2% of patients received dose reductions.
Jänne and colleagues said AZD9291 — which primarily targets EGFR in tumors rather than the skin and other organs — appears to cause fewer skin toxicities than other EGFR TKIs.
In addition, there were no dose-limiting toxicities and a non-tolerated dose was not defined, Jänne said. However, research moving forward will evaluate AZD9291 in daily 80-mg doses.
Researchers are still investigating the cause of six interstitial lung disease-like events.
“There is currently no standard treatment for patients with lung cancer who experience disease progression after initial therapy with an EGFR kinase inhibitor,” Jänne said in a press release. “Although it is still a bit early, our study suggests that AZD9291 may offer an effective new therapy option for these patients, without the skin side effects we typically see with existing EGFR inhibitors.”
AZD9291 has received an FDA breakthrough designation for the treatment of patients with metastatic, EGFR T790M mutation-positive NSCLC who progressed on an EGFR TKI, Jänne said.
For more information:
Jänne PA. Abstract #8009. Scheduled for presentation at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago.
Disclosure: The study was funded by AstraZeneca. Researchers report consultant/advisory board roles or employment/leadership positions with, stock ownership in, and honoraria, research funding or other remuneration from Abbott Laboratories, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharma, Clovis, Gatekeeper Pharmaceuticals, Genentech, InnoPharmx, LabCorp, Lilly, Merrimack Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi and Takeda.
Perspective
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Peter P. Yu, MD, FASCO
I’d like to highlight a few reasons why we find this study so interesting. First is the study of drug resistance. This has been the bane of chemotherapy treatment of cancers for decades: the observation that cancers that respond initially to chemotherapy lose that sensitivity and become resistant to therapy. Efforts to understand drug resistance, how it’s required and how to overcome that, have been very difficult to break through.
However, here we have a molecularly targeted therapy bringing the new science understanding of cancer biology to bear, which has identified a mutation which drives this form of lung cancer and subsequently develops first-generation treatments targeting the EGFR. But we’ve seen drug resistance develop, as we have with chemotherapy. Because we have a better understanding of the basis of cancer mechanisms in these cancers, we are able to more rapidly understand what the mechanism of resistance was — in this case, the acquisition of a new mutation — and subsequently develop drugs targeted against these new mutations.
But it’s more than that. In addition, as these tumors become more different than the normal tissues, and as the newer treatments fine-tune and hone their targets, we’re seeing less toxicity. In this study, two of the major limiting toxicities of the first-generation drugs, diarrhea and rash, were seen less frequently and were much milder. The reduced skin toxicity seen with AZD9291 heralds greater precision in targeting cancer mutations and sparing healthy tissues which retain normal germ-line EGFR status.
The second aspect about this study, is that this was an international effort. Genetic mutations in tumors do not occur equally across the board. There are some areas such as Asia where these mutations are more commonly seen. By combining our societal effort, we can learn more rapidly by sharing information and sharing efforts. This is another unique aspect about this study.
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