"Targets T790M mutation to overcome EGFR inhibitor resistance Could be effective in the first-line setting as well Selectivity particularly promising for a better side-effect profile"
AstraZeneca’s (LON:AZN) AZD9291 has generated high hopes for non-small-cell lung cancer (NSCLC) patients resistant to marketed EGFR inhibitors, according to oncologists. The selectivity of the drug makes it an attractive choice and could mean it has a better safety and tolerability profile, they added.
AZD9291 is under investigation in a 233-patient, open-label Phase I/II trial, with Phase I results expected at the American Society of Clinical Oncology (ASCO) annual meeting from 30 May to 3 June. It is a third-generation oral, irreversible inhibitor of both the sensitising EGFR mutation and the resistance mutation, T790M, according to a company spokesperson.
The drug has been specifically designed to target the classical EGFR mutations, but also the T790M mutations, said Dr Edward Kim, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina. The T790M mutation appears after resistance occurs to EGFR inhibitors, such as Roche’s (VTX:ROG) Tarceva (erlotinib), and is known to be the primary driver of resistance for these patients, he explained.
EGFR-refractory and first-line potential
Resistance means that patients cannot progress onto another first- or a second-generation EGFR inhibitor, such as Tarceva, AstraZeneca’s Iressa (gefitinib) or Boehringer Ingelheim’s Gilotrif (afatinib), Kim said. AZD9291 targeting the T790M mutation makes it an attractive and viable choice to patients with resistance, he added.
T790M occurs in roughly 50%-60% of patients after taking EGFR inhibitors, meaning this is a huge unmet medical need, Kim added. AstraZeneca’s NSCLC candidate fits into an area where there are no approved agents; i.e., for those who have progressed after another EGFR inhibitor, said Dr Giorgio Scagliotti, professor, respiratory medicine, University of Torino, Italy. If AZD9291 gets approved, patients with EGFR mutations would be able to take a first- or second-generation EGFR inhibitor followed by AZD9291, increasing the potential of long-term control, said trial investigator Dr Federico Cappuzzo, director, medical oncology, Ospedale Civile, Livorno, Italy.
AZD9291 has shown to be effective in Tarceva-resistant patients, said Dr James Chih-Hsin Yang, director and professor, Cancer Research Center, National Taiwan University, Taipei. Preliminary results from the ongoing Phase I part of the study demonstrated partial tumour shrinkage (as defined by response evaluation criteria in solid tumours (RECIST) criteria) in 12 of 26 patients, or a response rate of 46%, according to a poster presentation at the European Cancer Congress (ECC) 2013 [Abstract#33LBA].
A response rate this high is encouraging at an early stage in development as it suggests the drug has activity in a significant proportion of NSCLC patients with EGFR mutations, according to an oncologist.
The T790M mutation is also found de novo in a very small population of patients (1%-2% of patients with EGFR mutations), said Kim. These patients, who have the de novo T790M mutation, could benefit from AZD9291 in the front-line setting, said Scagliotti. There is significant activity in T790M+ tumours but also activity in T790M-negative tumours, he noted. Preliminary Phase I data showed that of the 12 who responded, seven had the T790M mutation, a response rate of 58% in the T790M-positive group, the poster stated. There were 12 patients in all who were T790M positive.
AZD9291 will likely be more potent than Tarceva because the mode of action is to suppress resistance as well as EGFRs, said Dr Ross Camidge, associate professor, University of Colorado School of Medicine, Denver. The drug’s response rates look very good and it is likely to be the next blockbuster drug in NSCLC, said Kim.
It is yet not known is whether AZD9291 will be utilised in the first-line setting, said Camidge. One of the questions that has to be answered to figure out AZD9291’s first-line potential is whether the benefit in survival time is greater if patients take AZD9291 in the first-line or take a first- or second-generation EGFR inhibitor and then AZD9291 once resistant, said Camidge. Median survival time for patients taking Tarceva was 10.5 months in the Phase III registration trial leading to approval, according to a Roche press release.
The Phase I/II trial is assessing AZD9291 in patients with advanced NSCLC who have progressed on at least one prior therapy with an EGFR inhibitor, according to ClinicalTrials.gov.
At the moment, AstraZeneca is targeting refractory patients, as this setting is a faster route to approval, Camidge noted. Additionally, the company would not want to compete with its own product Iressa, he said. Whether AstraZeneca attempts the front-line setting may depend on the status of its competitor’s compound, Clovis Oncology’s (NASDAQ:CLVS) CO-1686, and what setting Clovis targets, he added. On 13 January, Clovis announced plans to launch a Phase II/III registration trial in first-line EGFR-associated NSCLC with CO-1686, also a third-generation EGFR inhibitor in development.
Early data suggests improved selectivity
Initial clinical data suggests that AZD9291 is well tolerated and the typical EGFR-related side effects like severe rash (Grade 3 or higher) are not seen, said an oncologist. Preliminary Phase I results showed no reported dose-limiting toxicities, according to the ECC poster. Additionally, across the three dose cohorts, only Grade 1 diarrhoea and rash was reported, the poster stated.
The fact that severe rash was not reported in this group is very encouraging at an early stage because it has been such a prevalent problem with drugs such as Gilotrif and Tarceva, said another oncologist. This would suggest the drug is highly selective, which should indicate that this drug will demonstrate good safety and tolerability in a larger population, he added.
Preclinical data showed AZD9291 to be more selective than marketed EGFR inhibitors such as Tarceva, said Cappuzzo. Selectivity is important because AZD9291 is able to avoid targeting wild-type EGFR; therefore toxicity is lower than with first- or second-generation EGFR inhibitors, Cappuzzo and Yang added. The lack of off-target toxicities is clinically relevant because you have fewer side effects compared to other EGFR inhibitors, especially in terms of skin and gastrointestinal toxicities, said Scagliotti.
Lower toxicity could be very important for the future of targeted agents, as it is likely that these agents will be combined to improve efficacy, said Cappuzzo. Targeted agents cannot be combined now because of the excess in toxicity, he added.
AstraZeneca’s market cap is GBP 50bn (USD 83bn).
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