CHICAGO – The early data on the next generation of epidermal growth factor receptor inhibitors, including drugs from Clovis Oncology Inc., AstraZeneca PLC and Hanmi Pharmaceutical Co. Ltd., suggest significant advances in safety and efficacy over their predecessors in lung cancer, but individual side effect profiles could help differentiate the newcomers.

Results from studies of early stage studies in relapsed/refractory EGFR+ non-small cell lung cancer patients of Clovis’ CO-1686, AstraZeneca’s AZD 9291 and Hanmi’s HM61713 were presented May 31 at the American Society of Clinical Oncology annual meeting in Chicago.

Yale’s Thomas Lynch called for a combination trial of Clovis’ CO-1686 plus metformin.

The EGFR inhibitors emerged as options for mutation-positive forms of lung cancer 10 years ago, and drugs like Roche/AstraZeneca PLC’s Tarceva (erlotinib) and AstraZeneca’s Iressa (gefitinib), which is approved in Europe, plus Boehringer Ingelheim GMBH’s newcomer Gilotrif (afatinib) have made a significant impact – but there are multiple areas of mutation and resistance. In addition, the first-generation drugs are associated with significant diarrhea and rash.

Next-generation EGFR inhibitors are focused on the T790 mutation, which affects approximately 60% of lung cancers, and aim to improve on both the efficacy and safety profiles.

The objective response rates for CO-1686, AZD 9291 and Hanmi’s HM61713 in T790 mutation+ patients in studies presented at the ASCO meeting were 58%, 64% and 29% respectively. Median progression-free survival was 4.43 months for Hanmi’s drug and hasn’t matured for the other two candidates, though Clovis estimates PFS will exceed 12 months.

The Clovis and AstraZeneca drugs are seen in close competition, but research is still in early stages and Hanmi’s drug may need more time to develop a full efficacy profile, according to Yale School of Medicine’s Thomas Lynch, responding to the presentation of data for the three drugs at the ASCO meeting. “We need to keep an open mind about how [HM61713] fits into the group,” he advised. The dose hasn’t been defined yet, and the data are preliminary. But Lynch said that the data show that the drug has clear activity in pretreated TKI patients, particularly those with T790M mutations.

Clovis is preparing to submit CO-1686 for accelerated approval by mid-2015, and recently received “breakthrough” designation from FDA. “With a drug that has breakthrough status as we do and addresses an unmet medical need, one could envision initial approval based on response rate and durability of response,” CEO Patrick Mahaffy said in an interview. The firm plans to begin soon a comparative study against chemotherapy with a progression-free survival endpoint – the TIGER3 trial, which will be in T790-positive patients in the second-line setting, will serve as a confirmatory trial to gain full approval.

AstraZeneca also has breakthrough status for AZD9291 and has the drug on a fast track for development. The company is currently recruiting patients into the AURA trial, a Phase II extension of its Phase I study, to provide further assessment efficacy and tolerability of the 80 mg QD dose in patients with T790M+ NSCLC.

It is also currently enrolling patients in the global Phase II AURA2 study, which will be a confirmatory trial evaluating efficacy and safety and tolerability of the 80 mg once daily dose in T790m+ NSCLC. It will soon open AURA3, a Phase III trial evaluating efficacy and safety study of AZD9291 vs. platinum-based doublet chemotherapy in second-line patients with T790M+ advanced/metastatic NSCLC who failed therapy with another EGFR TKI.

No Rash Decisions

Aside from efficacy in the resistant population, the new EGFR inhibitors have potential to be better tolerated due to their greater specificity. “All show specificity against T790M and EGFR mutations while sparing EGFR wild-type, which explains the differential toxicity that we see to date,” Lynch explained.

While there is significantly less of the rash and diarrhea seen with the earlier options, the emerging profiles of the newer versions indicate that safety will be a differentiating factor.

The toxicities for the newcomers vary. Whereas Clovis’ candidate had hyperglycemia and QTc events, AstraZeneca and Hanmi’s candidates raised concerns about interstitial lung disease-like effects and had more events traditionally associated with EGFR inhibitors, Lynch said (see chart below).

Like Tarceva and Iressa, Hanmi’s 61713 does have rash and diarrhea side effects, but they are milder than with the first generation tyrosine kinase inhibitors. Lynch also noted that about 10% of patients developed a transient dyspnea, and it’s not clear if this is ILD.

As for CO-1686, early development was impacted by the variable solubility of a free base formulation, Lynch noted, but a hydrobromide salt version has reduced the variability. With the earlier version, there were issues with GI toxicity but this has been minimized with the current product, Clovis CEO Mahaffy said.

But while the formulation change has “made a big difference in being able to dose the drug,” CO 1686 still need needs to be given twice daily, Lynch pointed out, whereas candidates from AstraZenca and Hanmi are dosed once daily.

Of the three new drugs showcased at the May 31 ASCO session on EGFR inhibition, Clovis’ candidate had the least amount of toxicities typically seen with EGFR inhibitors, with a rash rate on par with placebo, Lynch pointed out.

“The common EGFR toxicities were dramatically absent,” Lynch said. There was a 22% rate of diarrhea, he said, but no Grade 3 events were reported.

High Blood Sugar Stands Out In Clovis Study

However, Lynch said that “the most concerning issue with this drug is hyperglycemia,” which occurred in 55% of patients, with 22% Grade 3 cases. This effect was treated with metformin. Metformin itself, Lynch noted, has been the subject of “spectacular interest” as an anti-cancer agent, so the clinician suggested that a combination trial of CO-1686 plus metformin in lung cancer should be performed.

Hyperglycemia hadn’t been an issue in animal studies, so it was an unexpected signal in the clinical trial. It can be easily managed with metformin and with dose reduction, Mahaffy said, and no patients had to stop taking the drug due to hyperglycemia. The company is still investigating the cause, but believes it could be linked to the same mechanism that makes the strong efficacy possible.

There’s also a QTc issue (7% Grade 3 in the study presented at ASCO) that could affect use of CO-1686 in combinations, according to Lynch. Mahaffy noted it was infrequent, dose-related and associated to hyperglycemia.

“But against [the safety signals] we see outstanding clinical activity – response rate of 58% and activity against CNS metastasis,” Lynch noted.

As for AZD 9291, interstitial lung disease-like events were the most concerning toxicity for this drug, with six events noted in both Asian and non-Asian patients. All responded to treatment and five of the six completely resolved. “It appeared milder than some of the ILD we’ve seen with erlotinib and gefitinib,” Lynch noted.

At the 80 mg once-daily dose, which AstraZeneca is taking forward, there was some diarrhea (20%) and rash (27%), but hyperglycemia and QTc were not problematic. There were no cases of Grade 3+ hyperglycemia and only three Grade 1-2 cases. As for QTc prolongation, there were no Grade 3+ cases, and four had Grade 1-2.

Wait And See On The Winner

Given the history with the earilier EGFR inhibitors, clinicians are used to managing toxicities in this setting, so the field should be accepting of the new profiles.

“Balancing and managing those toxicities will be important,” Lynch said, but “the winner will be determined by which drug has actually better clinical activity.”

Progression-free survival and response rates will determine the winner, he said, but it is “crucial” to let the efficacy data, including durability of response, mature. And, the drugs could easily move into the frontline setting. “Additional studies will determine the relative benefits of these agents as well as their role in the upfront treatment of EGFR mutation-positive disease, where I think they will also likely to gain a prominent role,” Lynch concluded.

Tarceva added a first-line NSCLC indication in May 2013, complementing maintenance and second-line approvals, but by this time it was already widely accepted as an off-label option for newly diagnosed EGFR+ patients Also see "Broader Indications For Tarceva As Astellas Scales Back In The U.S." - Pink Sheet, 15 May, 2013..

Lynch suggested that there is also a need to think ahead to immunotherapy – there’s evidence that activation of PD-1 may be important in resistance to EGFR-mutated cancers and there have been early reports of activity of anti-PD-1/L1 agents in some EGFR+ patients, including those who are treatment-naïve and who have had TKI therapy.

“How we integrate TKIs with immune checkpoint blockers will a major challenge for investigators moving forward,” Lynch said.

Comparison Of Side Effects, EGFR Inhibitors At ASCO
Candidate, dosing	Trial	Diarrhea	Rash	Interstitial lung disease/shortness of breath	Elevated blood sugar	QTc prolongiation
Clovis CO-1686, twice daily	Phase I/II dose-ranging, 72 patients, ASCO abstract # 8010	23%	4%	NR	55% (22% Grade 3)	15% (7% Grade 3)
AstraZeneca’s AZD 9291, 80 mg once-daily dose (dose selected for future trials)	Phase I dose-ranging study of 232 patients, ASCO Abstract #8010	20%	27%	3%	1%	1%
Hanmi’s HM 61713, once daily	Phase I dose-ranging study 83 patients, Abstract # 8011	21%	24%	10%	0	3%
Source: Adapted from May 31 ASCO presentation of T. Lynch (Yale), ASCO Abstracts Note: Studies initially included T790-positive and –negative patients, but were typically expanded to focus on T790+

Third-Generation EGFR Inhibitors’ Safety Profiles Under Scrutiny At ASCO

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