Year: 2016
Type: editorial
Abstract: In this issue of Annals of Oncology, Yver et al. [1.Yver A. Osimertinib (AZD9291) – a science-driven, collaborative approach to rapid drug design and development.Ann Oncol. 2016; 27: 1165-1170Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar] chronicle the history of the development of osimertinib (AZD9291), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor designed to target T790, a common mutation associated with resistance to first- and second-generation EGFR-targeted small molecule drugs. A commendable time of 32 months from first human dose to first approval was achieved through a combination of thoughtful clinical development strategy, close interaction with regulatory authorities and timely development of companion diagnostics. A number of other T790 targeted drugs are also in development. The most advanced amongst these is rociletinib, being developed by Clovis Oncology. There are numerous lessons to be learnt by comparing and contrasting the development of these two drugs. This brief perspective is an attempt to shed light on the clinical data on rociletinib and the lessons it provides for biotechnology companies, academic investigators (who often play a leadership role in the development of these drugs), regulators, and investors who choose to bet on the success (or failure) of oncology drugs. Rociletinib (CO-1686; Clovis Oncology) entered clinical testing about the same time as osimertinib and was also granted Breakthrough Therapy status based on the preliminary data. It is a small-molecule, mutant-selective, covalent inhibitor of both the activating EGFR mutations, such as exon 19 deletions and L858R, as well as the resistance mutation T790M. It lacks activity against exon 20 insertions [2.Sequist L.V. Soria J.C. Goldman J.W. et al.Rociletinib in EGFR-mutated non–small-cell lung cancer.N Engl J Med. 2015; 372: 1700-1709Crossref PubMed Scopus (561) Google Scholar]. Two formulations of the drug with the same active moiety were developed—a free-base form and a hydrogen bromide salt formulation (HBr). Rociletinib first entered the clinic in March 2013 as the free-base formulation and the company quickly transitioned to the salt formulation (August 2013) after demonstrating improved absorption and pharmacokinetic profile. Dosing schedules in the dose-escalation portion of the study included once daily, twice daily and three times daily oral administrations of the drug. One hundred and thirty patients with mutant EGFR-associated NSCLC who had received prior anti-EGFR therapy were enrolled in a phase I/II study [2.Sequist L.V. Soria J.C. Goldman J.W. et al.Rociletinib in EGFR-mutated non–small-cell lung cancer.N Engl J Med. 2015; 372: 1700-1709Crossref PubMed Scopus (561) Google Scholar]. The phase II portion of the study required that the patients' tumor also had evidence of the T790M mutation. The highest dose of free-base rociletinib administered was 900 mg twice daily. The starting dose of the HBr form was 500 mg twice daily up to 1000 mg twice daily. No protocol-defined maximum tolerated dose was identified. At the time of original publication, objective responses were consistently observed at a dose of 900 mg twice daily of the free-base form and all doses of the HBr form (defined as active doses [2.Sequist L.V. Soria J.C. Goldman J.W. et al.Rociletinib in EGFR-mutated non–small-cell lung cancer.N Engl J Med. 2015; 372: 1700-1709Crossref PubMed Scopus (561) Google Scholar]). Among 38 patients who received the free-base form at a dose of <900 mg twice daily, 1 partial response and some minor tumor shrinkage and sustained disease control were observed. The response rate, as defined by RECIST 1.1, among 46 patients with centrally confirmed T790M-positive tumors treated with an active dose was 59% [95% confidence interval (CI) 45–73]. The median follow-up was short—10.5 weeks (range, 0.1–53.9 weeks), and no duration of response was reported. The estimated median progression-free survival at the time of the analysis was 13.1 months (95% CI 5.4–13.1), with data on 82% of the patients censored [2.Sequist L.V. Soria J.C. Goldman J.W. et al.Rociletinib in EGFR-mutated non–small-cell lung cancer.N Engl J Med. 2015; 372: 1700-1709Crossref PubMed Scopus (561) Google Scholar]. The predominant grade 3 adverse event was hyperglycemia, occurring in 20 of the 92 patients (22%) who received therapeutic doses. Hyperglycemia is attributed to a metabolite of rociletinib [2.Sequist L.V. Soria J.C. Goldman J.W. et al.Rociletinib in EGFR-mutated non–small-cell lung cancer.N Engl J Med. 2015; 372: 1700-1709Crossref PubMed Scopus (561) Google Scholar] and was most often managed with dose reduction, an oral hypoglycemic agent (typically metformin), or both, and did not result in rociletinib discontinuation in any patient. Thirty-five of the 92 patients (38%) received glucose-lowering therapy to treat hyperglycemia. Grade 3 prolongation of the QT interval corrected for heart rate caused no symptoms and was managed in all cases by dose reduction; no ventricular arrhythmias were reported. Acneiform rash was not observed, though a single patient had a grade 1 maculopapular rash. Grade 1 or 2 diarrhea was noted in 20% of the patients, with no reports of diarrhea of grade 3 or higher. Dose reduction occurred in 44 of the 92 patients (48%) who received therapeutic doses. The preliminary activity of both rociletinib and osimertinib looked promising for patients with mutant EGFR NSCLC, and the sponsoring companies appeared to be neck-to-neck in competition for first approval. Both agents were associated with compelling response rates and relatively acceptable safety profiles. Clovis Oncology had secured Breakthrough Therapy status for rociletinib, and the Food and Drug Administration (FDA) agreed to a rolling submission and priority review of the New Drug Application (NDA). On the 3rd of August 2015, Clovis Oncology completed its NDA regulatory filing of rociletinib for the treatment of patients with mutant EGFR NSCLC who have been previously treated with an EGFR-targeted therapy and have the EGFR T790M mutation as detected by an FDA-approved test. The application for EU marketing authorization was also submitted at the same time. In November 2015, the Company announced that the FDA would focus its efficacy analysis solely on confirmed responses (Clovis Oncology Press Release; 16 November 2015). The press release stated: ‘As the rociletinib clinical trials were rapidly enrolling, Clovis presented interim data publicly and at medical meetings and these data therefore included a data set based primarily on unconfirmed responses. This was also true of the Company's Breakthrough Therapy designation submission. In the Company's NDA submission, both immature confirmed and unconfirmed response analyses were submitted. As the efficacy data have matured, the number of patients with an unconfirmed response who converted to a confirmed response was lower than expected. In the intent to treat analysis of the 79 patients in the 500 mg dose group, the current confirmed response rate is 28 percent, and 34 percent in the 170 patients in the 625 mg dose group, with an encouraging duration of response in both doses. The most frequent reasons that patients' responses were not confirmed in a subsequent scan were due to progression, often due to brain metastasis, and due to subsequent scans not demonstrating tumor shrinkage greater than 30 percent.’ Subsequently, the Company has also disclosed that it now intends to pursue 625 mg b.i.d. as the go-forward dose instead of 500 mg b.i.d. which it had previously disclosed as being the optimal dose. Instead of a 59% response rate in centrally confirmed T790M-positive tumors [2.Sequist L.V. Soria J.C. Goldman J.W. et al.Rociletinib in EGFR-mutated non–small-cell lung cancer.N Engl J Med. 2015; 372: 1700-1709Crossref PubMed Scopus (561) Google Scholar], the updated ‘confirmed’ response rate is 34% at 625 mg b.i.d. dose (n = 170) and 28% at 500 mg b.i.d. dose (n = 79) in patients with T790M-positive tumors, with a median duration of response of ∼9 months for both doses (Clovis presentation at the JP Morgan Healthcare Conference, 13 January 2016). It is conceivable that nothing out of the ordinary happened and that we are simply looking at the natural evolution of the data. Mature datasets often reveal the true efficacy of a new drug to be less than the efficacy observed in the initial data of on-going trials. However, a drop in response rate from 59% to 34% is quite extraordinary. So, the question is: did the efficacy actually drop over time or was it a case of lack of full disclosure of the data, consistently and repeatedly? For decades, a complete response (CR) or partial response (PR) in a cancer patient has required, by definition, confirmation of a defined threshold of objective tumor shrinkage by a re-evaluation performed at least 4 weeks later. Any unconfirmed responses can be reported in publications with appropriate annotations but are never the primary end point in a trial, especially in a pivotal trial designed to seek marketing authorization. The authors of RECIST 1.1 (the response criteria used for the rociletinib trials) could not have been more explicit in their guidance: ‘… Specifically, in non-randomized trials where response is the primary endpoint, confirmation of PR or CR is needed to deem either one the “best overall response”. …’[3.Eisenhauer E.A. Therasse P. Bogaerts J. et al.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247Abstract Full Text Full Text PDF PubMed Scopus (18111) Google Scholar]. A close look at the public chronology of rociletinib data disclosures raises concerns. Below are verbatim highlights from press releases issued by Clovis Oncology in conjunction with three successive ASCO Annual Meetings, the pre-eminent gathering of oncologists and cancer investigators. ASCO Annual Meeting 2013 Clovis Oncology's CO-1686 Demonstrates Encouraging Results from Ongoing Phase I/II Study in EGFR-Mutant Non-Small-Cell Lung Cancer•Four RECIST partial responses observed in heavily pretreated T790M+ patients•Three of four evaluable T790M+ patients treated at 900 mg b.i.d. achieved partial responses•CO-1686 appears well tolerated; no evidence of wild-type EGFR inhibition•Activity correlates with higher drug exposure•Phase II dose not yet defined; maximum tolerated dose (MTD) not yet reached (Author comment: this study was performed with a suboptimal formulation, hence the higher dose). ASCO Annual Meeting 2014 ‘Clovis Oncology's CO-1686 Demonstrates Compelling Clinical Activity and Progression-Free Survival (PFS) in Updated Phase I/II Study Results in Patients with EGFR-Mutant Non-Small-Cell Lung Cancer•Fifty-eight percent of objective response rate observed to date in 40 evaluable heavily pretreated T790M+ patients in phase I and early phase II expansion cohorts•Current estimate of median PFS greater than 12 months in T790M+ patient population; observed median not yet reached•Well tolerated—majority of treatment-related adverse events are grade 1–2 and manageable•Only tyrosine kinase inhibitor (TKI) to completely spare wild-type EGFR signaling•Breakthrough Therapy designation granted by FDA earlier this month•New Drug Application (NDA) submission planned by mid-2015 (Author comment: these data were based on ∼160 patients treated in the phase I part and two phase II expansion cohorts. Eighty-one patients were evaluable at the time of the analysis for the presentation). ASCO Annual Meeting 2015 Clovis Oncology's Rociletinib (CO-1686) Phase II Study Results demonstrate Consistent and Promising Clinical Activity and Disease Control in Very Advanced Patients with EGFR-Mutant Non-Small-Cell Lung Cancer•60% overall response rate (ORR) and 90% disease control rate (DCR) in heavily pretreated centrally confirmed tissue T790M-positive patients•Median progression-free survival (PFS) of 10.3 months observed in patients without a history of central nervous system (CNS) metastases;•Median PFS of 8 months observed in overall population of 270 heavily pretreated centrally confirmed tissue T790M-positive patients, including 40% of patients with a history of CNS metastases•Compelling activity in T790M-negative disease with 37% ORR observed•57% ORR and 80% DCR in heavily pretreated centrally confirmed plasma-genotyped T790M-positive patients—may allow for broader testing for mutations in patients ineligible for tissue biopsy•Well tolerated; only common grade 3 treatment-related adverse event (AE) observed is hyperglycemia•Breakthrough therapy designation granted by the US FDA; US and EU regulatory submissions to complete in July 2015 (Author comment: The ASCO 2015 data were from the 456 patients enrolled in the TIGER-X trial; the readers should note that the original phase I/II trial referred to above was subsequently renamed TIGER-X). None of the three press releases disclosed what proportion of responses, if any, were confirmed responses according to the usual and customary definition of response. It is worth emphasizing that the ASCO presentation was only about two months before the completion of the company’s NDA filing. Importantly, the majority of the patients in the TIGER-X trial had been enrolled in 2014 or earlier (Clovis Oncology ASCO 2015 investors’ event). This raises a very distinct possibility that the data from the TIGER-X trial were relatively mature with respect to confirmation of responses by ASCO 2015. (Readers should note that the NDA for rociletinib is based on the patients enrolled in the TIGER-X trial as well as TIGER-2 trial, another single arm trial). The concerns raised by the content of these public disclosures are obvious: When did the company become aware of the marked difference between the confirmed and the unconfirmed response rates? Did they disclose it to the investigators whom they asked to be quoted in the various press releases? Equally significant is that the main peer-reviewed publication resulting from these rociletinib trials made it to a leading medical journal, the New England Journal of Medicine, with the same data that included confirmed as well as unconfirmed responses [2.Sequist L.V. Soria J.C. Goldman J.W. et al.Rociletinib in EGFR-mutated non–small-cell lung cancer.N Engl J Med. 2015; 372: 1700-1709Crossref PubMed Scopus (561) Google Scholar]. This author would be remiss to not discuss another issue exemplified by the development history of rociletinib. During the course of these clinical trials, it became apparent that rociletinib treatment was associated with clinically relevant hyperglycemia in a significant proportion of patients. During the question–answer session of the ASCO presentation, the presenting author disclosed that this might be related to a metabolite of rociletinib inhibiting insulin-like growth factor receptor-1 (IGF1R)-mediated signaling. This side-effect has not been observed with osimertinib. In subsequent public meetings attempts were made to position this as a positive differentiating attribute of rociletinib given the preclinical additive/synergistic efficacy of the combination of EGFR-targeted and IGFR-targeted drugs. Of course, this posture is patently at odds with real human observations from already completed randomized clinical trials showing lack of any incremental clinical benefit of IGF1R-targeted drugs in combination with multiple other drugs, including EGFR inhibitors, in NSCLC. Oncology drug development is competitive. There is tremendous pressure on small and large companies from both shareholders and patients alike to create first- and best-in-class therapeutics and get them to the market quickly. One only has to look at the movement of Clovis stock price after each of the ASCO presentations to appreciate the financial stakes. Did the competition and the desire to move fast hamper decision-making around rociletinib development? Or was this simply bad luck that the mature data did not confirm the hype generated by immature data and that a large proportion of responses induced by rociletinib are not durable? Did the unique pharmacology of rociletinib, e.g. formulation challenges, inhibition of IGF receptor pathway signaling, contribute to the loss of efficacy over time? Of course, until all the facts come into the public domain (if that ever happens), it is impossible to get to a full explanation of the observed results. However, the following lessons can already be drawn:•Optimization of formulation and dosing is critical in the development of effective therapeutics. In this case, the initial formulation gave significantly lower exposure with greater variability in exposure. The new formulation should have been associated with, if anything, greater activity. Yet after treating over 600 patients, the optimal dose of rociletinib is still not clear. At ASCO 2015, the company disclosed 500 mg b.i.d. dose going forward, given similar efficacy and less hyperglycemia. As mentioned above, the company position now is that 625 mg b.i.d. will be the dose going forward.•Drugs that are touted as being highly selective for a particular target often hit other targets or lead to off-target toxicity. In this case, hyperglycemia was a meaningful clinical and pharmacological effect and in the end contributed to the overall safety and efficacy profile. Limited information has been presented by the sponsor at public meetings that attributes it to a metabolite of the parent drug, which inhibits IGF1R and, to a lesser extent, insulin receptor kinases in biochemical and cellular studies. A fuller presentation and discussion of such data is warranted when investigators present the study data in important scientific congresses. Illogical rationalizations to turn negative data to positive attributes should be avoided.•Strict adherence to criteria to designate response or non-response is absolutely essential. The response criteria are well defined and any sponsor wishing to deviate from these should adequately clarify these in every public presentation.•Academic investigators have an obligation to ensure that they have exercised necessary due diligence to ensure the accuracy of the data being presented in their name. It is important to not just be legally accurate, it is essential to convey the true ‘flavor’ of the efficacy and the safety of the drug so that other investigators, patients and oncologists are properly informed. Rociletinib is scheduled to be reviewed by the Oncology Drug Advisory Committee (ODAC) and FDA on 12 April 2016 in a public forum, with an expected PDUFA date of 28 June 2016. The Marketing Authorization Application is also under review by the European Medicines Agency (EMA). With the mature data in hand, important issues that regulatory agencies need to wrestle with include, among others:1)What is the true efficacy of rociletinib given the marked differences in the mature and the immature datasets? Is this confined to only the TIGER-X trial or was this seen in the other trials as well?2)How the efficacy of rociletinib with that of a drug that is already for marketing based on a are often to the approval of multiple drugs against the same especially if is some evidence of efficacy in unique patient or evidence of unique safety of drugs. Rociletinib significant hyperglycemia osimertinib to have a higher of rash. Is this of a for approval of rociletinib though its efficacy would to be to osimertinib based on trial is the dose of 500 mg 625 mg be a for rociletinib all T790 targeted to be in a randomized trial against osimertinib or demonstrate efficacy in patients to marketing the would have to wrestle with the same issues as in a less public In this of rapidly and we are all full to get important to patients quickly. The of rociletinib should as a that This author has for of targeted oncology drugs based on relatively small datasets from early clinical trials Oncology a drug development and approval Oncol. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar]. a thoughtful of drug development is in a of but it a data and course in the event that new data are not with the initial lessons will become important especially as we move and into the of especially and cellular on the of Advisory of a number of companies and of Advanced and, on the of by by by and by by among
Source: Annals of Oncology
Author: K. Dhingra
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,080
OpenAlex ID: W2328852893