New developments in the management of non-small-cell lung cancer, focus on rociletinib: what went wrong?

Figures & data

Figure 1 Timeline of EGFR-small molecule inhibitors, which shows the development of different generations of EGFR-TKIs up to 2015.

Abbreviations: EGFR-TKI, epidermal growth factor receptor-small molecule inhibitor; NSCLC, non-small-cell lung cancer; FDA, Food and Drug Administration.

Table 1 Key dates in the development of rociletinib

Date	Event
December 20, 2011	Initiation of the clinical development program for rociletinib (CO-1686) with the TIGER-X trial
March 2012	Start TIGER-X trial (NCT01526928): study to evaluate safety, pharmacokinetics, and efficacy of rociletinib (CO-1686) in previously treated mutant EGFR in NSCLC patients
May 14, 2013	Orphan drug designation granted for rociletinib in EGFR mutation-positive NSCLC^Citation63
April 2014	Start TIGER-2 trial (NCT02147990): a Phase II, open-label, multicenter, safety and efficacy study of oral CO-1686 as second-line EGFR-directed TKI in patients with mutant EGFR NSCLC
May 19, 2014	Breakthrough therapy designation granted by US FDA for treatment of patients with EGFR mutation-positive NSCLC with progression under prior EGFR-targeted therapy through T790M mutation^Citation63
November 2014	Start TIGER-1 trial (NCT02186301): safety and efficacy study of rociletinib (CO-1686) or erlotinib in patients with EGFR-mutant/metastatic NSCLC who have not had any previous EGFR-directed therapy
February 2015	Start TIGER-3 trial (CT02322281): open label, multicenter study of rociletinib (CO-1686) monotherapy versus single-agent cytotoxic chemotherapy in patients with mutant EGFR NSCLC who have failed at least one previous EGFR-directed TKI and platinum-doublet chemotherapy
May 5, 2015	Protocol amendment 2 submitted to change dose in TIGER-3 from 625 mg bid to 500 mg bid^Citation63
June 9, 2015	Preliminary report on efficacy Proposed dose for marketing: 500 mg bid^Citation63
June 24, 2015	Request for accelerated approval by US FDA^Citation64
November 9, 2015	Disagreement of US FDA with reported efficacy results due to the inclusion of unconfirmed responses^Citation64
December 15, 2015	Clovis states intention to change marketing dose to 625 mg bid Amendment to change dose to 625 mg bid for TIGER-3 trial
March 7, 2016	Enrollment of TIGER-3 starts
March 8, 2016	Amendment to add third study arm. Study now comprises 500 mg bid rociletinib, 625 mg bid rociletinib, and chemotherapy^Citation63
May 6, 2016	Announced stop of rociletinib development

Abbreviations: NSCLC, non-small-cell lung cancer; EGFR, epidermal growth factor receptor; TKI, small molecule inhibitor; bid, twice a day; FDA, Food and Drug Administration.

SequistLVGoldmanJWWakeleeHAEfficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts)Journal of Clinical Oncology – ASCO Annual meeting201533Suppl 158001

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FDAFDA Briefing Document Oncologic Drugs Advisory Committee Meeting NDA 208542 Rociletinib2016

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