Interim results for rociletinib, Clovis Oncology’s third-generation tyrosine kinase inhibitor have shown impressive activity in lung cancer patients with the T790M mutation – a patient population with few treatment options.

“Currently there are no approved targeted therapies for mutant EGFR-positive lung cancer patients who develop the T790M mutation,” said Jean-Charles Soria of France’s Gustave Roussy Cancer Centre, reporting results of a Phase II study at the recent EORTC-NCI-AACR meeting in Barcelona. “This means that their cancer will inevitably get worse.”

TKIs target the EGFR activating mutation found in 15% of Western patients, and 30-40% of Asian patients with NSCLC. However, currently available EGFR-targeting TKIs have two drawbacks.

First, inhibition of the wild-type EGF receptor can result in serious cutaneous toxicity, as well as diarrhoea, and secondly, efficacy of the approved TKIs is limited by the emergence of T790 resistance mutation in roughly 60% of patients; Rociletinib, an oral agent, was designed to both inhibit the T790 mutation, as well as avoid impacting the activity of wild-type EGFR.

Dr Soria reported the interim results of a Phase II study of 56 NSCLC patients who were EGFR mutation-positive, had received prior treatment with a TKI, and had developed the T790M mutation. The overall response rate for these patients was 67%, and the disease control rate was 89%. The median preogression-free survival of these treatment-experienced patients was an impressive 10.4 months.

Good side-effect profile

As for having a better side-effect profile than previous TKIs, the adverse events reported for rociletinib showed no cutaneous toxicity of note, and no serious GI toxicity. There were, however, a number of grade 3/4 events observed for hyperglycaemia (14% of patients), though these events resolved with treatment discontinuation.  

“The mechanism of action of the hyperglycaemia was identified as metabolite of rociletinib, which could not be predicted preclinically,” said Dr Soria. The metabolite appears to inhibit the insulin-like growth factor receptor-1 (IGFR1) leading to hyperglycemia.

He added that “this may appear as a liability, but I would stipulate that this could be also seen as an advantage since the IGFR1 pathway activation might play a role in acquired resistance to EGRF TKI inhibition, as has been seen in numerous experiments.”

Whether Dr Soria is right about the perceived advantage of activity on IGFR1, the observed efficacy has prompted numerous collaborative partners to come forward. Proposed pairings include rociletinib with a PDL-1, or PD-1 inhibitor, or a MEK inhibitor, or in combination with an inhibitor of aurora kinase.

Clovis expects to submit rociletinib in the USA in the second quarter next year. Phase I results led to the awarding of breakthrough designation by the Food and Drug Administration earlier this year.