New drug demonstrates early promise in metastatic breast cancer
Dr Amita Patnaik - South Texas Accelerated Research Therapeutics, San Antonio, USA
It’s a privilege to be able to present this data on behalf of my colleagues at START, UCLA, Dana Farber Cancer Institute, Eli Lilly and Massachusetts General Hospital. Shown here are disclosures, this research was funded by Eli Lilly.
You’ve just heard about the mechanism of action of CDK4/6 inhibitors so I’m not going to belabour this in too much detail. This slide shows you the mechanism once again for your reference. LY2835219, or bemacyclib, which I will call LY from this point onwards, is a structurally distinct and potent ATP competitive small molecule inhibitor which demonstrates a high level of selectivity for CDK4 and 6 at nanomolar concentrations while demonstrating dose dependent G1 cell cycle arrest. In preclinical pharmacology studies the properties of LY were favourable with a high level of oral bioavailability and principally biliary excretion and also evidence of distribution into the central nervous system.
The side effects were principally reversible effects on bone marrow and gastrointestinal tract consistent with what one would expect for a cell cycle inhibitor. Importantly, anti-tumour activity has been observed in a number of different preclinical models of human cancer, including non-small cell lung cancer, ovarian and breast cancer.
The current study represents a tumour-specific expansion cohort that was evaluated following completion of our phase I dose escalation study. We reported these results at ASCO last year and demonstrated at that point that LY could be administered safely on a twice daily continuous dosing schedule with the maximum tolerated dose having been 200mg every 12 hours. Fatigue was the dose limiting toxicity and the most common adverse events were that of diarrhoea, nausea, vomiting, fatigue and neutropenia. After the MTD was established for the twice daily oral dosing schedule, tumour specific cohorts were initiated for a number of different tumour types, as shown here. Cohort D, which represents a group of patients with advanced metastatic breast cancer, is the focus of today’s presentation.
So, for the breast cancer cohort the objectives were to evaluate safety and tolerability, document anti-tumour activity and evaluate biomarkers. We also performed next generation sequencing for those patients with available tumour tissue. Patients with advanced and/or metastatic breast cancer were eligible for the study if they had ceased to derive benefit from available standard of care therapies. Patients were required to have discontinued prior anti-cancer therapies with the exception that patients who were progressing on an endocrine therapy were permitted to continue that specific therapy. Patients were required to have measurable disease according to RECIST version 1.1 criteria and an ECOG performance status of 2 or less. Patients with a history of brain metastases were ineligible for study if they were unstable either clinically or radiographically within two weeks of going on the study.
Patient characteristics are shown on this slide. 47 patients were enrolled on this trial from three different investigational sites. The median age was 55 and the majority of patients had ECOG performance status of 0 or 1. As you can see from this information, patients were very heavily pre-treated, as demonstrated by a median of seven prior lines of therapy. 75% of patients had visceral involvement, that is involvement of either lung, liver or brain, and more than 40% of patients had three or more sites of metastases. A quarter of the patients had central nervous system involvement and about 77% of patients were hormone receptor positive.
The safety data for the breast cancer cohort really parallels that of the entire study population. The most common toxicities were that of diarrhoea, nausea, fatigue, neutropenia, vomiting, thrombocytopenia and leucopenia. Diarrhoea was the most common adverse event, occurring in 66% of patients, however the majority of instances were mild or moderate, that is grade 1 or 2 in severity, with 6.4% of patients having grade 3 or severe diarrhoea. Diarrhoea was manageable with supportive care and/or dose reduction. Grade 3 neutropenia occurred in 19% of patients and was uncomplicated. One patient had grade 4 neutropenia and one had grade 3 febrile neutropenia. It’s important to note here that no patients discontinued as a result of drug-related toxicities.
Shown here is a waterfall plot with best response for each patient in cohort D. Amongst the 47 patients that we treated there were 36 with hormone receptor positive disease shown by the dark blue bars and 9 with hormone receptor negative disease shown in light blue. There were 2 patients with unknown hormone receptor status. Overall 11 patients had greater than 30% reduction in tumour size by RECIST and thus met the criteria for partial response. None of these patients had confirmed partial response and thus the overall response rate for the entire cohort of patients with breast cancer was 19%. The other two patients with unconfirmed partial responses at the time of the analysis were classified as having had stable disease. Amongst the 47 patients in this cohort the disease control rate was 70% and the clinical benefit rate, which includes only patients with confirmed partial response or stable disease for at least 24 weeks, was 49%. Importantly, clinical activity was observed predominantly in hormone receptor positive disease which is really consistent with the preclinical activity of LY.
The next slide shows the response data for the subgroup of patients with hormone receptor positive disease and this is summarised on a waterfall plot. Of note, the nine confirmed partial responses and two patients with unconfirmed partial responses, shown here with a single cross, were all in the hormone receptor positive group. Amongst the 36 hormone receptor positive patients the response rate was 25%. The disease control rate was 81% and the clinical benefit rate was 61%. There were only eight patients, shown here with a double cross, who had progressed on endocrine therapy and continued that specific therapy. Importantly, however, amongst the eleven responders there were nine patients who received LY as monotherapy, meaning they had no other accompanying endocrine therapy. Thus, these results confirmed that LY has single agent activity in hormone receptor positive breast cancer.
For patients with hormone receptor positive disease the treatment duration is summarised on this plot. At the time of the analysis there were 18 patients still remaining on study, as shown by the asterisks. So for the hormone receptor positive cohort the current estimate of median progression free survival is 9.1 months.
Shown here is a CT scan of a patient who was 41 years old and received LY as single agent treatment. The patient was hormone receptor positive. As you can see here there’s a very dramatic reduction in the extent of her liver metastases. This patient had received extensive prior chemotherapy, similar to that of other patients enrolled on this study.
The next slide shows the incidence of neutropenia amongst the 11 patients who had partial responses. 5 of the 11 patients did not experience neutropenia of any grade, indicating that neutropenia is not a prerequisite for the anti-tumour activity associated with LY.
So, in conclusion, LY2835219 or bemacyclib demonstrates an acceptable safety profile when given as a single agent on a continuous oral twice daily dosing schedule with evidence of single agent activity in patients with metastatic breast cancer. Responses were observed principally in hormone receptor positive patients with an overall response rate of 25% in this population. Evidence of durable treatment effect was at clinical benefit rate of 61% in this group. The current estimate of median progression free survival is 9.1 months with eighteen patients still remaining on study. Hormone receptor positivity is currently the best available biomarker to select patients with breast cancer most likely to benefit from this treatment. LY2835219 thus warrants further investigation in larger confirmatory clinical trials for women with breast cancer.
Finally, I would like to acknowledge our patients and families who so graciously gave of their time. Thank you for your attention.