Esmo 2017 – Monarch positions Lilly for a safety battle royale


With the Monarch-3 study unveiled at last Lilly’s abemaciclib looks set to join Pfizer’s Ibrance and Novartis’s Kisqali as the third CDK4/6 inhibitor to reach the market in a key first-line breast cancer setting.

However, being a latecomer means that Lilly will have its work cut out, especially as the three competitors offer virtually identical survival advantages. One area that could mark a difference, however, is safety: abemaciclib causes less neutropenia, though more diarrhoea, Dr Angelo Di Leo, from the Hospital of Prato, Istituto Toscano Tumori, told this morning’s Esmo press conference (see table below).

Monarch-3 had been stopped early for efficacy, but results were held back for presentation at Esmo today. The setting was HR-positive, Her2-negative, first-line breast cancer – a disease where CDK4/6 inhibitors have potential on top of endocrine therapy, and analogous to that studied in Pfizer’s Paloma-2 trial of Ibrance and Novartis’s Monaleesa-2 with Kisqali.

CDK4 vs CDK6

Dr Di Leo stressed the differences in the three agents’ safety profiles, and provided a mechanistic rationale: “Abemaciclib, differently from the two other CDK4/6 inhibitors, is 14x more potent on CDK4 than on CDK6. The implication is ... you have less neutropenia; however, abemaciclib is associated with an increased rate of diarrhoea that you do not see with the other CDK4/6 inhibitors.”

The differences are striking. As for serious treatment-emergent adverse events – those at grade 3 or 4 – neutropenia and diarrhoea occurred respectively in 21.1% and 9.5% of abemaciclib-treated patients.

The CDK4/6 inhibitors – too close to call?
Product Ibrance Kisqali Abemaciclib
Study Paloma-2 Monaleesa-2 Monarch 3
PFS in active arm* 24.8 mth Not reached Not reached
PFS in control arm 14.5 mth 14.7 mth 14.7 mth
Hazard ratio 0.58 0.556 0.543
P value <0.000001 <0.0001 0.000021
Neutropenia (any grade) 79.5% 74.3% 41.3%**
Diarrhoea (any grade) 26.1% 35.0% 81.3%
Note: *Ibrance and Kisqali were given on top of letrozole, while abemaciclib was on top of letrozole or anastrozole; **1 case of non-serious febrile neutropenia.

Dr Di Leo stressed abemaciclib’s lack of association with neutropenic fever, and said diarrhoea could be treated by dose-adjustment and medication. This seems to be borne out by comparing Monarch-3 with Monarch-1, a second-line trial in which grade 3 or 4 diarrhoea was seen in 20% of patients.

Only one patient in Monarch-3 experienced febrile neutropenia, deemed non-serious, prompting the study investigators to say abemaciclib was not associated with neutropenic fever – in contrast to Ibrance and Kisqali.

“This of course can be important information for clinicians to tailor the treatment according to the individual needs of each patient,” said Dr Di Leo. “Some patients may live quite far from the hospital, and they may have difficulties in checking their blood counts regularly; in other situations it may be better to give a compound that doesn’t alter gastrointestinal function.”

Much of a muchness

Efficacy, of course, is virtually identical with the CDK4/6 inhibitor trio, with risk of progression being cut by around 45% in all three cases.

“They are quite similar in terms of efficacy. I don’t think there is a preferred [CDK4/6 inhibitor] at this moment,” said an Esmo expert, Dr Evandro de Azambuja, from the Jules Bordet Institute. He added that country-by-country availability of each agent, and each drug’s cost, would play a significant role in how the market panned out.

One point made by the Monarch-3 investigators concerned an exploratory analysis suggesting that poor-prognosis patients had derived a “substantial benefit” from abemaciclib. Meanwhile, in patients with a long treatment-free interval or bone-only disease single-agent endocrine therapy might be an appropriate initial treatment, they said.

Still, it will not be lost on investors that when Monarch-3 was stopped early Lilly stated that abemaciclib had the potential to be best in class. So far there is little to back up such a bold claim.

Sellside consensus compiled by EvaluatePharma sees Ibrance remaining by far the most popular anti-CDK4/6 agent, with revenue of $7.4bn in 2022 versus abemaciclib’s $1.7bn and Kisqali’s $1.5bn. Adverse events or not, Pfizer’s first-mover advantage might be hard to dislodge.

To contact the writer of this story email Jacob Plieth in Madrid at or follow @JacobPlieth on Twitter

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