CDK inhibitors: will palbociclib and LEE011 make it to market in breast cancer?
The next few weeks will see quite a lot of activity here on Biotech Strategy Blog with the segue from Miami Breast Cancer Conference to the World Lung Conference in Geneva and then onto the annual AACR meeting in San Diego.
Over the last year, we’ve seen a lot of attention focused on immuno-oncology, but very little of the data has emerged yet in breast cancer. Instead, we’ve seen a new approval for pertuzumab (Perjeta) in neoadjuvant disease, based on pCR. You can read more about new developments in targeting HER2 in neoadjuvant breast cancer in the last post.
One area that has generated a lot of interest in metastatic breast cancer is CDK inhibition, whether that be the potential for targeting 1 and 2 in triple negative disease, or targeting 4 and 6, in ER positive situations, for example. Some inhibitors are more specific (Pfizer’s palbociclib and Novartis’s LEE011 target CDK4/6), whereas others hit a broader spectrum such as Merck’s dinaciclib, which inhibits CDK1/2/5/9. The challenge with pan inhibitors is that if the target is doesn’t matter to the tumour then there is potential for unwanted off-target side effects.
Last month Pfizer announced that the topline phase II results from the PALOMA –1 trial with their CDK4/6 inhibitor, palbociclib, were positive – no doubt we will see an ODAC meeting soon to discuss the FDA application and possible accelerated approval. The company received Breakthrough Therapy Designation in April last year and given the survival curves from the phase II study that have previously been presented at SABCS, I think they make a very good case for early approval.
Recall that the interim analysis demonstrated very compelling median progression free survival (PFS) of 26.1 months for palbociclib when combined with letrozole compared to only 7.5 months with letrozole alone in women who were post-menopausal with newly diagnosed ER+ HER2- breast cancer. obviously the final results will be important in influencing any FDA decision, but by whatever yardstick you use, those were very impressive data indeed.
The phase III trials, PALOMA–2 and PALOMA–3, are already open and enrolling patients.
Bill Sellers, Source: NIBR
Other companies also have CDK4/6 inhibitors in clinical development, including Lilly and Novartis.
Today’s post focuses on progress in targeting CDK4/6, including highlights from an interview with William Sellers MD, PhD from the Novartis Institute of Biomedical Research (NIBR).
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7 Responses to “CDK inhibitors: will palbociclib and LEE011 make it to market in breast cancer?”
Hi Sally… I am under the impression that brain mets are common in patients with breast cancer – frequently the site of first recurrence after treatment for metastatic disease, although less often the site of first relapse after primary treatment. A recent PNAS publication suggests that ~40% of HER2+ or TNBC patients with Stage IV disease ultimately develop brain mets. http://ow.ly/uKhvS . Although ER+ tumours (Luminal A/B) carry a lower risk, they are the larger group of patients. According to UpToDate, breast cancer is the 2nd most common cancer associated with brain mets in the US… so the potential for an effective drug to treat primary and systemic sites, as well as to cross the blood-brain barrier is likely to be a significant advantage in breast cancer as well as in other tumours… If Lilly decides to pursue metastatic breast cancer they should be including site of first recurrence in the Phase 3 trial protocol!
Hi Amanda,
Well, it depends on what you define as ‘common’. To clarify, I think this is more of a relative than an absolute discussion since I’m not suggesting brain mets don’t occur in breast cancer – they certainly do in metastatic disease, particularly in high risk patients and those with TNBC. It is less common in the ER+ subset though as you note, which is what I was discussing here with the clinical programs for the CDK inhibitors; most of the trials are looking at ER+ HER2- disease. It would be very interesting to see what happens in TNBC and high risk patients with brain mets, absolutely. In a recent discussion with a couple of BrC researchers, they all thought it was less common that I did so while at MBCC, I asked a breast cancer thought leader for his perspective and his actual words were, “It’s not that common in ER+ disease, but much more common in TNBC” so I conceded the point 🙂
When you take breast cancer as a whole, irrespective of subtype, epidemiologic studies suggest that brain metastases occur with a frequency of ~10–16% in patients in this disease so while it exists, it’s not where the majority of mets are found – I suspect bone mets would be the most common out of bone, lung, liver, lymph nodes and brain.
Yes Amanda you are correct that brain mets do occur in breast cancer, and the incidence does vary by molecular subtype. TNBC and HER2+ (ER-ve) have higher rates than the ER+ subsets. Luminal A, which represents the population for which Pfizer is going for initial FDA approval have a 2.2% rate of brain mets at 15 years (per Kennecke, et al JCO 2012). Luminal B’s without Her2 still don’t have that high of a rate (4.7%). The role of CDK4/6 inhibitors in TNBC is minimal since the Rb pathway is more frequently deregulated, and cyclin E (which is cytoplasmic and constitutively active) in 70% of TNBC abrogates the G1/S checkpoint anyway making CDK4/6 inhibitors not useful in the majority of these high-risk patients. The landscape in HER2+ MBC now is much more complicated, and so while the brain penetration of LY’s may be an advantage, they would have to beat T-DM1+Pertuzumab likely, which isn’t particularly likely IMO.
Thank you both! Every day I learn a little more!
Ask away any time – that’s what I love about the oncology community – we all share and learn from each other!
I thought dinaciclib was more “dead” than that – thanks for the update!
Hi Andrew, well… I think there were plans to kill it judging from our previous discussion on pancreatic cancer when researcher feedback suggested it might be on it’s way out. However, if the pan can trial of diniciclib + MK2206 shows some really stunning results, many of us would hope that common sense will prevail!
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