Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘palbociclib’

Pfizer’s palbociclib data in ER+ breast cancer – hit or miss?

Dr Richard Finn Source: UCLA

Dr Richard Finn Source: UCLA

At AACR this weekend, Dr Richard Finn (UCLA) presented the much anticipated front-line phase II data for Pfizer’s CDK4/6 inhibitor, palbociclib (palbo) plus letrozole versus letrozole alone in ER+ HER2- breast cancer.

The PALOMA series of trials are designed to show that adding a specific CDK inhibitor to an aromatase inhibitor enhances efficacy and improves outcomes.

There are three metastatic breast cancer trials in all, with PALOMA–1 being the phase II study while PALOMA–2 and –3 are phase III randomised controlled registration studies aimed at confirming the initial phase II results in combination with letrozole and fulvestrant, respectively. In addition, palbociclib is also being evaluated in combination with standard endocrine therapy (PENELOPE-B) for certain early-stage breast cancers.

In short, an analysis demonstrated that the primary endpoint of progression free survival (PFS) was met, but the overall survival (OS) data was not significant at the time of the analysis.

What does this does this data mean and in what context should we look at the results?

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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

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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The future of cancer research – Part 2

Boston: Fallowing on from yesterday’s post about learnings from the AACR-NCI-EORTC conference in immuno-oncology, today’s post focuses on learnings from non-immune R&D, namely monoclonal antibodies and TKIs.

We know that cancer is a very complex topic and that adaptive resistance is increasingly a huge focus, but where are the new developments in this area and what can we learn from them in order to improve outcomes?

Another key area to consider is therapeutic index, that is are we shutting down enough of an oncogenic target’s activity in order to ensure efficacy? We’ve seen this in the anti-angiogenesis field, for example, where many VEGF inhibitors failed before bevacizumab (Avastin) finally cracked the nut in colorectal cancer and shifted the needle in terms of improving overall survival. We are now seeing this happen in other areas too, which will be covered below.

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AACR 2013 posters show potential new Pfizer cancer drugs

My overriding impression of large cap Pharma R&D from the 2013 annual meeting of the American Association for Cancer Research (AACR) was that Novartis and Genentech remain the front-runners in cancer drug development, with Pfizer very much up and coming.

AstraZeneca, however, reported data for several drugs that have or soon will be going to “dog drug heaven.”  If AstraZeneca receives an “A” for effort but a “C” for execution, then Bristol Myers Squibb (BMS) was in my view a “D” at AACR with little presence.

What interests me at a meeting such as AACR is trying to spot some of the early trends in the 6,000+ posters, and identify new products in development that are worth watching. I was generally impressed by the quality of the posters on Pfizer cancer drugs.

One of the Pfizer compounds that attracted my attention in the AACR posters (before news of its FDA Breakthrough Therapy designation in breast cancer) was palbociclib (PD-0332991), an inhibitor of cyclin dependent kinases (CDK) 4 and 6.  Karen Sheppard from the Peter MacCallum Center Centre in Melbourne, Australia (abstract #3416) presented a poster on genomic alterations of the CDK-4 pathway in melanoma and evaluation of the CDK4 inhibitor PD-0332991. According to Sheppard:

“Genomic alterations in the CDK4 pathway are frequent and are associated with worse survival”

Sheppard’s preclinical research supports the evaluation of CDK4 inhibitors in melanoma, so it will be interesting to see if clinical data supports the development of palbociclib in this indication. In the meantime palbociclib appears to be a winner in breast cancer.

Another Pfizer compound to watch is dacomitinib (PF-00299804) a second-generation inhibitor of the pan-epidermal growth factor receptor (EGFR) family of tyrosine kinases (ErbB family).  Previously, Pfizer had another pan ErbB inhibitor in development (neratinib) from their merger with Wyeth, but licensed it out to Puma Biotech and focused their development efforts on dacomitinib instead. That may well turn out to be a smart R&D decision.

A poster presented by Brett Broussard from the University of Alabama at Birmingham (abstract #2446) showed the effects of dacominitib on pancreatic ductal adeoncarcinoma (PDAC) and cancer-associated fibroblasts.  In his abstract, Broussard notes a possible reason why anti-EGFR therapies may have had little effect in PDAC:

“Indirect activation of Epidermal Growth Factor Receptor (EGFR) signaling through ErbB3 heterodimerization and stromal ligand production has been shown to act as an escape mechanism for EGFR directed therapies.”

Broussard’s research showed that dacomitinib targets multiple ErbB receptors, including ErbB3, and was an effective inhibitor of pancreatic ductal adenocarcinoma (PDAC) cell proliferation and tumor progression in vitro and in vivo.

He told me that Pfizer are expected to start phase 2 trials in pancreatic cancer with this compound later this year. There remains an unmet medical need in pancreatic cancer, so while it is too early to evaluate dacomitinib’s potential as a new treatment option, it is good to see translational research being done and new compounds entering the clinic.

Overall, my take home from AACR was that Genentech and Novartis remain the powerhouses of cancer drug development. I was impressed by the number and quality of the posters from Pfizer Oncology R&D and left the AACR poster hall thinking that Pfizer may well have some new cancer products in development that are well worth watching.

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