Pfizer’s Ibrance Disappoints: What’s Next?
Taking a Look at the CDK4/6 Inhibitors Landscape
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Pfizer’s Ibrance Disappoints: What’s Next?
On June 4th 2022, Pfizer announced disappointing results for its marketed CDK4/6 inhibitor Ibrance - again. Ibrance was first approved in 2015 in combination with letrozole, for the treatment of postmenopausal women with ER+/HER2- advanced breast cancer, as initial endocrine-based therapy for their metastatic disease.
Pfizer Inc. (NYSE:PFE) today announced overall survival (OS) results from the Phase 3 PALOMA-2 trial, which evaluated IBRANCE® (palbociclib) in combination with letrozole compared to placebo plus letrozole for the first-line treatment of postmenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC). With a median follow-up of 90 months, patients receiving IBRANCE in combination with letrozole had numerically longer OS compared to placebo plus letrozole (median (95% CI) 53.9 months (49.8–60.8) vs median 51.2 months (43.7–58.9)); the results were not statistically significant (Hazard Ratio (HR)=0.956 [95% CI, 0.777–1.177]). The PALOMA-2 trial was designed for a primary endpoint of progression-free survival (PFS) with OS as one of the secondary endpoints.
The PALOMA-2 trial is a double-blind phase III study that compares Ibrance (palbociclib) with letrozole versus letrozole with placebo as a first-line treatment for postmenopausal women with ER+, HER2- metastatic breast cancer. The CDK4/6 inhibitor and endocrine therapy (such as letrozole) combo is the standard of care for patients with HR+/HER2- advanced breast cancer. The primary endpoint - progression-free survival (PFS) - was met in 2016. The data also showed that time to chemotherapy was delayed in the Ibrance arm.
But now after over 7 years of follow up, Ibrance failed to extend the life span (in a statistically significant way) of patients who receive the Ibrance-letrozole combo. It is important to note the overall survival was not the primary endpoint, but a secondary endpoint - and that the PALOMA-2 trial was not designed to assess overall survival (OS).
Another issue to consider with the PALOMA-2 trial is that a large number of patients (13% in the Ibrance arm and 21% in the placebo arm) in both trial arms were lost to follow-up, which means that there is missing data.
But this is not the first time that Ibrance has disappointed. In 2018, Ibrance also narrowly failed to meet the overall survival endpoint in a statically significant way in the PALOMA-3 phase III trial (which evaluated Ibrance in combination with fulvestrant compared to placebo with fulvestrant in women with HR+ HER2- metastatic breast cancer whose disease has progressed after prior endocrine therapy).
Ibrance also failed in two other phase III studies, PALLAS and PENELOPE, where the drug was being tested as an adjuvant therapy.
The consecutive failures for Ibrance had led Pfizer to focus on real world data to support the use of Ibrance. Real world data is always a welcomed addition to data from randomized controlled trials, but can never be considered as an alternative by physicians. In other words, real world data can only strengthen conclusions from randomized clinical trials, not dispute them.
Ibrance was the first CDK4/6 inhibitor to be launched, followed by Novartis’ Kisqali (Ribociclib) and then Eli Lilly’s Verzenio (Abemaciclib).
Being first-to-market is always a considerable advantage because physicians will “get used” to prescribing the drug, and switching to a newer drug is not necessarily an easy task, especially in oncology.
The longer the lag time between the first-to-market and the second entrant, the more fortified the first mover’s position will become. In Kisqali’s case, the lag time was around one year.
Unlike Ibrance, Kisqali and Verzenio have satisfactory overall survival data in different combos as a first-line treatment, with Kisqali emerging as the only CDK4/6 inhibitor that has consistently good data in terms of overall survival (OS).
Verzenio was approved by the FDA for the adjuvant treatment of patients with HR-positive, HER2-, node-positive breast cancer at high risk of recurrence that have a Ki-67 score of at least 20% on the basis of the MonarchE trial.
Ki-67 is a protein that increases in cells as they prepare to divide into new ones. The Ki-67 score is the percentage of cells that are positive for Ki-67. A score of 20% or more means that at least 2 in 10 cells are dividing.
The Ki-67 score requirement was not only a bit surprising but it also limits - for now at least - the total addressable market for Verzenio as an adjuvant therapy to 10,000 -12,000 patients in the U.S.
Ki-67 testing is not traditionally used to guide therapeutic decisions, which is why the FDA decision baffled a lot of people.
Eli Lilly is obviously gunning for a label extension to include patients with a Ki-67 score of less than 20%. This will require some time since the FDA will need to see mature survival data - but the good news for Eli Lilly is that regulators might only need to see a trend in the data.
As I mentioned before, unlike Verzenio, Ibrance failed to get the approval as an adjuvant treatment since it flopped in both the PALLAS and PENELOPE trial.
Novartis also has its sights on the adjuvant therapy label for its CDK4/6 inhibitor Kisqali with its NATALEE trial. The first readout is expected in H2 2022. An interesting theory is that - like the PALLAS trial - the NATALEE trial recruited both intermediate and high-risk patients, which would thus have a higher risk of failing, just like the Pfizer-sponsored trials. On the other hand, the Eli Lilly-sponsored MonarchE trials only recruited high-risk patients.
In Q2 2021, Ibrance’s share in first-line new patient starts was 73% with U.S. sales of $862 million while Kisqali had revenues of $83 million.
Data from SVB Leerink and IQVIA show that - as of September 2021 - Ibrance’s new-to-brand prescriptions were averaging at 1,150 per week, and that Kisqali was averaging at 110 per week, while Verzenio had a spike in August-September 2021 reaching an average of 360 weekly prescriptions.
Things started to look bad for Pfizer’s Ibrance in 2022. In Q1 2022, sales decreased by 5%, and according to IQVIA, Ibrance’s new-to-brand share is also declining.
Pfizer was quick to point out that the drop in sales was due to patients getting Ibrance through assistance programs, but the truth is that both Verzenio and Kisqali were expanding their prescription metrics both in terms of new-to-brand and total scripts with Ibrance still maintaining - for now - its lead in terms of total scripts.
Trials evaluating all three CDK 4/6 inhibitors in combination with endocrine therapy were compared in a network meta-analysis. No statistically significant differences in terms of PFS were found.
Higher rates of neutropenia were linked to Ibrance and Kisqali when compared to Verzenio. Kisqali was associated to more liver function test abnormalities and a higher risk of causing QTc prolongation. A higher incidence of diarrhea was observed with Verzenio. The data also shows that Verzenio is preferred in patients with brain metastases.
Ibrance appears to be the safest of the 3 drugs.
It is important to note that there is currently no data from head-to-head comparisons of the different CDK 4/6 inhibitors.
Despite its arguably superior data, Novartis’ Kisqali, has been trailing Pfizer’s Ibrance since its launch. In a bid to overtake Ibrance as the market leader, Novartis announced in November 2021 that it is launching a new phase III study - HARMONIA - where Kisqali and Ibrance will go for the first time toe to toe. The trial is designed to assess the efficacy and safety of both drugs in patients with the HER2-E subtype.
HER2-E cancers are associated with a bad prognosis and represent 10-20% of HR+/HER2- advanced breast cancer patients.
The most important thing to note when it comes to the HARMONIA trial is that it is a superiority trial, not a non-inferiority trial, which means that the results have the potential to clearly and unambiguously show that one drug is superior to the other. As mentioned before, this will be the first ever trial to compare CDK 4/6 inhibitors head-to-head.
My Take: Even with the recent disappointing survival results, I expect Ibrance to maintain its market leader position for a quite a while. I don’t see a massive physician exodus towards Kisqali and Verzenio happening overnight like some are expecting - or hoping for. I am projecting two dynamics: physicians will think twice before making their patients on Ibrance switch to either Kisqali and Verzenio (especially if they’re doing well), but on the other hand, I don’t see physicians starting new patients on Ibrance. This will translate to a gradual shift in market shares that will favor both Kisqali and Verzenio on the long run. The results of the HARMONIA trial have the potential to speed-up this shift.
DISCLAIMER: This is for informational purposes only, you should not construe any such information or other material as legal, tax, investment, financial, or other advice.
DISCLOSURE: I am long $PFE, $LLY, and $NVS. I have no business relationships with any company that is mentioned in this article.