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Puma Biotechnology (PBYI) has made its entire game up on the back of one drug, a "pan-HER" inhibitor called neratinib (branded Nerlynx). It offers a unique proposition from the more commonly used HER2 therapies marketed by Roche (OTCQX:RHHBY), such as Herceptin, because it is given as pills. This opens up the possibility of continuous therapy, and we saw this realized with an approval in the "extended adjuvant" setting of patients with HER2-positive breast cancer last year.
Earlier this year, PBYI scored a coup when it was able to reverse the decision by the EMA to not allow its drug to reach market in the EU. Now, neratinib is available on both sides of the pond.
But neratinib may be useful for more than just HER2-positive breast cancer, which, by definition, is caused by amplification of the gene encoding HER2, leading to massive amounts of HER2 protein production. There's actually another way that HER2 can be made relevant, and that's through mutation. This is a lot less common than what we think of as "HER2-positive" disease, but it is nevertheless a significant issue in the field.
It's also one of the key directions that PBYI is taking its flagship drug in next. SUMMIT is a so-called "basket" trial, in that it does not recruit patients based on tissue type (i.e., breast cancer patients only), but rather it seeks to enroll and treat patients based on specific molecular features of their tumors. In the case of SUMMIT, this is either a HER2 mutation or amplification of the gene encoding EGFR.
PBYI presented an update to its analysis of SUMMIT, focusing on the cohort of patients with HER2-mutated, hormone receptor-positive metastatic breast cancer at this year's San Antonio Breast Cancer Symposium (SABCS). This cohort included 47 patients, who received neratinib along with an endocrine therapy called fulvestrant (Faslodex) and who were mostly heavily pretreated (median of 3 prior lines of therapy).
Of the 47 patients, 14 achieved an objective response, which had a median duration of 9.2 months. Another 8 patients had stable disease lasting at least 24 weeks while on neratinib and fulvestrant. When they looked at the subgroup of patients who had been treated with cyclin-dependent kinase inhibitors (such as palbociclib), the researchers saw that activity was not impaired substantially (see the table below).
Source: PBYI's press release
As for safety, neratinib has been hounded by concerns of diarrhea in patients, but this is now managed effectively with medications. Although there was frequent high-grade diarrhea, none of the patients discontinued therapy due to this complication. That's an important finding, since the onus is on patients to remain compliant with their dosing.
At this time, HER2-mutated breast cancer is a pretty pressing unmet need, since it's a lot more rare than HER2-enriched breast cancer. As such, if you look at the NCCN Guidelines, you'll note a distinct lack of recommendations for management of HER2-mutated disease. In fact, we don't even have a good read on how common these mutations are, because patients aren't routinely tested for them.
Therefore, you may end up in a situation where a patient has "hormone-positive" breast cancer, which is normally exclusive from HER2-positive, but that behaves like an aggressive, HER2-positive cancer.
It highlights an interesting problem for which PBYI seems to have a solution, at least in part. Neratinib is clearly active in metastatic, HER2-mutated breast cancer, and it is the first drug to my knowledge that is able to address this problem. SUMMIT may well end up being a stepping stone to approval, depending on how the FDA treats the need.
Key investment takeaways
The benefit here lands squarely on PBYI, which stands to carve out a specific niche for neratinib. There is nothing in the field that is known to adequately deal with HER2 mutations, and as we come to understand these cases better, we may find that a certain group of patients with inexplicably bad disease course were actually HER2 mutant, and for that we're going to need an effective therapy.
This also bodes well for neratinib in a totally separate space: non-small cell lung cancer. HER2 aberrations are quite rare in that tumor type, but when they do present, they are not typically amplifications. Rather, patients will have HER2 mutations, and this is becoming an increasingly important area of focus for clinical medicine. For lung cancer, mutational testing of that type is becoming increasingly widespread and deep, so PBYI may have a fast track to getting neratinib moved into that treatment space, as well.
Overall, activity in HER2-mutant breast cancer is an important step for PBYI, and it definitely improves the investment thesis.
Disclosure: I/we have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.