What would it take for you to prescribe a targeted precision medicine if you have problems proving that the target antigen is even there? Let’s see how Daiichi Sankyo and AstraZeneca answer this question!
Simple question. If you struggle to find your target antigen expressed in your tumor of interest, would you then go on to prescribe a cancer precision drug specifically targeting that antigen? Intuitively, you’d say ‘NO’ and you’d also begin to lecture me about how companion diagnostics work and why this is the basis of a multi-billion dollar industry. True, companion diagnostics are developed to find and validate those specific targets to a sufficiently high level of confidence for oncologists and clinicians to prescribe that specific drug. And that has been the immovable wisdom for as long as precision drugs have been around. Take Herceptin (trastuzumab), the trailblazing first oncology drug to prove this point. Herceptin was approved on the basis that its protein target HER2 has to be expressed at the IHC3+ levels for it to work effectively and meaningfully. Any tumor scoring IHC0, IHC1+ or IHC2+ was not going to cut the mustard. Conventional wisdom, right? Yup, totally logical and you can’t go wrong with that. Or can you?
Well, it’s been anecdotally known that in earlier Herceptin studies, some patients on low and very low HER2 IHC scores (supposedly negative controls!!) performed remarkably well and of course, the easiest explanation is that as long as HER2 is somewhat somewhere expressed on those tumors, Herceptin should work. Additionally, it’s well known that biopsies are notoriously heterogeneous depending on where you obtain the sample and coupled with the semi-quantitative IHC technology, these factors contribute to expected inaccuracies for its diagnostic final score. All true and in the interests of giving ” the right drug to the right patient”, we all subscribe to this mantra. But now, the Batman and Robin team of Daiichi Sankyo and AstraZeneca have decided to revisit and indeed challenge this scenario. And what they’ve done may instigate us to rewrite some operating rules and open up new thinking. DS & AZ’s ADC’s Enhertu has had phenomenal success, scoring 4 FDA nods to date, the latest just earlier this month (5th April 2024) on tumor-agnostic HER2 expressing tumors. Enhertu’s antibody is the aforementioned trastuzumab itself and you’d be rightly forgiven for assuming that the antibody’s past history and characteristics would be the decider for what target population to go for, i.e. HER2 IHC3+. Well, curious anecdotes have a habit of staying long in our memories because they are an irritatingly good source of debate, simply because we don’t have a logical answer. So, those anecdotal observations on low IHC scores that may have actually worked for breast cancer patients in the original Herceptin studies have instigated DS & AZ to design new studies using Enhertu. And this is not a new thing. Two years ago (5th August 2022), DS & AZ got an FDA nod for metastatic breast cancer with low HER2 scores, proving that a low HER2 score is no barrier to Enhertu’s efficacy. Based on the DESTINY-Breast04 trial, this was also a very very brave decision to challenge the perceived wisdom of the day. And what Batman and Robin proved is that we should NOT withhold this HER2 drug from a breast cancer sufferer on the basis that her tumor has a low IHC score. Brave call and a good day for HER2 lows. Well DS & AZ have gone one up and they’ve just posted topline results from the DESTINY-Breast06 study. What we’re all really interested in this study is the inclusion of the HER2 ultra-low group. These are the IHC-0, or anything that our histology colleagues would not put their jobs on the line and call IHC1+. So, for all intents and purposes, we would never put these IHC0s on any HER2 medication, right? Time to test this hypothesis! Well, the DESTINY-Breast06 results are outstanding. The HER2-lows (IHC 1+ or 2+/ISH-) demonstrated a statistically significant and clinically meaningful improvement in PFS compared to standard-of-care chemotherapy in the primary trial population of patients with HR-positive metastatic breast cancer. We expected that, based on the previous DESTINY-Breast04 trial. Now for the answer to the question we’ve been asking – in addition, a statistically significant and clinically meaningful improvement in PFS was also observed in the overall trial population (HER2-low and HER2-ultralow). A prespecified subgroup analysis showed the clinically meaningful improvement was consistent between patients with HER2-low and HER2-ultralow expression. We now have a good problem in that we’ll have to figure out how to explain efficacy in the ultra-low group! We’ve got the answer we’ve been asking and it’s also a ‘Yes’ from Simon Cowell.
So, what does this mean? 2 take-home messages:
- Dr Ken Takeshita MD, Global Head of R&D at Daiichi Sankyo commented “The topline results from DESTINY-Breast06 highlight the importance of continuing to challenge current treatment paradigms and established breast cancer classifications to evolve how we treat patients with HR positive, HER2 expressing metastatic breast cancer. Building on the practice-changing data seen in DESTINY-Breast04, these results reinforce the potential for use of ENHERTU earlier in the treatment landscape and in an even broader patient population.”
- And why is it so important to have Enhertu factored much earlier in treatment regimes or algorithms? It’s estimated that approximately 60-65% of HR-positive, HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow – making this subgroup that is hitherto denied any currently available HER2 therapy as much as 90%. Endocrine therapies are widely used in the early lines of treatment for HR-positive metastatic breast cancer; however after just two lines of treatment, further efficacy from endocrine therapy is often limited. The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes, i.e. pretty much end of the road. But with this DESTINY-Breast06 result, we can offer a pretty serious option to HR-positive, HER2 low mBR patients. A great example of a game-changer, if you ask me. Good for the patients and good for opening up another market.
I’m pretty sure Batman and Robin are buzzing right now and as ASCO 2024 is round the corner, have a lookout for the Enhertu posters if you’re there. I’ve seen the programme and there’s enough to keep you excited all day and night 😊.