Biotech Voices, Oncology

Brad Loncar’s ASCO18 preview: Past ASCOs point to the top drugs that will soon elbow for the Oscars of cancer R&D

To prepare for the future, it helps to look back on what has happened in the past. ASCO is a great benchmark for doing that. Drug development does not happen overnight. A pattern of real progress emerges if you view things in the context of two “ASCOs” ago, or five, or ten. I always try to approach it from this macro perspective as I prepare for the conference because it helps set the stage for how today’s new developments might fit in.

Consider the following:

  • One ASCO ago we were wowed by the ability of precision oncology to treat patients based on a specific genetic mutation (NTRK) rather than where cancer originated in the body. That drug (larotrectinib) is currently in front of FDA and another (Keytruda) has since been the first approved for a non-tumor specific indication. This trend will continue. Roche was smart to buy Ignyta, as these are small but potent indications. They were also smart to invest in Foundation Medicine a few ASCOs ago and their foresight on that is finally paying off. Expect to be hearing about precision strategies for many more ASCOs to come.
  • Four ASCOs ago, there were no PD-1s approved. Can you believe that? I know it feels more like a decade, but it is important to know that this is still only early days for the class. In those four years, we have learned what types of cancers the drugs work for as monotherapy, in what cases combinations are needed, how many patients of various cancer types are responding, and hints of biomarker strategies are starting to emerge. No doubt there have been disappointments on the combo side of things, but as our understanding of these drugs and the tumor microenvironment improves, so will the chances of something breaking through.
  • Cell therapy? One ASCO ago this was still just a concept and many doubted it could cross the regulatory finish line. Since then we have seen landmark approvals of CD19 CARs and a rush of investment from all around the world. I don’t think it is an exaggeration to say this is the fastest moving science in oncology. What is on the market today could be obsolete as soon as just a couple ASCOs from now. The next versions of these therapies are likely to be very dynamic and powerful.
  • Four ASCOs ago there were also no PARP inhibitors approved. While the first (Lynparza) was ahead of its time, it is only now that PARPs are getting interesting with newcomers on the market and some compelling combo trials underway. Combo data has largely been disappointing so far, but I think this is only a matter of time. Merck, a leader in oncology, made a significant investment in a PARP last year and you can bet it is because they see substantial utility in more cancers to come. 2018 could finally be a breakout year for this class.

With that past history in mind, here are things I am watching for at ASCO 2018 to build on the success. Note: these are things I’m personally interested in and this is definitely not an exhaustive list for the entire conference.


Targeted Therapies

Loxo is looking like it might be the star of ASCO two years in a row. Has such a small biotech company ever done that before? Has any company period? Welcome to 2018, where most of the innovation in drug development is coming from the mid and small cap range of our sector. As far as RET goes, this is clearly an excellent target. The only question at this point is whether $LOXO or $BPMC is going to come out on top.


Checkpoints

  • Merck’s Keynote-042 presentation has a chance to be the biggest news coming out of ASCO. This is Keytruda monotherapy in patients with >1% PD-L1 expression. We already know the trial succeeded on OS but what we don’t know yet is if the success is largely due to strong responses from the high PD-1 patients or if those closer to 1% also saw compelling results. We’ll need to see different cuts at the data at ASCO for the answer. “Chemo free” is a term that is sneaking into the advertising campaigns of these companies lately. With stellar results in low expressers, it would be a big win for immunotherapy and the “chemo free” movement. Good data here might make treatment choices (whether to go mono or combo) quite difficult for some physicians and patients in the future.
  • Bristol (does anybody remember them?) is presenting IO/chemo combo data from Checkmate-227 in 1L NSCLC patients with <1% tumor PD-L1 expression. The hazard ratio for PFS from the abstract looks comparable to what Merck has presented in the past and will lend some credence to Bristol’s suggestion that these two drugs are in fact Coke and Pepsi. However, we ultimately have to wait for OS results to make a final call on that. This is still an important presentation because Bristol could use some good news in 1L lung. AACR illustrated what a tough hill they have to climb to convince physicians on the validity of TMB so any presentation like this that doesn’t necessarily rely on it is a welcome event for them.
  • Roche’s IMpower131 late breaker studying Tecentriq in combination with chemo in advanced squamous NSCLC was setting up to be an interesting event (though only PFS data is available). And then the king of lung cancer Merck announced on Wednesday that its Keynote-407 study in the squamous histology hit on both PFS and OS. When it comes to lung cancer, all hail the king.

Cell Therapies

  • CAR-T was rightfully named ASCO’s 2018 clinical Advance of the Year. Will the data continue to live up to the excitement? Unfortunately there is only one truly enormous CAR-T presentation (BCMA) I see on the schedule this year.
  • It was a big deal one ASCO ago when bluebird and Legend showed early promise with BCMA CAR-T. To illustrate that cell therapies likely have utility beyond CD19 was a morale booster and I’m sure it was major factor in convincing Gilead and Celgene to do their big acquisitions.
  • However, BCMA isn’t out of the woods yet. Investors are nervous about relapses/durability. What will BCMA data look like with more time and more patients treated in trials? This could be Friday’s biggest story when bluebird presents an update on their BCMA CAR-T candidate bb2121. They also have a call scheduled Friday afternoon to discuss the data. We might have to broadcast it on loudspeakers at the unofficial tweetup.
  • Speaking of durability, CD19 CARs have been developed so quickly that we don’t actually know how durable the responses will be over the long-term. It has always been a hypothesis that durability will last for patients who are out a considerable amount of time, but companies still need to prove it. Gilead had long-term data from ZUMA-1 in NHL that looked spectacular at ASH, and ASCO data will likely be similarly good. The more proof these companies can show at major medical meetings that patients have lasting responses, the easier it will be to overcome the payer and logistic challenges that have emerged in the early days of commercial launch. Gilead will also have some Mantle cell lymphoma and ALL data.
  • To put it mildly, Celgene is having a bad year. After various problems have emerged from past BD deals, they desperately need the Juno acquisition to go smoothly. Or to say it in a glass-half-empty kind of way, they cannot have this one blow up in their face too. Fortunately, so far Juno data has looked good. There will be a JCAR017 update at ASCO in DLBCL and again at EHA. The key here is for it to continue to look competitive with Gilead and Novartis and that no surprising safety issues arise.
  • There has also been talk this last week about an abstract from a Chinese group comparing 4-1BB CAR-T (Kymriah) directly to CD28 CAR-T (Yescarta) to see if one is better than the other. Their conclusion was that 4-1BB had enhanced safety, efficacy, and expansion. Personally, I think this study is flawed and I wouldn’t draw many conclusions about U.S. products from it.
  • We know a lot about CAR-T but still know little about TCRs. When will this approach step up to the plate and have a breakout year? It is still too early for that, but look for data from Adaptimmune targeting NY-ESO and MAGE-A10 and data from NCI targeting HPV oncoproteins to provide some clues. The fact that Glaxo opted to continue their Adaptimmune collaboration is a positive sign.

Cytokines

Mike Gladstone

Atlas Venture’s Mike Gladstone had the call of the year last December when he predicted 2018 would be the Year of the Cytokine. We have since seen Bristol pay Nektar $1.85 billion upfront to own essentially 1/3 of its CD122 agonist and then last month Lilly came from out of nowhere to acquire Armo for $1.6 billion. The biology behind cytokines brings a familiarity and comfort factor given the decades it has been researched. Will today’s new approaches to harnessing them be the first major breakthrough in the IO combo race? Already this year $3B+ has been bet on it.

There is a ton riding on the Nektar data at ASCO. Bristol is both in need of positive news after being routed by Merck in 1L NSCLC at AACR and also must justify the cash they threw at Nektar to partner on this. Early data at SITC looked stellar, but it was just that….early data. How will the response rates hold up with more patients on drug and in more types of cancers? The abstract release caused some nervous butterflies and so we will have to look to the full ASCO presentation for more comfort. Nektar is hosting a hugely important analyst meeting on Saturday afternoon that is not to be missed.

  • Armo’s peg IL10 looked very compelling in pancreatic cancer, NSCLC and RCC. This appears to be a very smart purchase by Lilly even considering the early stage ARMO is at and the high price of the deal. Will another suitor step up and make things interesting before the June 22 tender deadline?

Other IO

  • Privately held Checkmate Pharma presented compelling data from its TLR9 agonist during a plenary at AACR, but none of the publicly traded TLR9 companies (Dynavax, Idera) have been able to match the excitement. Why? Dynavax traded sharply down when investors reexamined the 60% ORR published in its abstract (PD1 naïve melanoma) after realizing that 5 non-evaluable patients had been left out of the analysis. Will the higher 60%+ number turn out to be true as more data is reported at the conference?
  • It is always important when you get a first glimpse at clinical data from a company with a unique new platform. CytomX and its probody platform is that company at ASCO 2018. Can they maintain comparable efficacy to checkpoints while lowering the toxicities?
  • One of the biggest disappointments from the abstract release day was Jounce and its ICOS agonist. While most on Wall Street threw in the towel, there are still a few believers in this concept who are hanging on. The immunotherapy superstar founders of the company will be giving a talk at an analyst event on Monday night. Jounce (and their partner Celgene) needs to walk out of Chicago with some kind of positive because they have no other assets (besides a PD-1) anywhere near the clinic.
  • Merck KGaA’s PD-L1/TGF-β trap fusion protein looks promising in HPV associated cancers and will be a much-discussed trial. The TGF-β pathway and how it contributes to immunosuppression is a hot topic in general and there are a couple of abstracts addressing this. Expect to see a few new companies IPO soon with TGF-β programs in their pipeline. One just happened on Thursday.
  • Regeneron might be the only company (out of dozens) developing a new PD-1 that really matters from a competitive standpoint. This is because 1) they are Regeneron and therefore conduct terrific science and 2) they have done a good job of racing theirs through the clinic. How does Cemiplimab stack up against Keytruda and Opdivo? Can they actually compete commercially in existing indications or will they have to settle for using this as a combo development tool like everyone else?
  • I predict that one future ASCO will be the Year of Bi-specifics. We are not there yet, but watch for a handful of early studies this year to begin to set the stage.

Other Therapies

  • There has been much anticipation for PARPs to shine in combination with PD-1s, but the data has been lacking so far. Why? Tesaro’s TNBC data from TOPACIO doesn’t look much better than what we’d expect to see with monotherapy unfortunately. Speaking of monotherapy, QUADRA doesn’t seem to shake the ground in late stage ovarian either. The company’s stock has practically gone down every day for a year and many are waiting for it to get cheap enough to finally be acquired. That might not happen at any price until they can demonstrate broader utility.
  • With Rova-T continuing its cold streak this year, we are looking towards others for positive data in SCLC. PD-1s, PARPs, and lurbinectedin are possible candidates for this terribly aggressive cancer and huge unmet need.
  • Antibody-drug conjugates are still a thing, though much less today than back in the glory days when Roche was the darling of ASCO with T-DM1. Immunomedics recently filed its BLA for sacituzumab govitecan in triple-negative breast cancer. This uses SN-38, the active metabolite of irinotecan, conjugated to Trop-2. Data from their study presented at ASCO will help us better understand the approvability and commercial viability of the drug.

Thanks a lot for your interest. These have been some of the things I am watching and I hope it helps. Best of luck to all the companies, researchers, physicians, and patients who will no doubt make 2018 another great ASCO.


Brad Loncar is an independent investor focused on biotechnology. He can be reached on Twitter at @BradLoncar.

Image: 2017 annual meeting. ASCO


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