The 32nd annual meeting of the Society for Immunotherapy of Cancer (SITC) is taking place through Sunday near Washington D.C.. This meeting is always a marquee event for the immunotherapy community as it is the largest and longest running meeting that focuses exclusively on cancer research using immunotherapy. Companies and other researchers try to make the most of it by releasing important trial results here. For that reason, SITC is a great place to learn about what new immunotherapy approaches look promising.
Given SITC’s immunotherapy focus, you can bet that many components of the Cancer Immunotherapy ETF (Nasdaq: CNCR) will be presenting data at this year’s meeting.
To help you prepare, we have looked through the schedule of events and have highlighted five presentations below that have caught our attention. We have only chosen from ones that SITC has selected for oral presentations. Oral presentations often are a sign of prestige at meetings like this and they might signify a high level of scientific or medical merit. Below are our selections along with the specific date and time they will be presented.
Five Prime Therapeutics (Nasdaq: FPRX)
Saturday, November 11 • 4:30 – 4:45 PM
First-in-Human Phase 1 Dose Escalation and Expansion of a Novel Combination, Anti–CSF-1 Receptor (Cabiralizumab) Plus Anti–PD-1 (Nivolumab), in Patients with Advanced Solid Tumors
One of the biggest themes in cancer immunotherapy research right now is to add an additional drug on top of the successful PD-(L)1 inhibitors with the goal of making them work for more patients and in more types of cancers. Five Prime is a central player in this combo approach as they have spent many years looking for the right targets to create a synergistic effect. For this study that is being presented at SITC, they have added an anti-CSF-1R inhibitor (Cabiralizumab) on top of Bristol-Myers Squibb’s anti-PD-1 inhibitor Nivolumab (Opdivo).
Anti-CSF-1R drugs are meant to inhibit tumor-associated macrophages (TAMs) that have been shown to be immunosuppressive. Macrophages are a type of white blood cell that are mostly supposed to increase inflammation and stimulate the immune system when they come across pathogens and other substances not found on healthy cells. However, some types like TAMs actually play the opposite role and, therefore, make it hard for the immune system to naturally attack tumors. By inhibiting the TAMs, companies like Five Prime hope to remove this obstacle.
Cabiralizumab is a key asset in the company’s pipeline. In fact, CSF-1R is so promising that they signed a deal with Bristol-Myers Squibb to license and collaborate on developing it in October of 2015. Five Prime CEO Rusty Williams called it “transformational” at the time. Bristol agreed to pay Five Prime $350 million up front, a significant amount for such a deal, and up to $1.05 billion in development and regulatory milestone payments - along with royalties if Cabiralizumab is commercialized. As you can see, a lot is riding on its success for both companies.
This SITC presentation is especially newsworthy because it is the first time data has been presented for any human trial of an anti-CSF-1R drug. While this particular trial is still in a dose escalation phase and cannot be expected to give hard proof of activity, it will still provide an important initial glimpse into the viability of the combination. In fact, this abstract was chosen by SITC as a late-breaker, which is often reserved for presentations of the highest significance. The data will not only be important for Five Prime and Bristol, but also the handful of other biotech companies like Syndax that also have plans to work on CSF-1R.
Bristol-Myers Squibb (NYSE: BMY)
Saturday, November 11 • 12:00 – 12:15 PM
Saturday, November 11 • 12:00 – 12:15 PM
Preliminary antitumor and immunomodulatory activity of BMS-986205, an optimized indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, in combination with nivolumab in patients with advanced cancers
Another promising and closely followed asset being studied in combination with PD-(L)1 inhibitors is IDO. Incyte is currently the leader in this. By the end of the year, they will have phase 3 pivotal studies ongoing for their IDO drug Epacadostat in combination with Merck’s Keytruda in melanoma, lung, bladder, renal, and head & neck cancer, and also in combination with Bristol’s Opdivo in lung and head & neck. The melanoma study is expected to finish sometime in 2018 and is shaping up to be a key event for the sector. Some analysts have already valued Epacadostat at over $10 billion of Incyte’s market capitalization.
Indoleamine 2,3-dioxygenase (IDO) is an enzyme involved in tumor escape. Interestingly, it has an important purpose in biology. This is one of the main mechanisms that block a mother’s immune system from attacking her fetus. Tumors have unfortunately learned from that and hijacked it for the same purpose. When the IDO enzyme is expressed around the tumor microenvironment, the enzyme makes a key amino acid unavailable that T-cells need in order to mount an immune response. The idea behind IDO inhibitors is that they will stop this process and allow the immune system to more effectively do its natural job.
Saturday’s SITC presentation is important for Bristol because they are racing to catch up with Incyte in IDO. We first saw some initial safety data from this trial of their IDO inhibitor BMS-986205 in April at a meeting called AACR, but it was too early to tell what the drug’s efficacy looked like. As the title of the SITC abstract suggests, we will now see preliminary antitumor and immunomodulatory activity so it will be easier to begin comparing it to Incyte’s drug. Good data can also provide somewhat of a reputational boost for Bristol’s management. They acquired BMS-986205 by purchasing a private company called Flexus in early 2015 for $800 million upfront and potentially another $450 million in milestones.
The SITC presentation is not only an important chance to provide some initial validation for Bristol’s IDO, it is important for the IDO space in general. Even though a lot of market value has been ascribed to companies for IDO assets, the reality is that this is an emerging field and the value is not based on a lot of clinical data. The more evidence we have from multiple assets that IDO is active and adding a real boost to combinations, the better it is for the entire group of companies working on it. Good data here for Bristol might also be a positive for Incyte and NewLink Genetics, the two other leaders in IDO.
Syndax Pharmaceuticals (Nasdaq: SNDX)
Saturday, November 11 • 12:00 – 12:15 PM
ENCORE-601: Phase 1b/2 Study of Entinostat (ENT) in Combination with Pembrolizumab (PEMBRO) in Patients with Non-Small Cell Lung Cancer (NSCLC)
Syndax’s initial approach to researching combinations with PD-(L)1 inhibitors centers around their drug Entinostat. It is being tested with Merck’s Pembrolizumab (Keytruda) in melanoma, lung, and colorectal cancer, Roche’s Tecentriq in triple negative breast cancer, and Pfizer/Merck KGaA’s Bavencio in ovarian cancer. Entinostat is a Class-1 histone deacetylase (HDAC) inhibitor and does its work primarily against immune-suppressors called myeloid-derived suppressor cells. By inhibiting HDAC, the company believes they are reducing the ability of these cells to hold the breaks on the immune system.
At SITC they will be presenting some initial data from a combination study of Entinostat with Keytruda in non-small cell lung cancer patients. We already know the first phase of this trial succeeded in a group of patients who were no longer responding to Keytruda alone. The way the trial works is that the investigators treated 31 of those Keytruda refractory patients with a combination of Entinostat and Keytruda, and for neutrality purposes predetermined that at least three had to respond in order to keep the trial going. Since that did in fact happen, enrollment has been reopened and will expand to a total of 56 patients. At SITC we expect to see detailed data from that first successful phase of the trial.
The SITC presentation will be important to better understand Entinostat’s ability to enhance the activity of PD-1. HDAC’s role in cancer is not well understood, though Syndax has demonstrated in preclinical studies that the drug does in fact inhibit those myeloid-derived suppressor cells. We would like to see any biomarker data the company might have at SITC illustrate a similar effect in humans. Non-small cell lung cancer is sadly the most common type of cancer due to smoking so it is a positive for Syndax that their event-driven trial strategy has initially succeeded in this indication. Lung cancer patients who no longer respond to PD-1 inhibitors urgently need new treatment options and it could be meaningful if Entinostat plays a role.
Curis (Nasdaq: CRIS)
Friday, November 10 • 2:30 – 2:45 PM
Friday, November 10 • 2:30 – 2:45 PM
Phase 1 Trial of CA-170, a First-in-Class, Orally Available, Small Molecule Immune Checkpoint Inhibitor (ICI) Dually Targeting PD-L1 and VISTA, in Patients with Advanced Solid Tumors or Lymphomas
PD-(L)1 checkpoint inhibitors are currently the most widely used type of immunotherapy drugs. They work by inhibiting a protein marker that acts as a natural stop signal for T-cells before they would otherwise interact with tumors and try to kill them. The drugs have been approved for certain types of melanoma, lung, kidney, bladder, head & neck, Hodgkin lymphoma, and liver cancer, and are being studied in dozens more. In fact, there are currently approximately 1,000 combination trials using PD-(L)1s in conjunction with various other types of medicine. If just a fraction of these succeed, this class of drugs has the opportunity to become the foundation of care for many patients.
You might have already heard of some of the PD-(L)1s like Merck’s Keytruda, Bristol-Myers Squibb’s Opdivo, Roche’s Tecentriq, AtraZeneca’s Imfinzi, and Pfizer’s Bavencio. While there are subtle differences amongst them, they are not highly differentiated and one major trait they all share is how they are administered to the patient with an intravenous infusion. Curis is one of the few companies trying to come up with an alternative. They are developing what is called a small molecule version that is meant to be a standard daily pill. This would be more convenient if it works, and theoretically might come with safety benefits because the pills stay active in the body for a shorter period of time so treatment could be stopped more quickly if adverse events arise.
Another potential benefit of the Curis drug (CA-170) is that it not only targets PD-1, but also another checkpoint that is hypothesized to mediate T-cell response called VISTA. This dual-target aspect is important. Those 1,000 combination studies are currently being conducted with PD-(L)1s because researchers want to boost their efficacy and help more patients respond to them. By adding PD-1 and VISTA together in the same molecule, Curis is essentially running their own combination study, but with one pill. However, as great this all might sound, the technical hurdles of making it succeed are significant. Time will tell if the CA-170 pill is up to the task of being equal or better to PD-(L)1 monotherapy.
The SITC presentation will be closely watched because it is possible we might have an opportunity to see the first anti-tumor activity of this drug. Curis presented data from CA-170 for the first time at a meeting called ESMO in September, but all that could inferred back then was safety since it was so early into the trial and dosing began at a low starting level. Now that more time has passed, we want to see if the drug is actually making a difference medically and shrinking tumors like traditional PD-(L)1s do. It is possible that SITC might provide a first hint. Biomarker data will be key because biomarkers will illustrate whether CA-170 is just as active in the body and around tumors as the standard drugs. At minimum, it has to be equal to them.
Juno Therapeutics (Nasdaq: JUNO)
Friday, November 10 • 11:10 – 11:30 PM
Friday, November 10 • 11:10 – 11:30 PM
Severe Neurotoxicity in the Phase 2 Trial of JCAR015 in Adult B-ALL (ROCKET Study): Analyses of Patient, Protocol and Product Attributes
Arguably the most talked about area in immunotherapy right now is the CAR-T cellular immunotherapy space. CAR-T is the type of treatment where the patient’s own T-cells are drawn so they can be re-engineered outside the body and taught to look for cancer. Once re-infused, the cells recognize the cancer, expand into the billions, and aim to destroy it. This has been working amazingly well in certain types of blood cancers. In fact, you might have heard about how FDA recently approved two CAR-T therapies for commercialization. Novartis’ Kymriah was approved for relapsed pediatric ALL in August and Gilead’s Yescarta was approved for aggressive NHL in October. Gilead picked up Yescarta when they purchased its developer Kite Pharma for $11.9B.
While CAR-T is promising, it is still early and there is a lot to be learned and improved on. For example, there are serious toxicities that come with CAR-T therapies today – this has sadly even caused patient deaths at times. That is why for now they are almost exclusively reserved for advanced patients who are no longer responding to other treatments. Researchers and clinicians are urgently trying to better understand why toxicities happen and how to better manage them. Doing so will not only help patients today, but also hopefully even more in the future by enabling CAR-T to be used earlier in treatment and for more types of cancer.
The seriousness of these toxicities was illustrated in the news last year by a clinical trial Juno Therapeutics had been conducting with their CAR-T therapy JCAR015 in adult patients with ALL. In this case, one class of serious adverse events that arose were neurotoxicities and some even sadly led to fatal brain swelling. Signing up for a clinical trial is courageous and it is heartbreaking to see outcomes like that for some patients. Juno stopped development of JCAR015 and promised to research why it was happening. What they learn might hopefully help the entire field and lead to safer treatments for more patients in the future.
Juno will present detailed findings from their research for the first time here at SITC. While there are many theories, the reality is that nobody exactly knows why these neurotoxicities are happening. Some wonder if it is related to the type of chemotherapy used in preconditioning, while others think maybe the construct of the CAR-T cells plays a role. Perhaps patient attributes are the biggest factor. Given how complex biology is, it is likely to be a combination of many things. Hopefully Juno’s presentation on Friday will shed some light on it. We have already seen CAR-T make a difference for patients with these initial FDA approvals, but there is much yet to be learned to ensure these treatments reach their full potential.
Thanks, as always, for your interest in the field of immunotherapy and support of the Cancer Immunotherapy ETF. To see how it all unfolds at the conference, look for press releases from individual companies or you can watch news and commentary in real time by following #SITC2017 on Twitter through Sunday.
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Opinions expressed are those of the author or Funds and are subject to change, are not intended to be a forecast of future events, a guarantee of future results, nor investment advice.