Major trends in cancer drug development – Notes from TAT 2013

Earlier this month, I attended the TAT (Targeted anticancer therapies) congress in Paris. This conference focuses exclusively on targeted therapies for cancer, one of the most active areas in drug development. As a small conference (~500 participants), it does not generate a lot of high profile clinical data, still, it is a great opportunity to “feel the pulse” of oncology drug development. Speakers include clinical oncologists, basic scientists and industry researchers, which provide a fairly broad spectrum with respect to existing and upcoming trends.

Here, I focus on three major themes from the meeting: PD-1 inhibitors, antibody drug conjugates (ADCs) and cancer metabolism.

The PD-1 race

The first plenary session focused on drugs that inhibit PD-1 signaling. This class of drugs is probably the most exciting thing in oncology, based on unprecedented results across several tumor types. At the session, it was interesting to see the various approaches pursued by different companies in terms of choice of therapeutic agent and clinical strategy.

The session was preceded by a keynote lecture by Michael Atkins (Georgetown University), who gave an overview of the evolving landscape of immune checkpoints. Atkins, who has been a strong advocate of immunotherapy before it became so popular, emphasized that there are probably baseline parameters that dictate whether a patient responds to immune checkpoint inhibitors or not. A lot of it has to do with the microenvironment of the tumor including infiltration of immune cells and the various mechanisms cancer cells use to evade the immune system. This “immunogenic profile” can explain the dramatic variability in response to immunotherapy (some patients can be cured while others are inherently resistant).

4 PD1 programs were presented: BMS’s (BMY) nivolumab (anti-PD1), Merck’s (MRK) MK-3475 (anti-PD1), Genentech’s MPDL3280A (anti PD-L1) and GSK (GSK)/Amplimmune’s AMP-224 (PD-L2-Fc fusion). The first 2 are in late stage development based on positive phase I data. The other two are still in phase I and initial data are expected this year.

David Feltquate (BMS) reviewed published results with nivolumab (BMS-936558), a fully human PD1 antibody. Nivolumab demonstrated remarkable activity in melanoma, lung and renal cancer, which I previously discussed in my ASCO 2012 summary. Dr. Feltquate emphasized the depth of responses (many responders are progression free after 2 years) and the unusual kinetics of response (some patients respond after initial alleged progression, some maintain long term responses after very short exposure to the drug).

Alexander Eggermont (Institut Gustave Roussy) presented phase I data for MK-3475, a humanized anti-PD1 in melanoma. Response rate was very high (51%) and appeared numerically better than that observed with nivolumab. As this trial started in 2011, many of the patients had been treated with Yervoy, another immune checkpoint antibody. Response rate in this subpopulation was still quite high (41%), which proves that failure on one form of immunotherapy does not preclude benefit with another immunotherapy. Durability of responses also appeared very high, similarly to that seen with nivolumab.

It was very interesting to see how representatives from Genentech and GSK tried to differentiate their programs from the standard PD-1 antibodies.

Daniel Chen (Genentech) presented the rationale and initial results with MPDL3280A, an antibody targeting PD-1 ligand (PD-L1). PD-L1 is expressed by tumor cells and can suppress the immune system by binding PD-1 on T cells in the tumor microenvironment. In theory, targeting PD-L1 has two main advantages over targeting PD-1. The first advantage is the ability to inhibit another receptor on T cells (B7.1), which is also activated by PD-L1. The second advantage is avoiding the inhibition of PD-L2 binding to PD-1, which could result in lower toxicity. Chen stated they are seeing clinical activity and presented one example of robust tumor shrinkage. In order to improve safety profile even further, Genentech’s scientists engineered the Fc region to completely eliminate effector functions (ADCC, CDC)

It is important to note that BMS also has a PD-L1 antibody but decided to move ahead with nivolumab, since it was more active. Therefore, it is unclear whether blocking B7.1 is a worthwhile approach. The opportunity to have a better safety profile looks somewhat irrelevant to me given the excellent safety profile with PD-1 antibodies. Nevertheless, it is hard to make any definitive conclusions until results are published.

James Smothers (GSK) discussed AMP-224, which was licensed from Amplimmune in 2010. This is an Fc-fused PD-L2 which can bind PD-1 on T cells. Although often viewed as interchangeable with PD-1 antibodies, GSK claims it has a differentiated mode of action that may result in a different clinical profile. Similarly to MPDL3280A’s case, there is still no evidence for a differentiated clinical profile (let alone superior one) versus PD-1 antibodies.

Everybody agrees that results with both nivolumab and MK-3475 are one of the most impressive data sets ever seen with a single drug in solid tumors. The safety profile was also remarkably good, substantially better than that associated with other immunotherapies (Yervoy, high dose IL-2).

When asked whether PD-1 antibodies are going to cure metastatic melanoma, Michael Atkins replied: “Yes, in 25% of patients”. To put this in context, patients with metastatic melanoma have a life expectancy of 11-13 months with recently approved drugs (Zelboraf, Yervoy). To date, curing these patients has been either impossible or required complicated, expensive and toxic treatments (e.g. IL-2, TILs). For the first time, patients have a 25% chance of long term remissions with a safe drug that can be simply injected to them at every clinic.

My take home message from this session is that BMS is still well positioned with nivolumab, which has the most comprehensive data set and development program (5 phase III trials). Merck’s MK-3475 looks very active and numerically better (in melanoma) and is not too far behind with a very large (500 patients) randomized phase II trial. The trial is evaluating 2 dosing regimens of MK-3475 vs. chemotherapy and might enable accelerated approval.

Genentech’s and GSK’s approaches, although scientifically interesting, are both 1-2 years behind with products that might be safer but could also be inferior in terms of clinical benefit. Given the indications are fatal cancers and the benign safety profile seen with nivolumab and MK-3475, it will be hard to beat nivolumab or MK-3475 based on a better safety profile.

Aveo’s (AVEO) investors should follow PD-1 inhibitors as well, as this class of drugs could displace VEGFR inhibitors as the preferred treatment in renal cancer. Nevertheless, approval of PD-1 inhibitors in 1st line RCC is still years away (BMS’ phase III trial is in 2nd line patients). Moreover, combining the two classes of drugs could be a very powerful approach and Aveo’s Tivozanib is the best tolerated and therefore the most combinable VEGFR inhibitor. BMS is is evaluating nivolumab with Sutent or Votrient in renal cancer in phase I.

Antibody drug conjugates     

ADCs are another hot topic in oncology as they are very potent agents but have a relatively good safety and PK profile. There are two companies with validated ADC technologies that generated FDA approved drugs: Seattle Genetics (SGEN) and Immunogen (IMGN). Seattle Genetics’ Adcetris is approved for Hodgkin’s lymphoma and Roche/Genentech’s Kadcyla (T-DM1) is approved for breast cancer. Both agents have robust activity as single agents and a relatively benign safety profile.

Based on initial results with Adcetris and Kadcyla, there has been a surge in interest in ADC and consequently in number of programs in development. (See figure below from Credit Suisse’s report). Unfortunately, most of the other ADCs that entered the clinic could not replicate the clinical profile observed with Kadcyla and Adcteris. Still, some ADCs, including the ones presented in the meeting demonstrated clinical activity.  Many other still haven’t generated clinical data.

ADCs in development - CS 2012

       Source: Positive outlook for antibody companies (Credit Suisse, November 2012)

Veronique Blanc (Sanofi) started the ADC session with a comprehensive overview of the various technologies. The presentation illustrated the inherent complexity involved in ADC development due to the need to optimize multiple components in parallel. Identifying the “sweet spot” for all parameters (target epitope, payload type, linker type, amount of payload per ADC etc.) is very challenging. Another important point was that ADCs have toxicities that are unrelated to the target but stem from non-specific accumulation in healthy tissues. This explains why in most cases, ADCs cannot be dose escalated beyond 2-4 mg/kg and also implies that even when the target is very differentially expressed on tumors, general toxicity will appear.

Sanofi has been an early mover in the ADC field via a collaboration with Immunogen. To date, the collaboration yielded 3 ADCs that entered phase I. One ADC (AVE9633, anti-CD33) was discontinued due to lack of efficacy, whereas 2 ADCs targeting CD19 and CA6 are still in development.

Stuart Lutzker (Genentech) provided an overview of Genentech’s ADC pipeline. Genentech is by far the most active and capable developer of ADCs, with 8 programs in clinical trials and many more in preclinical development. All 8 programs utilize Seattle Genetics’ technology, making Genentech’s ADC pipeline Seattle Genetics’ most valuable growth engine for 2013. (Discussed here)

The presentation started with a recap of Kadcyla’s data in breast cancer. Lutzker emphasized Kadcyla proved superior to active approved chemotherapy regimens in 2 randomized trials (phase III 2nd line, phase II in 1st line). This superiority is driven in part by “deeper” (more durable) responses ADCs can induce. He then discussed Genentech’s earlier stage ADC pipeline and focused on the company’s CD22, CD79b and MUC16 programs.

Data for the CD22 and CD79b in NHL had previously been presented at ASH. Both ADCs appear very active with a 40%+ response rate in patients treated at clinically relevant doses. Genentech has a creative clinical strategy for the two ADCs: It is comparing them in a randomized phase II trial in combination with Rituxan. Interestingly, the trial is designed to allow crossover between the arms, which could provide important insights on resistance mechanisms (e.g. are they target or toxin related?).

To me, the most exciting part in Lutzker’s presentation was initial clinical data with a MUC16 ADC, currently in phase I for ovarian and pancreatic cancer. I originally thought this program was discontinued but it turns out that not only it is still active, the ADC appears to have activity in ovarian cancer with multiple cases of tumor shrinkage. Responses were specifically observed in patients with high MUC16 expression, which bodes well for the ability to identify the right patient population for this ADC.

Overall, Genentech’s ADC pipeline appears to be progressing very well, with more data expected this year. As discussed, this is extremely positive for Seattle Genetics, which is eligible for milestone payments and royalties for each program.

Anas Younes (MD Anderson Cancer Center) presented clinical results for SAR3419, Sanofi’s CD19 ADC based on Immunogen’s technology. Younes presented clinical experience using 3 dosing regimens, which included objective responses across various types of B cell malignancies. SAR3419 had a ~30% response rate at the higher doses and was well tolerated with ocular toxicity as the dose limiting toxicity. Sanofi is using a modified regimen which minimizes this side effect and is expected to present phase II results this year.

Overall, my personal impression is that SAR3419 is slightly inferior to other ADCs for NHL (primarily Genentech’s CD22 and CD79b programs and Seattle Genetics’ Adcetris for CD30+ DLBCL), however, cross trial comparisons are unreliable. In addition, as it employs a different payload (albeit with a similar mechanism) from the above ADCs, it might have a different activity spectrum. Despite being the first to put an next-gen ADC for NHL in the clinic, Sanofi has been somewhat slow in developing SAR3419. Consequently, it lost its early mover advantage and is now facing a lot of competition.

Raffit Hassan (National Cancer Institute) gave a very interesting talk on mesothelin-targeting immunoconjugates. He focused on the NCI-developed immunotoxin, SS1P, which is comprised of an antibody and a potent toxin. Conceptually, immunotoxins are similar to ADCs but they suffer from several limitations such as immunogenicity, toxicity and short half life. Still, SS1P demonstrated some efficacy signals alone and in combination with other drugs. In order to avoid immunogenicity, an improved version entered phase I, with data expected this year.

Hassan also mentioned Bayer’s BAY 94-9343, an ADC powered by Immunogen’s technology. Phase I results will be presented at the next AACR meeting (April 2013). Based on activity with SS1P, which validated mesothelin as a target, BAY 94-9343 has the potential to demonstrate early signs of efficacy. Importantly, as an ADC, it can be given repeatedly whereas immunotoxins can be given for only 1-2 cycles.

Cancer metabolism – the next big thing in oncology?

Meetings like TAT provide a glimpse of the industry’s preclinical pipeline, which often dictates upcoming trends in oncology drug development. Cancer metabolism is definitely emerging as one of the hot topics in oncology and one can expect to see many programs in the clinic in the coming 2 years.

The working hypothesis in cancer metabolism is that cancer cells have a different metabolic profile (consumption and utilization of nutrients) than healthy cells. This is supported by a growing list of metabolic enzymes that are mutated or aberrantly expressed in cancer cells. In theory, inhibition of these enzymes could lead to anti-cancer activity while sparing normal cells.

At TAT, 3 companies presented internal cancer metabolism programs.

Susan Critchlow (AstraZeneca) presented the company’s work with inhibitors of MCT, a family of lactate transporters. Cancer cells produce large amounts of lactate, which has to be secreted out of the cells, therefore, blocking its secretion could obstruct energy production. AZD3965, an MCT1 inhibitor, started phase I earlier this year and the company is working on additional inhibitors for related targets (MCT4).

Richard Wooster (GSK) presented work focusing on fat production and the enzyme FAS (fatty acid synthase) as a target. GSK developed a potent FAS inhibitor that has a broad anti cancer profile. Wooster also presented extensive work on the metabolic consequences of FAS inhibition, which further validated the molecule’s profile. FAS looks like a very bold choice, given its central role in fat metabolism, however, the drug appears to be well tolerated in animal models (no notable liver or cardiac toxicity). The drug (GSK526) is expected to enter the clinic this year.

Sam Agresta (Agios) presented Agios’ strategy of identifying genetically defined subsets of tumors which are addicted to specific metabolic enzymes.  The company’s most advanced programs are the IDH1 IDH2 inhibitors programs, partnered with Celgene (CELG). IDH1 and IDH2 are part of the Krebs Cycle and mutations in both enzymes are seen in many tumor types. Although there is still controversy around the role of these enzymes and respective mutations in cancer, Agios tells an elegant story supported by a large body of scientific evidence. The company plans to investigate its IDH inhibitors in biomarker –defined patient populations.

                Portfolio holdings – March 17th, 2013  Biotech portfolio - 17-3-2013

biotech etfs - 17-3-2013

38 thoughts on “Major trends in cancer drug development – Notes from TAT 2013

  1. Any speculation from BMY or MRK as to what baseline parameters that differentiate those with long term response from those without any response?

  2. Thanks very much for a detailed report on the conference proceedings, with focus on hot areas.

    I have a background in basic science ; and involved in cancer patient advocacy .

    I was wondering if the abstracts / presentations were published . Specifically interested in the immune check point therapies and their response/activity in non-melanoma cancers ?

    Initial reports indicated activity in ovarian and lung cancers with the anti-pd-l1 drugs and was wondering if the updated presentations / data presented at the conference indicate any trend in this class of cancers ?

    Will greatly appreciate your response.

  3. Ohad, are there no publicly-traded small-cap biotechs involved in any of these areas (outside of potentially AVEO down the road)?

  4. What are the chances of Eteplirsen receiving Accelerated Approval based on the very positive results of their study.
    Critics say the study is too small to be granted AA.
    However, proponents say that the drug has performed so well on a a debilitating disease with very few treatment options and a recent law has allowed the FDA to speed up the process for drugs for some diseases Moreover, they argue that their is indeed precedence that the FDA has already approved a drug with just 12 patients in the early 1990′s.

  5. With respect to immune checkpoints, most of the projects are already developed by large companies or private ones (amplimmune, macrogenics etc.)

  6. Hey Ohad
    what you think of teh news on INCY this morning, how will the PML case affect sales outlook for Jakafi…. ?
    Thanks!
    Dan

  7. Hard to tell… it’s never a good thing to have PML associated with a drug but given the rarity of the event (that could change with more exposure) ,the lack of clear correlation with Jakafi and the unmet need in myelofibrosis I still think Jakafi will be broadly used, perhaps with lower doses or treatment holidays.

    Ohad

  8. This is out from piper jaffray this morning:

    “We recommend buying on weakness following the announcement that a case of PML has been observed in a 75 year-old man who had been receiving Jakafi for ~8 weeks as part of the company’s expanded access program. This is the first observation of PML in >9.8k patients receiving Jakafi, and if we include other JAKs in development, particularly Pfizer’s tofacitinib which has a much larger safety database, the incidence is even lower. We are on the road with management today and initial commentary suggests that for PML to develop in such a short time suggests extended immunosuppression prior to initiation of Jakafi. Thus, we expect the investigation to focus on what drugs the patient received prior to entering the expanded access program. However, we remain confident in Jakafi’s long-term safety profile. We expect shares to be weak today as investors take a pause following INCY’s recent run. Reiterate OW, $23 PT.”

  9. Ohad
    What is yuor opinion about the PGNX/SGEN PSMA ADC program?
    Do you see PGNX following the path of CLDX? Thanks
    –andre–

  10. There is definitely hints of activity there but I would be cautious making an analogy to CLDX, since I am not sure this is potent enough. More data at ASCO hopefully.

    Ohad

  11. Ohad, Any thoughts regarding Micromets Bite products. Amgen seems to be very quiet regarding development!

  12. Hello Ohad,
    today news about Genmab: “Findings presented at a scientific session that Nordea hosted confirm Genmab’s daratumumab is a clearly unique asset in the growing market for treating multiple myeloma, the bank said. Nordea repeated a strong buy recommendation on the shares of the Copenhagen-based drugmaker.”
    Regrettably we hear nothing new about MOR 202. Has MOR 202 at all a chance to compete with daratumumab? It looks like daratumumab has a clear advantage because it’s ahead in the clinical trials.
    Toby

  13. Ohad, did you catch that CRIS disclosed a CR with the IAP inhibitor they in-licensed from Genentech at Roth on 3/18? There will presumably be more detail at ASCO but this was as a monotherapy treatment in a certain biomarker group (CRIS claims best activity for the drug is as part of combo treatment). CRIS is now one of my largest holdings, for better or worse.

  14. any thoughts on mdvn? xtandi appears to be more effective than zytiga plus they may be able to get approval for the prechemo market in a few years. stock price has come down quite a bit recently and im close to pulling the trigger. any thoughts are greatly appreciated!

  15. Dara clearly has the lead over other CD38 antibodies, in fact it is the only one with published data in humans. The main issue imo is whether Morphosys’ and Sanofi’s antibodies are as effective or does dara has unique properties that cannot be replicated by others antibodies.

    Ohad

  16. Nice catch! I wasn’t aware of that and just listened to the replay. The CEO clearly mentioned 2 responses in the p1 monotherapy including 1 CR with a potential biomarker.
    This is getting more interesting although skepticism around this program will likely persist based on the fact Genentech abandoned it. In any case, this program could generate real value only with ramdomized p2 data which will take a couple of years to emerge.

    Ohad

  17. Xtandi looks like a great drug but I am not sure it is superior to Zytiga. Numerically Xtandi had better OS (and HR) but the normalized difference from the control arm is comparable to what was seen with Zytiga.

    Xtandi’s main advantage is that patients don’t have to take steroids and a better safety profile overall. The steroid issue is controversial as some claim they lead to inferior survival and some claim the opposite.

    The 2 major overhangs long term are competition with generic Zytiga and next gen androgen inhibitors from Aragon and Tokai.

    Both Cowen and Barclays recently issued interesting notes about how Xtandi’s sale projections are overblown and that market opportunity is smaller than people think.

    Ohad

  18. Yeah it’s a fair point on Roche/Genentech outlicensing the program. Why do so if so promising? CRIS claims it’s outside their strategy now of focusing on targeted agents w/companion diagnostics. Still, one could ask why did Genentech settle for only single-digit royalties and not ask for double-digit? The key for me would be knowing if Genentech knew of the CRs at the time they outlicensed or did that come after and I just don’t know.

  19. Hey Ohad

    is it time to add more AVEO? The vote (ODAC) is coming soon and the stock is still down.
    Thanks
    Dan

  20. Ohad
    Any buzz about Stimuvax and whether the “notable treatment effects in some patient populations” observed in the START trial might amount to anything?

  21. the difference in results based on low/normal AAG look impressive to me. is it a valid biomarker?

    what do you think about safety profile?

  22. Still didn’t dive into it but overall it looks ok. There was nothing there to change my mind in either direction. The more important results is for the 520+dex combination.
    From what I understand, neutropenia is not a show stopper.

    Ohad

  23. Hi Ohad,
    This is completely out of the blue … you don’t know me but I’ve followed your work for some time, including your portfolio holdings. I’m an investor also and I value your comments. Have you heard anything recently about the Phase 2 trial Exelixis was running called the Randomized Discontinuation Trial (RDT) …. I’m particularly interested in the expansion of that trial which they called the Non-Randomized Expansion (NRE) . The last press release from the Company that mentions it was from last Sept. in connection with ESMO … in that release they describe the NRE as “ongoing” . Also last Aug. 27th you said that you thought the Phase 2 results in 150 pts (the NRE cohort in CRPC … there’s a similar cohort in ovarian cancer I think) would come out in the 1st half of this year. Finally, in the Company’s recent 10K filing on page 4 they say, “Lower starting doses of cabozantinib are being evaluated in CRPC pts in a non-randomized expansion cohort, or NRE, of the RDT …”

    You’re probably wondering what’s this all about? I think that Exelixis is putting together all the ingredients needed to apply for accelerated approval (Subpart H) of cabo in CRPC … i.e. compelling efficacy in pts who have exhausted all their treatment options and a confirmatory Phase 3 trial well underway. Onyx got accelerated approval for carfilzomib last year based on data from a single arm Phase 2b trial. Admittedly they had 266 pts and the NRE only has 150. In any case I think Exelixis isn’t waiting for the COMET trials to read about before seeking approval. Pure speculation on my part of course … but why don’t they talk about the NRE study if it’s still active? It appears to have disappeared off the face of the earth. Anyway, I’d be greatly interested in your thoughts … Mike Iles

  24. here a poster
    www arraybiopharma.com/_documents/Publication/PubAttachment563.pdf

  25. Hi Mike,

    I don’t know anything for a fact but I would be very surprised if Exelixis tried to pursue accelerated approval based on the NRE prostate cohort.
    It’s important to remember that the 2 major effects that have been observed are (i) bone mets scans and (ii) bone related markers (including pain). None of these can be viewed as a good enough surrogate endpoint in prostate cancer (i.e that it predicts ultimate outcome of patients). The resolution of scans is exciting but there is no proven correlation with survival and all the other markers are cannot be relied on in single arm trials.

    Usually, accelerated approvals with single arm trials rely on standard response rates (Kyprolis, Xalkori, Adcetris)

    One thing they might use the NRE cohort for is compendia listing, although this is still unclear.

    Hope this helps,
    Ohad

  26. Ohad, please explain $PGNX may not be potent enough. What is the scientific reason?

  27. This is based on the clinical data so far as well as results with other ADCs for prostate cancer. In general , it appears ADCs are more effective in certain tumors (breast, ovarian, NHL) than others (prostate, pancreatic etc.)

    Ohad

  28. Few here seem to notice that a single PD-1 blockader cured REPEAT cured 25% of Stage III and Stage IV Melanoma cancer sufferers.

    The side-effects are so mild these drugs can be used in combinations, that is why Pharma companies are cooperating. Worse than Aspirin lets say.

    These drugs have tested as equally useful across arrange of 6 cancers including melanoma. The can cure a lesser % of other cancers too.

    This new immune therapy offers a potential cure for the majority of cancers, no matter how terminal or old the patient.

    Didn’t anyone notice this?

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