Category Archives: PD-1

Immuno-oncology (IO) combination therapy- why the angst?

Thoughts triggered by discussions over the last month or two, perceived sentiment on social media, reaction to clinical updates, and pre-AACR butterflies.

In 2015 Gordon Freeman of the Dana Farber Cancer Institute, one of the discoverers of the PD-1/PD-L1 axis, rang me up and asked if I would help write a review with he and Kathleen Mahoney, an oncologist doing a research rotation in his lab. We ambitiously laid out the argument that PD-1/PD-L1 directed therapeutics would be the backbone of important combination therapies and reviewed the classes of potential combinatorial checkpoints ( We covered new immune checkpoint pathways within the Ig superfamily, T cell stimulatory receptors in the TNF receptor superfamily, stimulatory and inhibitory receptors on NK cells and macrophages, targets in the tumor microenvironment (TME), and so on. Importantly we also stopped to consider combinations with “traditional” cancer treatments, e.g. chemotherapy and radiation therapy, and also with “molecular” therapeutics, those directed to critical proteins that make cells cancerous. Regardless, it’s fair to say that we believed that pairing an anti-PD-1 mAb or an anti-PD-L1 mAb with another immuno-modulatory therapeutic would quickly yield impressive clinical results. A massive segment of the IO ecosystem (investors, oncologists, biopharma) shared this belief, and largely still does. Those stakeholders are betting clinical and R&D resources plus huge amounts of money on the promise of IO combinations. After all, the first IO combination of anti-CTLA4 mAb ipilimumab and anti-PD-1 mAb nivolumab has dramatically improved clinical response in advanced melanoma patients and to a lesser extent in advanced lung cancer patients. The downside is additive toxicity, and so the palpable feeling has been that new IO combinations would give a similar efficacy bump, perhaps even with less toxicity.

It’s now about two and a half years since we began drafting that paper and the inevitable letdown has set in. What happened? Let’s cover a few issues:

- Several marque IO combinations have been disappointing so far. Last year we saw unimpressive results from urelumab (anti-4-1BB) in combination with nivolumab (anti-PD-1) and of epacadostat (an IDO inhibitor) paired with pembrolizumab (anti-PD-1).

- Monotherapy trials of therapeutics directed to hot new targets (OX40, CSF1R, A2AR etc.) did not produce any dramatic results, forcing a reevaluation of the potential for truly transformative clinical synergy in the IO combination setting.

- These first two points also reminded the field of how limited preclinical mouse modeling can be.

- Combinations of standard of care with anti-CTLA4 mAb ipilimumab and with PD-1 pathway inhibitors have begun to show promising results, raising the efficacy bar in a variety of indications. There have been several startling examples: the combination of pembrolizumab plus chemotherapy in first line lung cancer, which doubled response rates over pembrolizumab alone; the combination of cobimetinib (a MEK inhibitor) with atezolizumab (anti-PD-L1 mAb) in colorectal cancer (MSS-type) which produced clinical responses in patient population generally non-responsive to anti-PD-1 pathway inhibition; the combination of atezolizumab plus bevacizumab (anti-VEGF) in renal cell carcinoma, showing promising early results; and so on.

- We can add the realization that relapses are a growing issue in the field, with approximately 30% of anti-CTLA4 or anti-PD-1 pathway treated patients eventually losing the anti-tumor response.

Note here that all of this is happening in a rapidly evolving landscape and is subject to snap-judgment reevaluation as clinical data continue to come in. For example, rumors that IDO inhibition is working well have been spreading in advance of the upcoming AACR conference. Indeed the clinical work on all of the immuno-modulatory pathways and IO combinations has increased, and the race to improve care in diverse indications continues. There will be additional success stories.

Why the perception of angst then? The sentiment has been summed up as “everything will work a little, so what do we research/fund/advance? How do we choose? How will we differentiate”? Such sentiment puts intense pressure on discovery, preclinical and early clinical programs to show robust benefit or, and perhaps this is easier, benefit in particular indications or clinical settings. I started thinking about this recently when a friend of mine walked me through a very pretty early stage program targeting a novel pathway. It was really quite impressive but it was also apparent that the hurdles the program would have to clear were considerable. Indeed it seemed likely that validation of the therapeutic hypothesis (that this particular inhibitor would be useful in IO) would not come from preclinical data in mice (no matter how pretty), nor from a Phase 1 dose escalation safety study, nor from a Phase 1 expansion cohort, but would require Phase 2 data from a combination study with an anti-PD-1 pathway therapeutic. That is, 5+ years from now, assuming all went smoothly. To advance such a therapeutic will take intense focus in order to build a fundable narrative, and will require stringent stage-gates along the way. Even then it will be very hard to pull it off. If this reminds you of the “valley of death” we used to talk about in the biotech realm, well, it should.

What should we look for to shake up this landscape? As mentioned, this is a rapidly evolving space. We have already seen a shift in language (“step on the gas” vs. “make a cold tumor hot” is one good example), but let’s list a few:

- “Cold tumors” have no immune response to stimulate. Making them “hot” is a hot field that includes oncolytic virus therapeutics, vaccines, “danger signals” (TLRs, STING, etc), and, to loop back around, chemotherapy and radiation therapy.

- Relapsed patients – as noted above we are seeing ~30% relapse rate in immunotherapy treated patients. Understanding the basis for relapse is a promising field and one that an emerging therapeutic could (and very likely will) productively target.

- Targeting the TME in cold tumors and in unresponsive tumors (the difference is the unresponsive tumors look like they should respond, in that they contain T cells). This is a vast field that covers tumor cell and stromal cell targets, secreted factors, tumor and T cell metabolism and on and on. One can imagine a setting in which a particular TME is characterized (by IHC, Txp or other means) and the appropriate immuno-modulatory therapeutics are applied. We see this paradigm emerging in some indications already. This would certainly be useful as a personalized medicine approach and could be an excellent way to position an emerging therapeutic.

We could go further to talk about the neoantigen composition of particular tumor types, the role of the underlying mutanome, the plasticity of the TME (it’s a chameleon), metabolic checkpoints, and other, potentially novel, targets.

All of this is under intense and active investigation and important data will emerge in time. Until then, nascent immunotherapy programs need to tell a clear and compelling story in order to attract the interest of investors, biopharma and ultimately, oncology clinical trialists. Those that fail to develop a compelling narrative are likely to struggle.

I’ll just end on a few narratives I really like for IO combinations going forward:

- the role of innate immunity in activating immune responses and expanding existing responses (e.g. immune primers like STING agonists and NK cell activators like lirilumab)

- the role of adenosine in maintaining an immunosuppressed (ie. non-responsive) TME (thus inhibitors of A2AR, CD39, CD73)

- the role of beta-catenin signaling in non-responsive tumors (while carefully selecting the mode of inhibition)

- the role of TGF-beta activity in resistance to PD-1 pathway therapeutics (again, with care in selecting the mode of inhibition)

of course at Aleta we’ve charted a different course, ever mindful of the need to focus where we see clear yet tractable unmet need. so we’ll see, starting with AACR in early April, kicking off an active medical conference season.

stay tuned.

ICI15 presentation is now available

Over 100 slides on immune checkpoint combination therapy, novel targets and drug development in immuno-oncology, created for a 3 hour workshop at ICI15 (link).

As always we work from indications to discovery and back again, keeping one eye on the rapid evolution of clinical practice in oncology and the other on novel targets and therapeutics.

on SlideShare now:

The French Connection – Lirilumab Edition

Bristol-Myers Squibb (BMS) has quietly changed the protocol of clinical trial NCT01592370. This Phase 1 clinical trial has evolved from a nivolumab (anti-PD-1) study in hematological malignancies (5/4/14) to include ipilimumab (anti-CTLA4) with nivolumab (4/8/14) to now include nivolumab, ipilimumab and lirilumab (anti-KIR) as of 10/30/14. The changes were noted on Twitter (where else?) by several biotech experts who posted this screen shot:

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The striking thing to notice is the addition of lirilumab across the board.

The clinical trial includes the following indications/inclusion criteria:

  • Subjects must have histological confirmation of relapsed or refractory hematologic malignancy
  • Subjects with non-Hodgkin’s lymphoma or Hodgkin lymphoma must have at least one measureable lesion >1.5 cm as defined by lymphoma response criteria. Tumor sites that are considered measureable must not have received prior radiation therapy
  • Subjects with Multiple Myeloma (MM) must have detectable disease as measured by presence of monoclonal immunoglobulin protein in a serum electrophoresis: IgG, IgA, IgM,(M-protein ≥0.5 g/dl or serum IgD M-protein ≥0.05 g/dl) or serum free-light chain or 24 hour urine with free light chain. Excluded are subjects with only plasmacytomas, plasma cell leukemia, or non-secretory myeloma
  • Subjects with Chronic myelogenous leukemia (CML) must have evidence of the Philadelphia chromosome by polymerase chain reaction (PCR) or chromosome analysis
  • Life expectancy of at least 3 months
  • For subjects with lymphoma, either an archived Formalin fixed tissue block, or 7 to 15 slides of tumor sample for performance of correlative studies
  • Subjects must have received at least one prior chemotherapy regimen. Subjects must be off therapy for at least 3 weeks (2 weeks for oral agents) prior to Day 1

The trial covers Non-Hodgkin Lymphomas (NHL), Hodgkin Lymphoma (HL), Multiple Myeloma (MM), Acute Myelogenous Leukemia (AML), a subset of Chronic Myelogenous Leukemia (CML) and other hematologic malignancies. The requirement for biopsy tissue is to support biomarker analyses.

Lirilumab is an antibody developed by Innate Pharma (IPH.PA) that binds to the KIR2DL1, -2, and -3 receptors and prevents them from binding to HLA-C. HLA-C is a B2-microglobulin bound MHC family member with antigen presenting function. As an ancient system of antigen presentation, HLA-C is expressed on virtually all cell types. Binding of HLA-C to KIR2DL isoforms induces an inhibitory signal that prevents NK cells from engaging in cytotoxic control of tumors. By preventing KIR-mediated suppression of NK cells, lirilumab increases NK cell–mediated killing of HLA- C+ tumor cells.

Lirilumab showed signs of clinical activity in a Phase 1 trial and acceptable toxicity was observed (Vey et al. 2012. Blood 120: 4317, Vey et al. 2013. Blood. 122: 21, abstracts). A Phase II study of lirilumab in AML is in progress and combination Phase 1 trials of lirilumab in combination with ipilimumab and nivolumab for a variety of tumor types have begun. Lirilumab is also being tested in combination with the depleting antibody elotuzumab (anti-CS1) in refractory MM. The lirilumab-titled trials are listed below:

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So what to make of all this activity? One reasonable conclusion is that enough data from interim analyses of the AML trials has come in to convince BMS to double-down on the partnership with IPH and move lirilumab forward aggressively. The breadth of indications is impressive. A second, related, conclusion is that preliminary data on lirilumab’s clinical activity in AML is ready for presentation at the American Society of Hematologists (ASH) Conference in December. The abstracts from that conference will come out on November 6th, so we’ll see.

There is considerable interest in combining T cell directed immune checkpoint therapeutics with those that act on NK cells. Innate Pharma (IPH.PA) has additional programs of interest in the NK cell space, including an antibody that targets MICA, a negative regulator of NKG2D-mediated activation of NK cells and an antibody that targets NKG2A, an inhibitory receptor.

The focus of this company on NK cell biology is impressive and may finally drive strong valuation. Innate has some very vocal supporters, but many investors seem reluctant to back this company. One reason perhaps is that it trades in Europe and liquidity of the corresponding US shares (OTC:IPHYF) is low. Another reason is perhaps the relationship with Novo Nordisk, which owns about 15% of company equity. From the scientific perspective the company is innovative and exciting, and I would love to have someone explain the stock valuation issues. Innate raised significant capital earlier this year with a round led by Orbimed, Redmile, FMR and about a dozen other top tier investors. An early look at AML results for ASH, or perhaps at ASCO, and strong clinical data thereafter could make many retail and institutional investors happy.

stay tuned

PD-1 Pathway Inhibitors & Cancer Therapy – PART 2

Other PD-1 pathway therapeutics in advanced melanoma therapy.

Yesterday we focused on nivolumab, particularly in combination with ipilimumab, for the treatment of advanced melanoma. There are competing PD-1 pathway inhibitors that have now reported out substantial trial data. See part 1 for a list of PD-1 pathway therapeutics in development. Much attention has gone to Merck’s pembrolizumab, formally called MK-3475. The activity of pembrolizumab in melanoma is very similar to that of nivolumab, so it’s worth taking a closer look at the characteristics of the antibodies. Included here is pidilizumab, another anti-PD-1 antibody, developed by CureTech.

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Attributes of note include the different sources of the antibodies (fully human vs humanized murine antibody), different isotypes (IgG4 vs IgG1) and affinities ranging more than 200-fold from sub-100pM to 20nM. However, this is a small number of antibodies and it will be hard to discern how each of these attributes contributes to efficacy. Pembrolizumab closely resembles nivolumab except that the affinity for PD-1 is as much as 10 fold better. At the doses given it is difficult to know if this makes any difference, as drug levels may be saturating. We’d have to dig out target occupancy data from the trials to figure this out, but let’s look at the pembrolizumab results first, as it will become clear that this antibody has similar efficacy as nivolumab. How these therapeutics are being developed is different, as we’ll see.

The pembrolizumab (“pembro”) data reported at ASCO are from a huge Phase 1 clinical trial in advanced melanoma. Importantly, Merck made the strategic decision to stratify patients by prior exposure to the anti-CTLA4 antibody ipilimumab (“ipi”), from Bristol-Myers Squibb. This gave the company a jump on the field, allowing them to pursue FDA approval first for ipi-refractory patients. Due in part to the toxicity associated with ipi therapy, there are a lot of these patients. First, though, a brief look at the data, which has been widely reported. The data are compared to published data for nivolumab (“nivo”) treatment of ipi-naive advanced melanoma patients                 ( A guide to the clinical abbreviations is included in part 1.

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If we focus on the ipi-naive ORR and 1 year survival data I think we have to conclude that these drugs are pretty comparable, and we’ll wait for additional data before trying too hard to differentiate these. That data will have to come from longer duration of ongoing trials and various combination studies. It is clear from the monotherapy data is that for advanced melanoma patients, anti-PD-1 therapeutics offer a chance at extended benefit. If we look more closely however,we see that in the nivo trial referenced above, half of the responding patients stopped therapy for reasons other than disease progression, most likely dropping off study due to AEs. It is true that 3/4s of the nivo patients stopping therapy maintained a response, some for extended periods. In the pembro study, the SAE rate was 12% but only 4% of patients discontinued therapy as a result of AEs, so that’s good. The catch is that in order to move ORR higher than 40%, combination therapy may be needed. As we saw with the ipi/nivo combo, this comes with much higher toxicity and drop-out rates. Of course the hope is that moving to earlier line therapy will boost response rates with the same or less toxicity and that data will come with time. As an aside, the question of ORR is the reason we have basically ignored the anti-PD-1 antibody pidilizumab, which had a 5-6% ORR. The 1 year OS was similar to the other anti-PD-1 therapeutics, but with such a low ORR it’s hard to believe this therapeutic from Curetech will gain much traction.

Anti-PD-L1 antibodies constitute the second class of therapeutics targeting the PD-1 pathway. These are in early clinical development in multiple tumor types, and will be addressed later. PD-L1 is also important in the context of predicting response to therapy in melanoma, and the utility of this marker as well as PD-1 is the subject of considerable discussion. When the ORR is 40%, it is helpful to select patients prospectively. We can take a close look at one of the smaller cohort studies to get a good look at this. In a study of responsiveness to pembro, Richard Kefford et al (abstract #3005) used an analysis of PD-L1 expression to demonstrate a remarkable difference in clinical response between patients who had > 1% tumor PD-L1 expression versus those who were PD-L1 negative. Biopsy was required in the 2 months preceding the start of pembro therapy; tumor PD-L1 expression was assessed by immunohistochemical staining. Patients received pembro at either 10 mg/kg Q2W, 10 mg/kg Q3W or 2 mg/kg Q3W. With a median treatment time of 23 weeks and ≥13 months follow-up, ORR was 41%, median PFS was 31 weeks and median OS was not reached. The 1-year survival rate was 81%, so this was a terrific cohort within the larger pembro study, likely due to the higher doses used. PD-L1 expression was associated with improved ORR by (51% vs 6%), PFS (median 12 vs 3 months) and 1-year survival rate (84% vs 69%). Note that while there were no treatment-related deaths; 14% of patients experienced drug-related SAEs (grade 3/4) again reflecting the aggressive dosing schedule.

In the large trial of ipi-naive patients treated with nivo, PD-L1 positive tumor staining was associated with ORR, but only weakly with PFS and OS. Why the data are less robust than the Kefford study is unclear. What is abundantly clear however is that there were profound responses in patients scored as PD-L1 negative, as shown in this screen grab from Dr Weber’s Discussant review of the melanoma oral poster session:

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These data suggest that caution should be exercised in the use of PD-L1 staining as a prognostic tool, and the search for better biomarkers of response continues.

We will revisit some of these issues as we move on to NSCLC, RCC, bladder, ovarian and solid tumors more generally.

PD-1 Pathway Inhibitors Reveal Unique Benefit/Risk Profiles Across Cancer Indications


Anyone attending the immunotherapy sessions at ASCO earlier this month would have heard several distinct messages about PD-1 pathway inhibition in oncology. PD-1 appears to be a central control point for curtailing T cell responses in the peripheral tissues, similar to the role that CTLA4 plays in regulating initial T cell activation in secondary lymphoid organs such as the lymph nodes and spleen. Remarkable progress has been made in the 13 years since Gordon Freemen and colleagues first proposed in Nature Immunology that the PD-1 pathway was used by tumor cells as a shield against immune system attack (

It is clear that PD-1 pathway antagonists show tremendous promise in treating diverse cancers. Less clear is an understanding of why certain patients respond or don’t, what biomarkers might predict response, how to increase response rates, how to accurately measure response, and how to safely combine PD-1 pathway inhibition with other therapies.

Table 1 lists the PD-1 therapeutics in development (some of these therapeutics did not have updates at ASCO).

 Screen Shot 2014-06-12 at 3.52.08 PM

As the table demonstrates, the PD-1 pathway inhibitors are being developed in diverse tumor types. As late Phase 2 data and Phase 3 data are coming out we can begin to see the real promise of these drugs in clinical responses measured in large numbers of patients. The amount of data presented at ASCO was a bit overwhelming so to simplify the landscape we can address each tumor type individually, when possible. Some terms we will use are given in the table below.

Table 2 defines the RECIST1.1 clinical response parameters and their abbreviations.

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To put these terms in perspective we can just consider that a meaningful clinical response is a measureable response to therapy (SD < PR < CR) that is durable and leads to an increase in PFS, which in turn allows a significant increase in OS. There are other terms used to describe clinical responses but these are the most common. We will start with some of the most recent data, and see where that takes us.

Part 1: Immune Checkpoint Combination Treatment of Melanoma 

The very first trials of PD-1 pathway inhibitors began with the investigation of nivolumab in metastatic melanoma. As such, there was an impressive amount of progress reported and we now have mature data on different therapeutics. To set the stage, we can consider the benefit shown by nivolumab monotherapy compared to standard of care treatment protocols, and also to ipilimumab (brand name Vervoy) an anti-CTLA4 antibody, also from Bristol-Myers Squibb (BMY). Ipilimumab is approved for the treatment of metastatic melanoma based on Phase 3 clinical trial data in metastatic melanoma patients that had failed prior therapy (a chemotherapy regimen). The trial compared ipilimumab to a tumor vaccine targeting the melanoma antigen gp100. Ipilimumab treatment improved median OS to 10 months versus 6 months with the vaccine treatment (which was no better than standard of care). The 1 year survival rate was 45%. ORR however was low, just about 10%. Also, adverse events (AEs) were a problem, and included autoimmune manifestations (colitis, pituitary inflammation) and some treatment-related deaths (2% of patients). In a separate study of treatment-naive metastatic melanoma patients, ipilimumab therapy was associated with an OS = 11.2 months and a 1 year survival rate of 47%, falling to 21% by year 3. Patients were given ipilimumab or placebo plus chemotherapy (dacarbazine), and then moved to ipilimumab or placebo alone if there was a response measured or if the initial therapy caused toxicity. One consequence of this scheme was that AEs went up dramatically, with 38% of patients experiencing an immune related, grade 3 or 4 severe AE (SAE). We dwell on the anti-CTLA4 antibody ipilimumab because it is the benchmark for other immunotherapies such as nivolumab.

Nivolumab therapy for advanced melanoma has produced impressive data, with median OS = nearly 17 months, and 1 and 2-year survival rates of 62% and 43%. ORR was 33%. AEs were significant if less severe than those seen with ipilimumab. Grade 3-4 treatment-related AEs were seen in 22% of nivolumab-treated patients. Immune-related adverse events (all grades) were seen in 54% of treated patients, and included skin, GI and endocrine disorders. However only 5% of patients experienced immune-related SAEs of grade 3 or 4 and there were no drug-related deaths. These data from Topalian, Sznol et al. from John Hopkins University School of Medicine were presented at ASCO last year and published earlier this year                       (

So with that as our backdrop lets update the state of PD-1 pathway antagonism in melanoma. One of the obvious next steps in the development of immunotherapy is to combine treatments and we saw dramatic long-term data from the combination trial of ipilimumab plus nivolumab in advanced melanoma. Early trial results presented at ASCO last year introduced 4 cohorts of patients given different doses of nivolumab and ipilimumab in combination, with an ORR across all four cohorts of 40% and a 1 year survival rate of 82%. Median OS had not been reached. SAE rate across the 4 cohorts was 53%. This quickly gets complicated so let’s define the cohorts. Numbers are doses of nivolumab and ipilimumab, respectively, in mg/kg: Cohort 1 (0.3 + 3), Cohort 2 (1 + 3), Cohort 3 (3 + 1), Cohort 4 (3 + 3). No data were presented for Cohorts 6 and 7 so we’ll skip those. Cohort 8 is designed to mimic the dose schedule chosen for later clinical trials.

Note that after the induction phase, patients are moved onto maintenance therapy, as show below.

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The slide is taken from the trial update presented at ASCO by Dr Sznol (Abstract #LBA9003). The data updates drove home several critical points. First, at the optimal dose rates of 1 + 3 and 3 + 1 the ORR ranged from 43-53%. The author’s introduce a new classification of clinical response to capture the observation that many patients are experiencing benefit while not strictly meeting RECIST1.1 criteria, this is termed “Aggregate Clinical Activity Rate” and reaches 81-83% in Cohorts 3 and 4 (note that Cohort 4 (3 + 3) was the maximum tolerated dose due to SAEs and will no longer be used). Perhaps more meaningfully, the percent of patients whose tumor burden was reduced by > 80% at 36 weeks was 42% across the cohorts. This is a remarkable number suggesting sustained clinical benefit. Indeed, in those patients who responded, the median DOR in Cohorts 1-3 plus Cohort 8 has not been reached. In Cohorts 1-3, 18/22 patients are still responding and 7 of those had discontinued therapy due to AEs (more on this below).

Dose cohorts were analyzed for impact on 1 and 2 year survival. In Cohorts 2-3 the 1 year OS = 94% and the 2 year OS = 88%. Most stunning of all was this data showing a median OS in Cohorts 1-3 of 40 months. Median OS in Cohort 3 (1 + 3) has not yet been reached.

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These data are best-in-class for treating advanced melanoma, and place ipilimumab plus nivolumab at the forefront of therapeutic options for these patients. The one outstanding issue remains that of toxicity. 23% of patients had to discontinue therapy due to toxicity, and one patient died of complications resulting from treatment. While Dr Sznol repeatedly pointed out that the toxicities observed are controlled by standard interventions, the problem is that these standard interventions include cessation of therapy. We have already learned from the ipilizumab experience that responses to immune checkpoint inhibition can take time, and for those patients who have to stop treatment after 1 – 2 doses due to toxicity, time may not be kind. It will certainly be beneficial to reduce SAEs so that more patients can remain on therapy.

Tomorrow we’ll look at other PD-1 pathway therapeutics and combinations in melanoma before moving on to other tumor types.