Notes from BCAN Think Tank day 3

2017 BCAN Think Tank Day 3

The day started with presentations by BCAN’s recipients of its young investigator awards: “Identifying Genomic Determinants of Chemoradiotherapy Response in Muscle-Invasive Bladder Cancer.” Kent Mouw, MD, PhD, Dana-Farber Cancer Institute, and “Role of antigen-specific immunity in BCG therapy for bladder cancer.” Niannian Ji, PhD, University of Texas Health San Antonio. These were followed by presentations by the 2017 John Quale Travel Fellows. These awards set BCAN apart from many other patient-founded cancer advocacy organizations, because they are targets to get more researchers involved in finding new therapies for bladder cancer.  

Breakout groups followed. There were a several that were of interest to me: the survivor’s working group intended to focus research on patient-centered outcomes; the presentation on restoring and enhancing sexual function after RC, chemotherapy, and other treatments for bladder cancer; a discussion of bringing precision medicine to bladder cancer therapy; and the session that Jennifer opted for, Unmet Educational and Psychosocial Needs across the Bladder Cancer Continuum. But I ended up attending the session on Novel Immuno-Combinations. The summary promised the following:

Antibodies targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis have known therapeutic activity in patients with metastatic bladder cancer. However, only a 15-25% of patients will derive clinical benefit when treated with single agent therapy. Therefore, there is an urgent need to design optimal combinations to improve patient outcomes. Discussion highlights combination approaches to improve outcomes to front-line immunotherapy regimens as well as overcome acquired mechanisms of resistance to immune checkpoint blockade.  We will provide an overview of emerging preclinical data and contextualize the current clinical trial landscape of immunocombinations in urothelial cancer.

I figured that I should learn more about what therapy options were out there if and when my current remission failed and my cancer resumed its attempt to kill me. Along those lines, Dr. Andrea Apolo told me earlier in this conference that she had just opened a three drug trial with cabo, nivo and ipi, and that it looks promising. Maybe that's for me in the future.

Dr. Hahn introduced the session with a slide how 5 new immunotherapy drugs had been approved for mets BC in the past year, and more were in the pipeline. The challenge is how we select the appropriate drug for treatment. Chemotherapy works. But we’ve got an “embarrassment of riches” of therapies and targets. His slide had 55 different targets. If we were to do a 20 patient test for each one, that’s more than 1000 patients and years of data. It’s going to be a challenge to better design trials for efficacy and translational data.

Panelist # 1: Dr. Chris Hoimes explained how the different responses of patients was based upon spatial and temporal tumor heterogeneity. A patient with resistant subclones will be less likely to respond to therapy. Patients with high tumor heterogeneity has a much higher chance of dying sooner. (Lilu et al, Abs 4512, ASCO 2017). Post-treatment genomic alterations can enable those to become the dominant clone. Paradoxically, tumors with a higher baseline mutuation or noeantigen burden experienced a greater decrease with GmeCis (Lilu et al, Abs 4518, ASCO 2016). These data can help guide our decisions on future treatment decisions.

Drawing from studies of chemo+immunotherapy in lung and breast cancers, we can deduce that such combinations may be more effective for BC patients. In May 2017, FDA approved a combination of Pembrolizumab with chemo for mets Lung cancer. We don’t know exactly why this appears to work. A large phase III trial is underway. For breast cancer, the I-SPY2 study showed that patients that got combination of pembro and paclitaxel, then AC chemo, then surgery. Even triple negative patients were having good response rates. Side effects were manageable.

Urothelial cancer combination drug studies are underway, including GemCis chemo with ipi, pembro, atezo, and other immunotherapy drugs. We need more patients and await the data.

What is the rationale for combination therapy of chemo with immunotherapy? Chemo can induce immunogenic cell death, and immunotherapy can enhance tumor control. The two together can have a synergistic effect. Cisplatin may not bring around immunogenic cell death (ICD), but instead bring TCD. We’re rather see ICD than TCD.

The tumor microenvironment and metabolism considerations tell us that lower pH in the tumor interferes with the reproduction.

Conclusion: chemo and immunotherapy might be an attractive option for bladder cancer, either as neoadjuvant or adjuvant. There might even be a role for this combination in NMIBC. (See slide 16). The variables (slide 17) need to be better understood. For example, the timing – chemo first , or immunotherapy first, or concurrent? MSKCC is looking at that. Also to be determined is whether to give the full dose, or less than the full dose of chemo. Additional concerns (slide 18) are that steroids are usually given with cisplatin, but steroids don’t pay well with immunotherapy. 

Challenge #1: How does anyone actually survive MIBC? Neoadjuvant chemo followed by surgery provides the best odds for survival. But why are there differences/ We need to better understand clonal divergence and evolutionary pressures.

Challenge #2: No nodal disease at RC, but it shows up months later. (Markowitz Science 2017, Nxerova et al, Science 2017). This reflects changes in the tumor genomic landscape post-therapy.

Challenge #3: Mets with a transient response to therapy likely reflects tumor repair mechanisms. Identifying these omic changes should reveal why this is happening.

Tumors in “deep remission” still need to be followed and understood.

Panelist #2: Dr. Charles Drake, Columbia. Pathways and possibilities for immunotherapy. PD-1/PD-L1; CTLA-4; agonist antibodies; and metabolic and TME targets (IDO+A2A), and MANA from heaven – personalize vaccines? (non-personalized vaccines have been mostly unsuccessful).

When an antigen meets a tumor, the CD8T expresses PD-1. When that happens, the CD8 T cell expresses interferon, and that kills the tumor. We’re getting a better understanding of why that doesn’t work. You need to have ongoing antigen presentation for checkpoint inhibitors to work. With no antigens present at the tumor, immunotherapy will not work.

CTLA-4 (ipi and others) can help, but it has significant adverse events. We’re studying how to make CTLA-4 more tolerable in mouse models. A depleting antibody is one idea. The idea is a combined checkpoint blockage. For example, both anti-PD1 and an LAG-3 have an 80% response rate in mice.

The second idea is using immune agonist antibodies. OX40 works in mice, but not in humans. Why? We’re working on that. There are lessons that can be applied, but I don’t understand all of the technical details. Likewise for IDO pathways.

Panelist #3: Immune-Targeted Combinations, by Prof. Bart Cowles. Ipi plus nivo isn’t significantly better than nivo alone. But both are better than ipi alone. Other immunotherapy drug combinations likewise have been mixed. We’re not seeing the spectacular results we’d like to see. But the data is still early and young, and there are lots of exciting things to study. But let’s not get ahead of ourselves. We still have not properly tested immunotherapy combinations in bladder cancer. We know that BC is molecularly heterogeneous disease, and harder to find effective agents. The triple trial of cabo with nivo and ipi looks promising. Also promising is BISCAY for MIBC (four arms Durv+AZD4547; Durva+AZD8186; Durva+Lynparza; Durva+AZD1775). A targeted triplet therapy for mets BC with chemo and two immunotherapy drugs. It sounds “bat-shit crazy”, but it’s not.

Panelist #4: Dr. Naidoo, epigenetic therapy and immunotherapy. We’ve seen this tried with lung cancer, and it has shown better results than monotherapy. But it’s not a home run. There is a theory for epigenetic priming before immunotherapy. Sometimes it appears to work. Further studies are underway.

Combination studies with nivolumab are also underway in NSCLC’s. They appear to have better results. We need to move those studies into the BC realm.

Afternoon session:

Future Targets and Therapeutic Approaches–Beyond Immunotherapy, Matt Galsky, MD, Mount Sinai Hospital. Three new drugs are being tested.

1) Enfortumab Vedotin is having a very promising response. Response rate are in the 40-60%. This is a heavily pretreated population. There is a fairly robust response for patients with liver mets, which is a hard mets to reach. It’s a quite active agent. Patients have also had reductions in bone mets. These are areas that we don’t see activity in with most other drugs. We’ve sen steep reduction in bone pain in some patients. When it works, it’s really working well. ORR is 53%. Phase II study is planned. There is also a Phase Ib study with immunotherapy.

2) ADG-15ME. Small studies have a 50% response rate. Phase II studies are planned. The manufacturer may be shutting down, so we’re not sure of longer-term availability.

3) Sacituzumab Govitecan (IMMU-132) is a pan-epithelial antibody that reaches across tumor types. Small studies have suggested promise, with an ORR of 50%. Updated data will be presented at ESMO 2017.

These antibody-drug conjugates are a type of chemo-lite. They have promising second line responses. The question everyone is asking is whether these drugs can be combined with immunotherapy. We’re testing that. We also need to learn how to use them – dose frequency, total number of doses, etc.

Peter H. O’Donnell, MD, University of Chicago Medicine. Targeting angiogenesis. History: 1985 was the first year that MVAC was reported to work on urothelial cancer. 2012 was the first year immunotherapy was reported to work in urothelial cancer. The 30 intervening years was mainly spent rearranging cytotoxic deck chairs on the Titanic. We don’t want to say that about immunotherapy in 30 years. Focusing on three targets:

ERBB2 (HER2). Breast cancer has been looking at HER2 for some time. Relatively few breast cancer patients have this mutation. By contrast, the majority of BC patients have this mutation. It’s an area that has the potential for a large benefit. Afatinib has been studied in for ERBB receptors in a phase II study. 5/6 of the patients with HER2 achieved PFS3 endpoint – they had genomic alterations, and lived longer as a result. (Choudhury et al, JHO 2016). Measuring HER2 amplification by IHC or FISH may not be determinative in response, but it is suggestive. 3+ patients response better, but 2+ patients results are mixed. So we’re seeing some promising results in HER2 therapy. Micropapillary might be especially promising. We’re trying to recruit additional patients (and institutions) for our study. The Afatunib drug needs close management since it has so many toxicities.

FGFR3. Has shown promise for advanced mets patients. 5 of 8 patients saw long-term reduction of tumor burden. Some patients have seen prolonged responses. The data is similar to immunotherapy. Janssen is bringing this drug forward for BC.

ERBB3 (HER3). We’ve also seen promising response in small studies relating to ERBB2.

Targeting angiogenesis, Arjun Balar, MD, New York University Langone Cancer Center. Sunitinib has been tested is several studies. Waterfall plots showed there is was modest response. We looked at combination studies with chemo an saw that there might be a higher response rate, but these were small phase I studies. Lilly has a positive result in the RANGE study using Cyramza.

Unanswered questions for immunotherapy: 5 drugs have been approved for second line therapy; two for first line for chemo ineligible therapy. But a minority of our patients respond. We need to do better.

Studies show that a higher VEGF level can inhibit tumor growth. Maybe we can combine VEGF blockages with immunotherapy. A phase I study combined atezo and bevacizumab was well-tolerated, had evidence of synergy, and had good responses in 4/10 patients. Beva appears to be working in the small molecular compartment. We’re preparing a Phase II of atezo+beva vs. atezo alone. Other studies have been done (e.g., Apolo et al, using cabo, ipi, nivo), and axtinib+pembro showing up to a 70% durable ORR; a phase 3 is pending.

Targeting tumor metabolism, Ubaldo Martinez-Outschoorn, MD, Thomas Jefferson University. The Warburg effect shows that the main metabolites for cancer is pyruvate. It’s an inefficient process. Why is cancer using such an inefficient process to generate ATP? There is altered tumor vascularization and relative failure of antiangiogenic therapy. Think of tumors like coral reefs – both can thrive in poor environmental conditions.