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The Future of Cancer Immunotherapy: Combination Treatments

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Immunotherapy Forum Video #29: In part 2 of 2, Dr. Jason Luke discusses treating cancer with immunotherapy and another drug, such chemotherapy or targeted therapies, as well as what we know about biomarkers that predict if an immunotherapeutic will work.


GRACE Video

The Right Time for Cancer Immunotherapy: Before or After Surgery?

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Immunotherapy Forum Video #28: Doctors are still weighing the pros and cons of giving a cancer patient immunotherapy before or after resection surgery. In part 1 of 2 videos, Dr. Jason Luke details those risks and benefits.


Dr West

Is there a harm in discontinuing Avastin (bevacizumab)? The evidence says no.

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One question that has emerged with the increasing use of anti-angiogenic (blood vessel-inhibiting) therapy like Avastin (bevacizumab) for many different kinds of cancer is whether, as some lab-based research has suggested, the removal of the anti-angiogenic effect when the agent is discontinued leads to a rebound increase in pro-angiogenic signaling. If that happens, perhaps it will lead to an acceleration of the rate of progression and even potentially early death after stopping Avastin. Though it’s not part of the standard approach for managing Avastin, some physicians have patients continue Avastin after they’ve shown clear progression on it, potentially out of fear that there will be a harmful effect from stopping it. But now we’ve got some evidence that suggests this isn’t the case.

A new article just coming out in the Journal of Clinical Oncology reviewed the pooled results from five different randomized phase III trials, totaling over 4000 patients with either breast, colorectal, renal, or pancreatic cancer who received chemo or the same chemo with Avastin. The authors analyzed whether the patients who discontinued Avastin, either due to side effects or for any reason, experienced a faster time to progression and worse survival than patients who hadn’t been on Avastin.

The answer from this pooled analysis was that there was neither an earlier time to progression or worse overall survival when checked at multiple different time points after discontinuing Avastin, as shown below:

efs-for-bev-after-dc (click on image to enlarge)

mortality-after-dc-of-bev

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Dr West

Cancer Treatments with Big Benefits for Small Populations

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Earlier this week, I wrote about the very promising early work with the novel, still investigational agent crizotinib (PF-02341066) in treating the 4-5% of NSCLC patients with a tumor positive for an ALK rearrangement. For this minority of patients, the benefit was of a kind we don’t see enough in cancer and certainly not in lung cancer, with about 2/3 of patients showing a significant response in terms of tumor shrinkage, and 87% achieving at least stable disease; nearly 3 out of 4 remained on it without progression 6 months later, and many are on it now for much longer, with responses still ongoing.

These data, presented in the Plenary Session of our ASCO Annual Conference, were really not controversial, except for the question of whether crizotinib should be approved by the FDA (and potentially by other similar regulators in countries around the world) based on these overwhelmingly positive results, in a limited population. The larger studies are ongoing that I think are exceptionally likely to lead to its official FDA approval, but in the meantime, there is no question that many patients will miss the opportunity to benefit from it while it remains available in only very selected settings around the world. There will also be less awareness of the test for ALK rearrangements and the benefits of crizotinib in the appropriate target patients while it is not commercially available and marketed.

The biggest problem of all, though, is that having a very effective treatment for a limited segment of the population creates a whole new set of problems that we’ll see more and more. In many ways, we are fortunate to have found the right target for the right targeted therapy here. If crizotinib had been tested in a broad NSCLC population, as is the ritual default paradigm for our treatments, it would likely be just one more drug with a 3-4% response rate that would be discarded rather than progressing through additional clinical testing. How many other crizotinibs are there that just haven’t had their appropriate targets identified and remain undeveloped by a drug company because they appear to be minimally active in an overly broad population? We should also remember that many, many agents have now been tested in too broad a population and had safety problems. Many of the anti-angiogenic agents have been shown to have increased mortality compared with placebo in patients with squamous NSCLC; in fact, it’s easy to imagine that Avastin (bevacizumab) would be tainted as the drug that regularly kills people by hemoptysis if investigators hadn’t identified the problem early in its development in lung cancer (as reviewed in this post) and excluded patients with squamous NSCLC in the larger phase III studies that led to its ultimate approval.

But we should also be concerned that pharmaceutical and biotech companies will do the calculations of offering treatment to a smaller population and find that it isn’t worth their costs and efforts to pursue therapies for a small subset of patients. Here is one of the first slides from Dr. Pennell’s excellent podcast on molecular therapies for NSCLC, showing that until 10 years ago, NSCLC was essentially viewed as one entity with a market of 60-70,000 patients with advanced disease (and smaller numbers with other stages as well) in the US each year:

lc-classification-1900-2000 (click on image to enlarge)

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Dr West

High Blood Pressure and Anti-Angiogenic Therapy: A Beneficial Side Effect?

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One of the most common side effects of many different anti-angiogenic agents, which are felt to decrease the tumor’s blood supply, is high blood pressure, also known as hypertension. The cause of this isn’t really known, but most patients develop some degree of high blood pressure. What is interesting is that there is growing evidence that this may not just be an unwanted side effect, but rather a marker of a probability of doing better, similar to the correlation of rash with longer survival in patients receiving EGFR inhibitors.

For this, we can start by looking at results from a recent study of the anti-angiogenic agent sorafenib (nexavar) in renal cell carcinoma (kidney cancer). Here, patients were classified according to whether they demonstrated evidence of a high blood pressure, which was defined as a systolic blood pressure (the higher number) of 140 or greater, and/or a diastolic blood pressure (the lower number) of 90 or greater over the course of their treatment with sorafenib. The 441 of 534 (83%) who had hypertension had a remarkably higher response rate (54% vs. 10%, p < 0.0001), and a significantly longer median progression-free survival (12.5 vs. 2.5 months, p < 0.0001) and median overall survival (30.5 vs. 7.8 months, p < 0.0001) than the patients with advanced RCC who didn’t have hypertension on the study:

motzer-rcc-and-htn

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