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:

(click on image to enlarge)

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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:

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To many outside of oncology, thalidomide is primarily known for causing severe birth defects in women who received it in the 1960s as a sedative and treatment for morning sickness. These birth defects, in which babies were born with no arms or legs but with hands and feet directly attached to their trunks, was likely related to the anti-angiogenic (blood vessel blocking) effects of thalidomide. Over the last several years, however, its anti-angiogenic activity has been employed as an oral treatment for some cancers, and it is an approved treatment for multiple myeloma and has been studied in several other cancer settings, including lung cancer. Specifically, one of the settings in which thalidomide has been the subject of several studies has been extensive disease small cell lung cancer (ED-SCLC), as small cell is a blood vessel rich tumor that has been suspected to be potentially vulnerable to anti-angiogenic drugs (for instance, I covered some early work with Avastin in SCLC in a prior post). In addition, thalidomide appears to have immunostimulatory activity in lab-based work, and this may also contribute to potential anticancer activity.

A friend of mine, Dr. Afshin Dowlati at Case Western Reserve University in Cleveland, recently published on his group’s experience giving thalidomide to patients as a maintenance therapy after initial chemotherapy (abstract here). They enrolled 30 patients who had received 4-6 cycles of initial chemotherapy, which was not specified, who had achieved either a complete or partial response, or else stable disease. (In other words, they enrolled patients who did not demonstrate progression on chemo, which we don’t expect to see after first-line treatment of ED-SCLC.) After 3-6 weeks off of treatment, a total of 30 patients received thalidomide at 200 mg by mouth every evening, with a primary goal of the study to determine the one-year overall survival and overall tolerability of this treatment. Recall that there is no established benefit for maintenance therapy after initial chemotherapy for ED-SCLC (see my prior post on the topic), but we continue to study it because we know that ED-SCLC is often responsive early and then tends to be much more resistant when it returns. The idea of postponing that recurrence with a manageable oral therapy is very appealing, but we still haven’t seen a significant survival benefit despite the compelling rationale behind it. With only 30 patients enrolled, Dr. Dowlati wasn’t going to establish anything definitive, but he did demonstrate that it was a feasible treatment. Patients stayed on thalidomide for a median of 2.4 months, or 79 days. The median survival was pretty encouraging at 12.8 months, and the one-year survival was 52%. The leading side effects were peripheral neuropathy (numbness and tingling in the longest nerves of the body, affecting the fingers and toes, primarily) in about 30%, and constipation in 16% of patients, despite a bowel regimen that was started on everyone at the time of starting thalidomide. The investigators considered the results encouraging enough to warrant further study. Read the rest of this entry »

First, I want to thank members Jim (dadawg001) and Neil (neilb) for bringing up this topic in the Discussion/Q&A Forum yesterday. Amazingly, yesterday morning I happened to be reviewing slides in my collection on a novel agent and approach that I thought would make a good topic for a post here: the drug DMXAA, which is a “vascular disrupting agent”. Later that same day, Jim raised a question about a new agent, ASA404, which had promising results reported in a press release by its manufacturer, Antisoma, based in London. I noted that I was unfamiliar with the agent, which was only partly true. In fact, it has been known previously as AS1404 and DMXAA, so even though I was thinking about this agent for reasons other than the press release (which I’ll get to), we were all circling around the same drug yesterday. Definitely worthy of a full discusison now. (Antisoma also needs to work on it’s brand identity so that people can actually figure out that ASA404 is AS1404 and also DMXAA.)

Anti-angiogenic drugs like Avastin (bevacizumab) are felt to work largely by causing regression of new blood vessels to tumors as well as inhibition of a new blood supply to a tumor that would otherwise be growing and is now limited by an inability to receive nutrients and oxygen and also to dispose of waste products. In contrast, ASA404 is a vascular disrupting agent that works directly on the endothelial (blood vessel inner wall) cells to cause apoptosis (programmed cell death). In addition, it causes release of the glycoprotein Von Willebrand factor in blood that can lead to clotting of blood vessels (potentially a good feature, also potentially bad) and also a cascade of cytokines, basically proteins with hormonal activities that often contribte to making people with cancer feel terrrible, such as tumor necrosis factor, another focus of cancer treatment modalities. The end result is that this agent can cause the breakdown of existing (not just newly forming) blood vessels and destruction of cancer cells.

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A few new agents emerged from the ASCO 2007 meeting as very real potential players in lung cancer. Probably at the lead of that list, in my opinion, was axitinib (AG-013736, now a Pfizer product). Similar to agents like sunitinib and sorafenib, this is an oral agent that blocks a target called the Platelet-Derived Growth Factor Receptor (PDGFR) and also is a potent, and selective inhibitor of three different receptors in the Vascular Endothelial Growth Factor (VEGF) family: VEGFR-1, VEGFR-2, and VEGFR-3 (scientists are very clever and original with such names, as you can see). As is typical for any complex biological process, there isn’t just one ligand, the protein that fits fits the target, and a single receptor for it, but rather a family of ligands and receptors that act in a coordinated fashion to balance a mechanism like blood vessel and lymphatic channels (the vessels that move lymph, a plasma-based filtering fluid, between lymph nodes). Here’s a basic schema of the VEGF ligands and receptors (VEGFR-2 is the dominant one):

(Click to enlarge)

Axitinib connects to the intracellular, back end portion that has kinase activity, which basically means that it turns on an enzymatic signalling pathway inside the cell with multiple activities, which in this case ultimately promote blood vessel production that can benefit a growing tumor. Like lots of promising drugs, it inhibits cancer cells in test tube and animal models, but more encouragingly, it’s been studied and looks like it has anti-cancer activity human patients with kidney cancers and some other oncology settings. This year, Dr. Joan Schiller, who heads the oncology program at the University of Texas-Southwestern Medical Center and also chairs the ECOG Lung Cancer Committee, presented results of axitinib as a single agent in previously treated patients with advanced NSCLC (abstract here). Read the rest of this entry »

While there have been studies of the COX-2 inhibitor celebrex in combination with chemo for treating NSCLC, the palpable buzz about celebrex in treating lung cancer has been from a trial by my friend Karen Reckamp, formerly at UCLA, now recently moved to City of Hope Cancer Center in nearby Duarte, CA. Several studies have shown that EGFR expression is associated with increased cell growth, increased angiogenesis, increased tissue invasion and metastasis, and a worse survival compared with patients who have tumors that don’t overexpress EGFR. And as I wrote in my introductory post on COX-2 inhibition, high expression of this enzyme can also lead to worse patient outcomes among folks with NSCLC (COX-2 actually hasn’t been shown to be expressed significantly in SCLC). In fact, these two pathways interact to regulate cell proliferation, migration, and invasion (reference article here).

(complex, isn’t it? Click to enlarge — but it won’t help, unless you’ve got a PhD in biochemistry)

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