Sunitinib (SU11248), with the marketing name Sutent, is another multikinase inhibitor, an oral agent that blocks several potentially important anticancer targets in the cell with one drug.  This drug is FDA-approved in treating advanced kidney cancer and also a cancer called GastroIntestinal Stromal Tumor (GIST) after progression or intolerance of Gleevec (imatinib).  It inhibits the tumor blood supply by blocking the Vascular Endothelial Growth Factor (VEGF) Receptor family, and it can inhibit cancer cell growth by blocking a target called Platelet-Derived Growth Factor (PDGF) Receptor, as well as some other growth signal targets:

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We know that greater expression of both VEGF and PDGF by cancers are associated with worse survival.  In fact, you can see the remarkable difference in survival for patients in a European study of 120 stage I patients who underwent surgery and then had their tumors stained for VEGF expression and the functional correlate of it, microvessel density (the density of small blood vessels in the tumor, which are induced by VEGF), divided into levels above or below the median (half-way point):

 WOW! Huge difference. This test isn’t routinely available, at least not yet.

   The first trial to test this drug in lung cancer was reported at our big ASCO meeting in June of 2006 (abstract here).  There, friend and international lung cancer expert Dr. Mark Socinski at University of North Carolina presented the results of a trial in which 63 previously treated patients with advanced NSCLC received sutent at 50 mg by mouth every days for four weeks followed by a two week break, for a six week cycle, until progression or toxicity problems.  These patients had received at least one prior chemo regimen (some many more than that) and could have received prior EGFR inhibitors.  Patients with recent surgery or chest radiation, a history of significant bleeding, or brain metastases were not eligible, due to concerns for significant and potentially fatal bleeding complications similar to those seen occasionally with avastin.  Importantly, the trial did allow patients with squamous cell NSCLC, unlike most avastin trials.  Among the patients enrolled from the 10 centers (including some the US and some in Europe), 43% received sutent as their second therapy, 44% as their third therapy, and 13% as their fourth or later therapy; 33% had received prior EGFR inhibitors. 

   The study was designed to see if sutent would lead to encouraging single-agent activity, and it did show an impressive 9.5% response rate (all partial responses).   This compares favorably to the response rate for our other agents approved for previously treated NSCLC (taxotere, alimta, and tarceva), which all show response rates in the high single digits in larger studies (often in less heavily pretreated patients). Importantly, the “waterfall curve” that shows the degree of overall tumor shinkage regardless of whether a patient met the specific criteria for a response (there are some very particular rules, including a need for the shrinkage to be verified with a later scan, which isn’t always done), shows that the majority of people on the trial had at least modest tumor shrinkage (bar goes down instead of up, which means overall growth):

Treatment lasted an average of 12 weeks before progression or toxicity (side effect) problems, with a few patients continuing for many months beyond that.

   So there’s clearly some promise with sutent, with a response rate as good as anything we’ve studied in previously treated patients, and a majority of patients showing some degree of tumor shrinkage.  However, the side effects of this approach were challenging.   About a quarter of patients required dose interruption, 21% required a dose reduction, and a striking 38% came off of sutent not because of progression but because of serious side effects.  And what were those side effects?   In order of frequency of more severe problems, they were profound fatigue, aches and pains, nausea/vomiting, mouth sores, and shortness of breath, with less frequent but sometimes severe high blood pressure also seen.  The more complete lists are here:

  Unfortunately, there was one more thing… the bleeding deaths.  It does appear that the antiangiogenic drugs as a class, and not just avastin, have an increased risk of life-threatening or fatal bleeding. On this trial, three patients died on the trial, and two of them had squamous cancers (although only 22% of the patients on the trial had squamous cell NSCLC), while the third was a patient with an adenocarcinoma that spread to the brain and had a bleeding episode from that brain metastasis.  So it appears that it would be a mistake to reassure ourselves that we can treat a broader population with sutent than the avastin-eligible population.  At least that’s my interpretation of what we know thus far.

  Unfortunately, Pfizer, the company that makes and markets sutent, has been somewhat slow out of the gate in developing new opportunities with sutent in lung cancer.  One randomized phase II trial is comparing sutent + tarceva to tarceva alone in the second-line setting for advanced NSCLC.  A single-arm phase II trial, not yet open, is specifically assessing the safety of sutent in patients with brain metastases.  And at my own institution, the institutional review board is discussing and hopefully approving a trial this very week that I’m leading, for patients with either bronchioloalveolar carcinoma (BAC) or a history of never smoking and no brain metastases.  These patients, who would be expected to have a low risk of bleeding complications, will receive single-agent sutent until they show progression or significant side effect problems that require stopping the drug.

   With these early studies and what I am sure will be several more still being developed to evaluate sutent in many settings for both non-small cell and small cell lung cancer in the near future, we should be able to clarify whether sutent’s early promising activity exceeds the side effect concerns enough to be added to our arsenal of treatment options for lung cancer.