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Redefining Success and Failure in Cancer Immunotherapy Trials

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Immunotherapy Forum Video #30: Immunotherapy for cancer has rewritten the rules for what we consider a successful response to treatment. Some tumors grow before they regress. Dr. Jedd Wolchok discusses why a new measurement criteria was developed.


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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.


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Questions & Answers with Drs. Topalian and Wolchok about Immunotherapy for Melanoma

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Immunotherapy Forum Video #18: Drs. Topalian and Wolchok sat for a moderated Q&A with Dr. Louise Perkins from the Melanoma Research Alliance following their presentations on immunotherapy for melanoma.


Dr West

EGFR Inhibitor Combination Tested in Advanced NSCLC

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As I’ve described in various posts about targeting the epidermal growth factor receptor (EGFR), one of the main signals that is important in many lung cancers, there are agents like gefitinib (iressa) and erlotinib (tarceva) that target the internal switch that triggers activity inside the cell, and there are agents like cetuximab (erbitux) that work on the external front end receptor to block activity:

Inhibiting EGFR figure

(Click on image to enlarge)

I must admit that I’ve always been curious whether combining these two appoaches, giving an oral EGFR tyrosine kinase inhibitor (TKI) with a weekly IV EGFR monoclonal antibody would potentially provide a synergistic inhibition and impressive activity. For the first time, Ramalingam and colleagues have published their limited experience of combining iressa and erbitux in a small trial of patients with advanced NSCLC (abstract here). Unfortunately, the results don’t look particularly impressive.

My friend Dr. Ramalingam has just recently moved from Pittsburgh to head the lung cancer program at Emory University in Atlanta, but while at the University of Pittsburgh he and colleagues there conducted this study to assess the safety and get a sense of the activity of a combination of iressa with erbitux. Iressa, the first EGFR TKI approved for NSCLC, was studied at the previously approved standard dose of 250 mg daily (subsequently found to not be significantly superior to placebo in a large trial of previously treated patients with advanced NSCLC and taken off the market). Erbitux was given at increasing doses, starting at a rather low dose and escalating to a point of maximum safe/tolerable dose for the combination. For these “phase I” trials of safety, small numbers of patients are usually enrolled. This study included 13 patients who had received at least one prior chemo regimen for advanced NSCLC.

Although the numbers were small, there were no responses seen, and only 4 patients (31%) even showed stable disease. Progression was pretty quick, and 3 patients developed severe declines in blood magnesium levels, which is a known side effect of erbitux, but this was a high rate.

The investigators also tried to do some molecular studies from the subset of 10 patients who had some tissue to work with. They didn’t find any EGFR mutations that would be expected to be associated with robust EGFR TKI responses. They also did not detect any RAS mutations that are generally recognized as being very unlikely to show a response on EGFR TKIs.

There are many reasons why this little study is far from the definitive word on the subect. Iressa at the dose tested is not as effective as tarceva, so perhaps the results would have been more favorable with tarceva. Perhaps these results just happen to be particularly disappointing in a small number of patients who happened to not benefit, but a larger study would have shown better results that represent reality better. Or maybe this combination isn’t particularly useful in a general population but could be very impressive in a more selected population, based on EGFR mutations or never-smoker status. I’ve also wondered whether adding erbitux to tarceva in a patient who has now become resistant to tarceva after a prior good response would restore activity. But we don’t have any evidence on any of these questions.

For now, I think all we can say is that a combination of EGFR TKI and monoclonal antibody doesn’t lead to blockbuster activity in NSCLC. But expect to see a lot more trials of targeted agents in coming years.


Dr West

Recent Results with Talactoferrin: Reason to Move Forward

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As I described in part I of this subject (last post here), lactoferrin is an immunostimulatory protein that is found in highest concentrations in breast milk (hence the name), and the recombinant form talactoferrin alfa (TLF) was combined with chemo in a randomized phase II study of front line advanced NSCLC in which the combination was associated with an impressively higher response rate than chemo alone. The rate of side effects was also significantly lower among the patients who had TLF added instead of a placebo. While these results are promising, the agent made relatively little splash in the lung community, generating little attention from the poster presentation of this work in 2006. But this was just a phase II trial with 110 patients, so it’s reasonable to hope for corroborating evidence of benefit before believing these results are more than a fluke. In 2007, another randomized phase II trial of TLF vs. placebo, now as single agents, was reported that supported the findings from the first line trial, this trial with overall survival as the primary endpoint.

The trial presented last year by Parikh and colleagues from several centers in India enrolled 100 advanced NSCLC patients who had previously received either one line (about 3/4 of patients) or two lines (about 1/4 of patients) of prior systemic therapy, who were randomized to receive oral TLF or placebo (ASCO abstract here, subsequent World Conference on Lung Cancer abstract here). Treatment with this oral agent was twice daily for twelve weeks, followed by two weeks off, for a total “cycle” of a rather unconventional 14 weeks. Repeat CT scans were done about 7 weeks into the treatment, with a total of 81 of the original 100 patients getting that follow-up scan and considered evaluable.

So what happened? As shown in the figure below, overall survival was significantly higher in the recipients of TLF, whether you look at the median survival an “intent to treat (IIT)” analysis of everyone enrolled (whether you received enough treatment to be re-scanned seven weeks later), the 81 patients who were evaluable. In addition to median survival, six month survival was significantly greater for TLF recipients by both an IIT analysis and looking at just the evaluable patients:

Parikh OS rand ph II bars

(Click on image to enlarge) Continue reading


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