Tag Archives: clincial trial crizotinib targeting ROS1

A new mutation on the block: ROS1

There is a newly identified oncogenic mutation in NSCLC, ROS1. Although present in but a small percentage of patients, its discovery represents an additional breakthrough in understanding what ‘drives’ individual cancers. Better yet, crizotinib (Xalkori) would appear to be a potent inhibitor of ROS1.

My friend Craig, who, if he wasn’t so busy being a lung cancer patient would make a fine medical researcher, has the ROS1 mutation and is a veritable encyclopedia of knowledge on all things ROS1. Craig has made it his mission to educate as many people as possible on the importance of being tested for ROS1 in the absence of other identifiable mutations, with numerous postings on both INSPIRE and GRACE. I asked Craig if he would be willing to recant his experience yet again, and he has obliged with an information filled guest blog. Should you have any questions about ROS1, I am certain Craig would be happy to respond.


“The first mutation-targeted miracle drug Linnea successfully used was Xalkori (crizotinib). Crizotinib was remarkable because it was a designer drug, not just a discovery, originally designed to inhibit a lung cancer “driving mutation” called c-MET, but it soon became apparent that it worked dramatically well for ALK-driven cancer. Well, back in January 2012 research was finally published by my favorite superdoc Dr. Alice Shaw and her colleagues at MGH showing that crizotinib seemed to have a similarly dramatic effect on ROS1-driven cancer, a mutation that occurs in about 1% or so of non-small cell lung cancers (NSCLC) vs. about 4% for ALK.

I want to bring you up to speed on this second breakthrough discovery about Xalkori (crizotinib). That January article (http://www.ncbi.nlm.nih.gov/pubmed/22215748) described pre-clinical laboratory research and a dramatic near-complete response in one patient. That work was from last year and in the meanwhile Pfizer’s phase 1 trial of crizotinib for ALK was expanded to add patients with cancer driven by ROS1.

By April 2012 fourteen ROS1 patients were enrolled in that trial and Dr. Shaw presented some data results for them at the ASCO conference early this month. (That ASCO conference is the big annual 5-day event for over 30,000 oncologists and cancer experts where they showcase their research in presentations, educational sessions, and a science fair-like exhibition hall with about 500 exhibitor experiment posters at a time that change each morning and evening.)

As you can see in the graph shown in the article at http://chicago2012.asco.org/ASCODailyNews/Abstract7508.aspx , the responses of the patients to crizotinib was pretty dramatic. In fact, every ROS1 patient had some benefit from the drug, not counting one patient whose test result was ambiguous and probably didn’t really have the ROS1 rearrangement mutation, and one who had to drop out early due to a bowel problem but later had 60% shrinkage from crizotinib. A drug that benefits 100% of patients (including me) is truly remarkable in oncology research. We’ll have to wait to find more of those rare ROS1 patients before we can know if this success rate will hold up and before we’ll know if the duration of benefit is similar to that for ALK or longer.

What is ROS1? It’s a gene that makes a receptor tyrosine kinase (RTK) type of protein which sits on the surface of a cell like a hairpin with the points stuck through to the inside. When certain chemicals come in contact with it this RTK, those points come together and align certain chemicals together inside the cells so they can react and become activated (energized or phosphorylated). That, in turn, begins a cascade of reactions that cause cell behaviors like growth and stubborn survival. In the case of a cancer-causing ROS1 rearrangement, the RTK is misshaped so that it runs amuck, locked into an “on” position that activates chemicals continually whenever they come near.

Fortunately, the normal ROS1 gene isn’t used much in adults, so it isn’t very harmful to try to shut it down when it runs amuck. Even though the ROS1 and ALK genes are located on different chromosomes, they are similar and the RTKs they create fold into a similar molecular shape. That is why crizotinib can inhibit both of them similarly. But they are a little different, and we don’t yet know if the differences will confirm greater odds of benefit from crizotinib, differences in shrinkage, duration, or mechanisms of resistance, or which 2nd generation drugs would work best or longest, but it does seem like they might be similar or analogous.

The first challenge for this research is finding enough ROS1 patients for the clinical trials and research, not just in lung cancer but possibly in other cancers. At about 1% or so of NSCLC, you have to pick through tons of proverbial hay to find those needles. But the odds of ROS1 improve a lot once testing has ruled out the more common driving mutations EGFR, ALK, and KRAS, especially in never-smoker adenocarcinoma. So if you know someone with NSCLC, probably adenocarcinoma in particular, who claims to not have any of the mutations, have them ask their oncologist about ROS1 testing.

I believe knowing the driving mutation of one’s cancer is very valuable. Even if there’s no drug for it yet, there could be a new discovery tomorrow morning. That’s how I felt when I asked my local oncologist where I could get further testing beyond the common ones. He recommended Dr. Shaw 250 miles away in Boston. Until then, the prospects for my kind of cancer seemed grim; I was expected to live only a couple of years or so if nothing worked, and that felt likely. But Dr. Shaw guessed I might have ROS1 and confirmed it with the reliable FISH test for ROS1. With her trial already underway, crizotinib was just waiting for me to show up. My cancer symptoms pretty much vanished within a day or so of starting the trial, my cancer shrank and became a lot less dense, the side effects have been minimal, and it’s been smooth sailing for several months so far. To other NSCLC patients who don’t have any of the more common driving mutations, I hope they will follow my example to find out if there might be a miracle drug waiting for them in Boston, too.”

Craig in PA
June 2012

Crizotinib shows promise for ROS1

XALKORI TRAILBLAZER: crizotinib inside

The cool shirt was created by my friend Craig, who wasn’t keen on modeling his handiwork. However, as Craig was kind enough to gift me with a tee, a self portrait will have to do.

Craig is enrolled in a clinical trial for crizotinib at Mass General Hospital. He does not, however, have an ALK mutation. Rather, Craig has a relatively rare ROS1 mutation. From the Massachusetts General Hospital press release:

Mass. General study defines a new genetic subtype of lung cancer

Crizotinib treatment may be able to control another subset of deadly lung tumors

BOSTON – A report from investigators at the Massachusetts General Hospital (MGH) Cancer Center has defined the role of a recently identified gene abnormality in a deadly form of lung cancer.  Tumors driven by rearrangements in the ROS1 gene represent 1 to 2 percent of non-small-cell lung cancers (NSCLC), the leading cause of cancer death in the U.S.  The researchers show that ROS1-driven tumors can be treated with crizotinib, which also inhibits the growth of tumors driven by an oncogene called ALK, and describe the remarkable response of one patient to crizotinib treatment.

“ROS1 encodes a protein that is important for cell growth and survival, and deregulation of ROS1 through chromosomal rearrangement drives the growth of tumors,” says Alice Shaw, MD, PhD, of the MGH Cancer Center – co-lead author of the paper which has been published online in the Journal of Clinical Oncology.  “This finding is important because we have drugs that inhibit ROS1 and could lead to the sort of dramatic clinical response we describe in this paper.”

The current findings add ROS1 to the list of genes known to drive NSCLC growth when altered – a list that includes KRAS, mutations of which account for about 25 percent of cases; EGFR, accounting for 10 to 15 percent; and ALK, rearranged in about 4 percent.  Altogether, known cancer-causing genetic changes have been found in a little more than half of NSCLC tumors.  Originally identified in brain tumors, ROS1 rearrangement previously had been identified in one NSCLC patient and one NSCLC cell line.  The current study was designed to determine the frequency of ROS1 rearrangement in NSCLC and to define the characteristics of patients with ROS1-rearranged tumors.

The investigators screened tumor samples from more than 1,000 NSCLC patients treated at the MGH, Vanderbilt University, the University of California at Irvine, and Fudan University in Shanghai, China.  ROS1 rearrangement was identified in 18 tumor samples, for a prevalence of 1.7 percent; ALK rearrangements were identified in 31 samples, with no samples showing alterations in both genes.  Patients with ROS1-positive tumors tended to be younger, never to have smoked and to have a type of lung cancer called adenocarcinoma – characteristics very similar to those of ALK-positive patients.

An earlier MGH study of an experimental ALK inhibitor had found the drug suppressed the growth of a ROS1-positive cell line in addition to ALK-positive cell lines, suggesting that ROS1-positive tumors might be sensitive to the ALK-inhibitor crizotinib.  This observation led corresponding author John Iafrate, MD, PhD, and his team to develop a diagnostic test that could identify ROS1-positive tumors.  Around the time that test became clinically available, a lung cancer patient whose tumor had not responded to drugs targeting EGFR mutations was referred to the MGH Cancer Center for genetic testing.  His tumor was negative for ALK but later proved to harbor a ROS1 rearrangement, and he was enrolled in an extension of the crizotinib clinical trial first reported in the October 28, 2010, New England Journal of Medicine.

“When he enrolled in the trial last April, this patient was extremely sick – with significant weight loss and very low oxygen levels – and was barely able to walk,” says Shaw.  “Within a few days of starting crizotinib, he felt better; and by the time we scanned his chest at seven weeks, the tumors had essentially disappeared from his lungs.”  Nine months after starting crizotinib therapy, this patient continues to do well.  Additional ROS1-positive patients have been enrolled in this trial at MGH, at UC Irvine and at the University of Colorado.

Shaw is an assistant professor of Medicine and Iafrate is an associate professor of Pathology at Harvard Medical School. Co-lead authors are Kristin Bergethon, MGH Pathology, and Sai-Hong Ignatius Ou, MD, PhD, University of California at Irvine.  The study was supported by grants from the National Institutes of Health and from Pfizer, which received FDA approval for crizotinib in August 2011.

Additional co-authors are Ryohei Katayama, Eugene Mark, Julie Batten, Eunice Kwak, Jeffrey Clark, Jeffrey Engelman, and Mari Mino Kenudson, MGH Cancer Center; Christina Siwak-Tapp, University of California at Irvine; Keith D. Wilner, Pfizer; Christine Lovly, Nerina McDonald, Pierre Massion, Adriana Gonzalez, David Carbone, and William Pao, Vanderbilt University Medical Center; Pierre Massion, Nashville Veterans Affairs Medical Center; Rong Fang and Hongbin Ji, Shanghai Institutes for Biological Sciences; and Haiquan Chen, Shanghai Medical College, Fudan University.

Massachusetts General Hospital (www.massgeneral.org), founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $750 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine.


So, for those of us with NSCLC, this is just another missing piece in the puzzle found. For my oncologist Dr. Alice Shaw and her partners, yet another exciting development in ongoing research. And for people like my buddy Craig, a life extending treatment with relatively few side effects. Fabulous news all the way around.