Just 15 months after Ret proto-oncogene fusions were first identified in 1%-2% of non-small cell lung cancer cases, early data from a Phase II trial of Exelixis Inc.'s Cometriq cabozantinib suggest that blocking the target could be effective in this patient population.1 At least four additional investigator-initiated trials are seeking to test marketed Ret proto-oncogene inhibitors in fusion-positive lung cancer.

In addition, at least seven clinical trials are testing compounds that inhibit other recently identified oncogenic drivers of lung cancer, including amplifications or mutations in fibroblast growth factor receptors (FGFRs) and mutations in discoidin domain receptor tyrosine kinase 2 (DDR2 (see "Selected new targeted therapies in lung cancer" and Box 1, "Squamous smorgasbord").

The rapid move to the clinic validates the prediction made by clinicians and industry researchers that the identification of new oncogenic drivers of lung cancer would spur the development of targeted therapies for new subsets of patients.2-5

In late 2011 and early 2012, four independent teams reported the expression of a KIF5B-RET oncogenic fusion protein in non-small cell lung cancer (NSCLC) patient samples and showed that the protein was necessary and sufficient to drive unchecked cellular proliferation.6-9 This drew immediate comparisons to the 2007 identification of the EML4-ALK oncogenic fusion protein, which drives about 5% of NSCLC cases.10

A key difference is that when EML4-ALK was discovered, there were no marketed anaplastic lymphoma kinase (ALK) inhibitors. Pfizer Inc.'s Xalkori crizotinib, a dual inhibitor of c-Met receptor tyrosine kinase and ALK and their oncogenic variants, entered the clinic in 2006 and was approved in August 2011 to treat ALK fusion-positive lung cancer.4

In contrast, Ret proto-oncogene (RET) kinase is inhibited by multiple marketed nonspecific tyrosine kinase inhibitors, including Cometriq, Nexavar sorafenib, Sutent sunitinib, Caprelsa vandetanib and Iclusig ponatinib.

Cometriq is marketed by Exelixis to treat medullary thyroid cancer (MTC). Nexavar is marketed by Onyx Pharmaceuticals Inc. and Bayer AG to treat liver and renal cancers. Sutent is marketed by Pfizer to treat gastrointestinal stromal tumors (GISTs) and advanced renal cell carcinoma (RCC). Caprelsa is marketed by AstraZeneca plc to treat MTC. Iclusig is marketed by Ariad Pharmaceuticals Inc. to treat certain refractory leukemias.

Naiyer Rizvi, a medical oncologist at Memorial Sloan-Kettering Cancer Center, told SciBX that the availability of these inhibitors made it possible to immediately test whether inhibiting RET would have clinical benefit in patients with RET fusion-positive lung cancer.

"The stars aligned to allow us to move this forward so quickly. When the RET fusion was first reported in December 2011, we saw that it fit the profile of other oncogenes that have been described in lung cancer in that it is a tyrosine kinase fusion in patients who have never smoked. We were in a lucky position where there was a drug available that targets VEGF and c-Met but also targets RET, so we contacted Exelixis and they provided us with the compound," he said.

Rizvi started a Phase II trial of Cometriq at Memorial Sloan-Kettering in July 2012. As of this month, the trial has enrolled 4 patients of a planned 25. He said Exelixis has agreed to provide undisclosed funding for the trial.

In data published in March in Cancer Discovery, Rizvi reported that 2 of the first 3 patients enrolled had confirmed partial responses to Cometriq, with a 66% decrease in measurable disease in one patient and a 32% decrease in the other. Both patients have remained progression free on treatment for 4-5 months.

The third patient has had stable disease for eight months on treatment. The fourth patient just started treatment and is too early to evaluate.

Alice Shaw, assistant professor of medicine at Harvard Medical School and a thoracic oncologist at Massachusetts General Hospital, said these results are comparable to other targeted lung cancer therapies and noted that Xalkori has a response rate of about 60% in ALK-positive lung cancer.

"This is what we would have expected to see in an oncogene-addicted cancer-the preclinical data would predict that patients should be sensitive to a RET inhibitor. We know cabozantinib is a very good RET inhibitor, so it was a very logical step to identify these patients, test an available inhibitor and see a response," she said.

She compared the frequency of RET mutations to rearrangements of c-ros proto-oncogene 1 receptor tyrosine kinase (ROS1), a tyrosine kinase related to ALK, which are found in 1%-2% of NSCLC cases and predict response to ALK inhibitors including Xalkori. The fusion was first found in lung cancer in 2007, but its prevalence has become more widely appreciated in the last few years as more lung cancer samples have been genetically characterized.

Rizvi said the preliminary result was "sufficiently encouraging to expand the trial to be conducted as a multicenter study as part of the Lung Cancer Mutation Consortium." The consortium is a National Cancer Institute initiative to prospectively examine NSCLC samples from patients and match them to appropriate therapies. It involves 16 cancer centers.

Rizvi said it was reassuring to see the clinical responses because other RET inhibitors were discontinued in lung cancer after poor clinical trial results. For example, Caprelsa missed its primary endpoint in two out of three Phase III lung cancer trials. The trials were completed before the fusion had been identified.

"These data speak to the importance of molecular characterization of NSCLC and identification of appropriate subsets for targeted therapy," said Rizvi.

James Vasselli, director of clinical research at AstraZeneca, said the company has conducted a retrospective analysis on lung tumor samples from previous vandetanib trials in NSCLC and has submitted an abstract to the American Society of Clinical Oncology. Results were not disclosed.

Gisela Schwab, EVP and CMO of Exelixis, said that based on Rizvi's early results, the company is designing its own trial of Cometriq in RET fusion-positive lung cancer.

"We're continuing the support of this study, but we are also evaluating and are interested in starting a company-initiated trial, and we are talking to various investigators, Dr. Rizvi included," she said. "The initial signal, even if only collected in a few patients, is strong, and that is one thing to consider when developing a drug-is the effect size going to be convincing enough to make a difference for that small of a patient population."

Rizvi said it will be important to run a multicenter trial to accrue enough patients to make a convincing case for the clinical benefit of RET inhibition.

Schwab agreed. "Given the rarity of the fusion gene, in only 1%-2% of NSCLC patients, one has to screen quite a few patients," she said. "However, you can narrow down the number of patients a little bit by only screening those patients who aren't K-Ras or EGFR or ALK positive to enrich the population."

Indeed, Rizvi showed that 5 of 31 patients (16%) screened were positive for RET fusions. He attributed the enriched percentage to the prerequisite that patients had never smoked and were negative for most other known drivers of lung cancer, including mutations in epidermal growth factor receptor (EGFR), K-Ras, neuroblastoma Ras viral (v-Ras) oncogene (NRAS), BRAF, HER2 (EGFR2; ErbB2; neu), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit-a (PIK3CA), MAP kinase kinase 1 (MAP2K1; MEK1) and protein kinase B (PKB; PKBA; AKT; AKT1), and fusions of ALK and ROS1.

One of the five RET-positive patients had a previously unseen tripartite motif containing 33 (TRIM33)-RET fusion, whereas the other four had KIF5B-RET fusions. Foundation Medicine Inc. collaborated on screening patients for the mutations.

Schwab said even at a 1%-2% incidence, RET-positive NSCLC cases would still account for a large number of patients.

The American Cancer Society estimates that 228,190 cases of lung cancer will be diagnosed in 2013, and about 80%-85% of lung cancers are NSCLC. At the low end, that would translate to about 1,800 RET-positive patients.

RET party

In addition to Exelixis, AstraZeneca and Ariad are now supporting investigator-initiated trials of their compounds in RET fusion-positive lung cancer.

AstraZeneca is working with two groups, one based at Seoul National University Hospital in South Korea, which plans to start a Phase II study this year, and one at the National Cancer Center Hospital East in Japan, which is enrolling patients.

"Based on the six-plus published papers on RET fusions in NSCLC, key opinion leaders in the field of NSCLC and we at AstraZeneca think that inhibition of RET in NSCLC patients carrying a RET fusion in their tumors has the potential for activity in this disease, so AstraZeneca is interested in evaluating vandetanib in RET fusion-positive NSCLC," said Vasselli.

Tim Clackson, CSO and president of R&D at Ariad, said the biotech is supporting a multicenter, investigator-initiated trial of Iclusig in RET fusion-positive patients. The study will be run by Massachusetts General Hospital's Shaw.

Clackson noted that Iclusig has greater potency for RET than other marketed drugs and suggested that the structure of the drug could help combat the emergence of drug resistance.

"Our compound is two orders of magnitude more potent as a RET inhibitor than vandetanib or cabozantinib, at least in terms of IC50 in nonclinical studies," he said. "Also, by virtue of the design of the compound, we would expect Iclusig to overcome gatekeeper resistance mutations. It was designed to overcome all known resistance mutations in BCR-ABL because we built structural features into the drug that allow it to bypass gatekeeper mutations, and that ability translates to other kinases."

In research presented this week at the American Association for Cancer Research meeting in Washington, D.C., the company showed that Iclusig has an IC50 value of 0.16 nm for RET kinase and inhibits the growth of KIF5B-RET-transformed cells with an IC50 value of 11 nm. In separate studies published by Exelixis and AstraZeneca, Cometriq had an IC50 value against RET of 5.2 nm, whereas Caprelsa had an IC50 value of 100 nm.11,12

Schwab said the overall target profile of Cometriq may contribute to its efficacy in patients with RET fusion.

Rizvi and Shaw noted that resistance always arises when targeted therapies are used, and they both plan to monitor the emergence of resistance in patients receiving RET inhibitors in their trials.

Rizvi said that despite the high activity of available drugs, there could be a place in the future for more selective RET inhibitors with fewer off-target effects. Caprelsa, Cometriq and Iclusig each carry black box warnings of toxicity on their labels.

"All three patients in our cabozantinib study have had dose reductions over time for toxicity, and there is significant interest in trying to identify and test more selective inhibitors," he said.

Cain, C. SciBX 6(14); doi:10.1038/scibx.2013.326 Published online April 11, 2013


1.   Drilon, A. et al. Cancer Discov.; published online March 27, 2013; doi:10.1158/2159-8290.CD-13-0035 Contact: Naiyer A. Rizvi, Memorial Sloan-Kettering Cancer Center, New York, N.Y. e-mail: rizvin@mskcc.org

2.   Cain, C. SciBX 4(2); doi:10.1038/scibx.2011.34

3.   McCallister, E. BioCentury 19(39), A1-A4; Sept. 19, 2011

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American Association for Cancer Research, Philadelphia, Pa.

American Cancer Society, Atlanta, Ga.

American Society of Clinical Oncology, Alexandria, Va.

Ariad Pharmaceuticals Inc. (NASDAQ:ARIA), Cambridge, Mass.

AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K.

Bayer AG (Xetra:BAY), Leverkusen, Germany

Bristol-Myers Squibb Co. (NYSE:BMY), New York, N.Y.

Dana-Farber Cancer Institute, Boston, Mass.

Exelixis Inc. (NASDAQ:EXEL), South San Francisco, Calif.

Foundation Medicine Inc., Cambridge, Mass.

Harvard Medical School, Boston, Mass.

Massachusetts General Hospital, Boston, Mass.

Memorial Sloan-Kettering Cancer Center, New York, N.Y.

National Cancer Center Hospital East, Kashiwa, Japan

National Cancer Institute, Bethesda, Md.

Novartis AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland

Onyx Pharmaceuticals Inc. (NASDAQ:ONXX), South San Francisco, Calif.

Pfizer Inc. (NYSE:PFE), New York, N.Y.

Seoul National University Hospital, Seoul, South Korea

University of Cologne, Cologne, Germany