Drugs to Treat ROS1+ Cancer


” …although pemetrexed-based chemotherapy has activity in ROS1-positive NSCLC, it is almost certainly less efficacious than ROS1-targeted therapies. Taken together, the single-arm data with crizotinib, entrectinib, and now ceritinib support upfront therapy with ROS1 TKIs in patients with advanced ROS1-positive NSCLC.”
–Dagogo-Jack and Shaw, Journal of Clinical Oncology, May 2017

The drugs listed on this page are all targeted therapies, not chemotherapy. ROS1 targeted therapies go into every cell in the body and bind to the ROS1 protein (specifically, tyrosine kinase receptors), which is coded by the ROS1 gene. This protein is not active in typical adult cells, but in cells with oncogenic ROS1 fusions, the protein makes the cell act like cancer. Once the drug binds to the protein, the drug inhibits the protein’s actions in the cell, which is why these drugs are called “tyrosine kinase inhibitors,” or TKIs. Because they only inhibit cells with certain genomic alterations (instead of acting on all fast-growing cells as chemo does), TKIs tend to have fewer side effects than chemo. However, TKIs only inhibit the cancer cells, so they cannot cure it. Most all patients treated with TKIs find their cancer eventually starts to grow again because the cancer cells develop “resistance mutations.”

These drugs are in various phases of development and testing against ROS1+ cancers.  Only one (crizotinib) has received approval from some regulatory agencies for treatment of ROS1+ cancer.  However, some of the other drugs are approved for treatment of other cancers, and so may be available for purchase even though they are not approved for all ROS1+ cancers.

crizotinib (Xalkori) — Pfizer

Crizotinib is the standard of care for metastatic ROS1+ non-small cell lung cancer (NSCLC) in the USA. In clinical trials, crizotinib was shown to be effective for 70-80% of patients. Some patients achieved no evidence of disease on the drug.  The average progression-free survival was 19.2 months, and some patients have a response lasting for years. Crizotinib is effective even in patients previously treated with chemotherapy. Pfizer offers financial assistance to help pay for crizotinib for some patients. One case study suggests patients who develop certain lorlatinib resistance mutations might be resensitized to crizotinib.

Crizotinib is approved by US FDAJapan, Taiwan, and Israel, and has marketing authorization in the United Kingdom for treating ROS1+ NSCLC.  It is also available via clinical trial in other countries and for ROS1+ cancers other than NSCLC (via Clinical Trials and expanded access.

lorlatinib (PF-06463922) — Pfizer

A Phase 2 clinical trial has shown Lorlatinib (a tyrosine kinase inhibitor) is effective in the majority of ROS1+ non-small cell lung cancer patients, and treats cancer in the brain as well as the body. It has the potential to overcome certain resistance mutations that develop during treatment with crizotinib, and is well tolerated.

Lorlatinib was granted US FDA Breakthrough Therapy Designation for ALK+ NSCLC patients previously treated with TKIs on 27-Apr-2017. The status of any FDA filing for ROS1+ NSCLC is unknown.

entrectinib (RXDX-101) — Ignyta

The entrectinib STRTRK-2 trial is a basket design, which allows patients with any solid tumor to enroll if their tumor tests positive for ALK, ROS1, or TRK rearrangements.  Ignyta recently published an update on the trial and showed promising results for ROS1+ non-small cell lung cancer (NSCLC) patients who have not taken other targeted therapies, especially those patients who have brain metastases. Entrectinib is not an effective treatment for ROS1+ cancers that have progressed on crizotinib. However, patients who cancer is controlled by crizotinib in the body may enroll in the trial if they develop brain mets.

Entrectinib received US FDA Orphan Drug Designation for Treatment of Molecularly Defined Subsets of NSCLC (5-Feb-2015) and was granted breakthrough therapy designation by US FDA for NTRK fusion-positive, locally advanced or metastatic solid tumors (15-May-2017).  In its recent communication to shareholders, Ignyta indicated it is pursuing approval of entrectinib for ROS1+ cancers.

TPX-0005 — TP Therapeutics

The TPX-0005 Phase I clinical trial opened in March 2017 for patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements. This drug was designed by Dr. Jean Cui, the lead chemist for the Pfizer team that designed crizotinib and lorlatinib.  Preclinical data shows is it a potent inhibitor of ROS1+ cancer. It received FDA orphan drug designation on June 27, 2017 for “treatment of non-small cell lung adenocarcinomas harboring ALK, ROS1, or NTRK oncogenic rearrangements.”

DS-6051b — Daiichi Sankyo

The DS-6051b clinical trial opened in 2014, but has been slow to accrue.  Few ROS1+ patients have enrolled. The trial was halted for a while, but has since reopened and now accepts only patients who have ROS1+ solid tumors.

ceretinib (Zykadia, LDK378) — Novartis

Studies found ceritinib demonstrated potent clinical activity (including treating the brain) in ROS1+ NSCLC patients who had previously received platinum-based chemotherapy. In preclinical studies, ceritinib is unable to overcome most ROS1 resistance mutations, including ROS1 G2032R. It has more severe side effects than crizotinib for many patients.  Ceretinib is FDA approved for first line treatment o f ALK+ metastatic non-small cell lung cancer.

ensartinib (X-396) — Xcovery Holding Company

Preclinical data shows ensartinib has activity against ROS1+ cancer. It is in clinical trials for pediatric ROS1+ patients.

cabozantinib (Cometriz, Cabometyx) — Exelixis

Cabozantinib is US FDA approved for metastatic medullary thyroid cancer (as Cometriq) and renal cell carcinoma (as Cabometyx). It has shown ability to overcome crizotinib resistance in ROS1+ cancer in early studies, but the required dosage makes the drug difficult to take due to side effects.  Memorial Sloan Kettering has been running a Phase 2 clinical trial since 2012 to explore the effectiveness of cabozantinib for ROS1+ non-small cell lung cancer.

DRUGS WITH NO ROS1 CLINICAL TRIALS

brigatinib (Alubrig, AP26113) — Ariad Pharmaceuticals

Preclinical data shows brigatinib inhibits ROS1+ cancer.  However, no clinical trials  have explored the effectiveness of brigatinib for ROS1+ cancer, and Ariad has indicated it will not run a ROS1+ clinical trial of the drug in the USA (due in part to the large number of ROS1 drugs already in clinical trials, and the small number of ROS1+ patients available for trials). Brigatinib was approved by US FDA for ALK+ NSCLC patients who have progressed on or are intolerant to crizotinib (28-Apr-2017).

foretinib (GSK1363089) — GlaxoSmithKline

Preliminary research suggested foretinib is a potent inhibitor of ROS1+ cancer. However, in 2015 GlaxoSmithKline withdrew the NSCLC clinical trial of foretinib prior to enrollment because they stopped developing the drug.

alectinib (Alecensa, CH5424802, RO5424802) — Genentech

Although alectinib is effective against ALK+ lung cancer, it is NOT effective against ROS1+ cancer.

Last updated 8-Aug-2017