” …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 FDA, Japan, Taiwan, and Israel, and has marketing authorization in the European Union and 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.
- Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer
- Phase II Study of crizotinib in east Asian patients (pts) with ROS1-positive advanced non-small cell lung cancer (NSCLC)
- Pfizer Receives U.S. FDA Breakthrough Therapy Designation For XALKORI® (crizotinib) For The Treatment Of Patients With ROS1-Positive Non-Small Cell Lung Cancer
- Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F
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.
- PF-06463922 is a potent and selective next-generation ROS1/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations
- Safety and efficacy of lorlatinib (PF-06463922) from the dose-escalation component of a study in patients with advanced ALK+ or ROS1+ non-small cell lung cancer (NSCLC).
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.
- Alka-372-001: First-in-human, phase I study of entrectinib – an oral pan-trk, ROS1, and ALK inhibitor – in patients with advanced solid tumors with relevant molecular alterations.
- Entrectinib and STARTRK-2 2nd Quarter 2017 Update (April 27, 2017)
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.”
- P3.02a-009 TPX-0005: A Multi-Faceted Approach to Overcoming Clinical Resistances from Current ALK or ROS1 Inhibitor Treatment in Lung Cancer
- TPX-0005, a novel ALK/ROS1/TRK inhibitor, effectively inhibited a broad spectrum of mutations including solvent front ALK G1202R, ROS1 G2032R and TRKA G595R mutants
- Abstract 2132: The novel, rationally-designed, ALK/SRC inhibitor TPX-0005 overcomes multiple acquired resistance mechanisms to current ALK inhibitors
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.
- Preclinical characterization and antitumor efficacy of DS-6051b, a novel, orally available small molecule tyrosine kinase inhibitor of ROS1 and NTRKs
- Abstract CT024: First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors (July 2016)
ceritinib (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. Ceritinib is FDA approved for first line treatment of ALK+ metastatic non-small cell lung cancer.
- Expanding the Roster of ROS1 Inhibitors (May 2017)
- Open-Label, Multicenter, Phase II Study of Ceritinib in Patients With Non–Small-Cell Lung Cancer Harboring ROS1 Rearrangement (May 2017)
- Ceritinib in ROS1-Rearranged NonSmall-Cell Lung Cancer: An Update of Korean Nationwide Phase II Study (January 2017)
- Ceritinib in ROS1-rearranged non-small-cell lung cancer: a Korean nationwide phase II study (October 2016)
- Clinical activity of ceritinib in ROS1-rearranged non-small cell lung cancer: Bench to bedside report (May 2016)
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.
- Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer.
- A Novel Crizotinib-Resistant Solvent-Front Mutation Responsive to Cabozantinib Therapy in a Patient with ROS1-Rearranged 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).
- ARIAD Presents New Preclinical Data Showing AP26113 Inhibits Clinically Relevant Mutants of ALK and ROS1
- Abstract 3644: Identification of existing targeted agents that inhibit NTRK and ROS1 in lung cancer
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
“Notably, the ALK inhibitor, alectinib, does not inhibit ROS1 at all, so should never be used in ROS1-positive NSCLC.”
Dr. Alice Shaw, interview in Cancer Therapy Advisor, June 29, 2017Last updated 29-Aug-2017
