” …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 majority of drugs listed on this page are targeted therapies. 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 normal adult cells. In cells with oncogenic ROS1 fusions, the protein is always on, and makes the cell act like cancer. Once the drug binds to the protein, the drug turns off the protein’s signaling 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. Two drugs (crizotinib and entrectinib) has received approval from some regulatory agencies for treatment of ROS1+ cancer. Their effectiveness in the body is comparable, but only entrectinib can treat the brain effectively. Some other drugs with activity against ROS1 are approved for treatment of other cancers, and so may be accessible off-label even though they are not approved for ROS1+ cancers.
Due to the small population of ROS1+ cancer patients (about 1%-3% of non-small cell lung cancers, and a similar fraction of about a dozen other cancers), it’s unlikely a phase III clinical trial comparing different treatment options will happen. The data below comes from Phase 1/2 clinical trials and other sources.
Note that many ROS1 experts believe patients on TKIs should not take “drug holidays” if the drug is effective and the patient is tolerating the drug well.
Summary of ROS1 TKIs
crizotinib (Xalkori) — Pfizer
Crizotinib has been the standard of care for metastatic ROS1+ non-small cell lung cancer (NSCLC) in the USA and other countries. 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, Israel, and Australia, 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 for those who cannot swallow crizotinib tablets).
- Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer
- Phase II Study of Crizotinib in East Asian Patients With ROS1-Positive Advanced Non-Small-Cell Lung Cancer
- 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
entrectinib (Rozlytrek, RXDX-101) — Roche (was Ignyta)
Entrectinib may become the new standard of care for ROS1+ NSCLC due to its ability to effectively treat the brain, which crizotinib doesn’t do for most patients. The drug was approved by the US FDA for ROS1+ NSCLC (also for NTRK+ solid tumors) on August 15, 2019.
The entrectinib STRTRK-2 trial was a basket design, which allowed 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 were allowed to enroll in the trial if they developed brain mets. The clinical trial stopped enrolling ROS1+ patients in January 2018 but the trial continues for patients with other types of ROS1+ cancer.
In a pooled analysis of Phase I and Phase II trials presented at WCLC 2018, entrectinib’s objective response rate was 77.4% for the 53 patients evaluable for response, and the median duration of response was 24.6 months. Among 23 patients (43.4%) enrolled in the trial with evaluable brain metastases, the intracranial response rate was 55%. The duration of intracranial response was 12.9 months. (Data was not presented on ROS1+ cancers other than NSCLC because too few patients with those cancers participated in the trial.)
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 a 2017 communication to shareholders, Ignyta indicated it is pursuing approval of entrectinib for ROS1+ cancers.
- Entrectinib Shows Activity in ROS1-Positive NSCLC — WCLC 2018
- Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC) — WCLC 2017
- Interim Analysis of Ignyta’s Entrectinib Suggests Potential Best-in-Class Profile as a First-Line Targeted Therapy in Patients With ROS1-Positive Non-Small Cell Lung Cancer — Ignyta press release Oct-2017
- Entrectinib and STARTRK-2 2nd Quarter 2017 Update (April 27, 2017)
- Entrectinib, an oral pan-Trk, ROS1, and ALK inhibitor in TKI-naïve patients with advanced solid tumors harboring gene rearrangements — AACR 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 approved for first line treatment of ALK+ metastatic non-small cell lung cancer in the USA and several other countries. Some ROS1+ patients are able to have it covered by insurance as an off-label prescription.
- 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)
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. Lorlatinib was approved for ALK+ NSCLC in Japan in September 2018, and the FDA approved lorlatinib for second- or third-line treatment of ALK+ NSCLC on November 2, 2018. Lorlatinib is available off label for ROS1+ NSCLC, and some US ROS1 NSCLC patients have been able to obtain insurance coverage with assistance of their oncologists. It is available to ROS1+ NSCLC patients in other countries via expanded access and compassionate use.
The status of lorlatinib FDA filings for ROS1+ NSCLC is unknown. Despite this, the 21-Nov-2018 NCCN Guidelines for NSCLC added lorlatinib as a treatment option for ROS1+ metastatic NSCLC after progression on crizotinib or ceritinib.
- 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).
repotrectinib (TPX-0005) — TP Therapeutics
The TPX-0005 Phase 1/2 clinical trial opened in March 2017 for patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements in the US and South Korea. 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.” Preliminary phase 1 trial results were announced at ASCO 2018, and show the drug can treat brain mets. Phase 2 sites are enrolling in several countries, and are open to patients 12 years and older.
- Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations
- TPX-0005 with an EGFR tyrosine kinase inhibitor (TKI) overcomes innate resistance in EGFR mutant NSCLC — poster at IASLC WCLC 2018
- A phase 1 study of the next-generation ALK/ROS1/TRK inhibitor TPX-0005 in patients with advanced ALK/ROS1/NTRK+ cancers (TRIDENT-1) — poster at ASCO 2018
- 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
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, particularly the G2032R on-target resistance mutation. However, the required dosage makes the drug difficult to tolerate for more than about 2 months. 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, and reported discouraging results in a poster at WCLC 2019.
- Lengthy Progression-Free Survival and Intracranial Activity of Cabozantinib in Patients with Crizotinib and Ceritinib-Resistant ROS1-Positive 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
taletrectinib (AB106) — Baoyuan Biopharmaceuticals Technology/ AnHeart Therapeutics (was DS-6051b by Daiichi Sankyo)
The Phase 1 DS-6051b clinical trial opened in 2014 in both the USA and Japan, but was slow to accrue in the US. Phase 1 data for the Japanese trial was published in May 2018. Data for all Phase 1 sites was published in October 2020. In December 2018 Daiichi Sankyo granted AnHeart Therapeutics worldwide exclusive rights for the development, manufacturing and commercialization of DS-6051, and the drug was renamed AB106. AnHeart plans to open a Phase 2 trial in late 2020.
- Efficacy of taletrectinib (AB-106/DS-6051b) in ROS1+ NSCLC: an updated pooled analysis of US and Japan phase 1 studies
- The New-Generation Selective ROS1/NTRK Inhibitor DS-6051b Overcomes Crizotinib Resistant ROS1-G2032R Mutation in Preclinical Models
- Daiichi Sankyo Out-Licenses ROS1/NTRK Inhibitor DS-6051 to AnHeart Therapeutics
- Safety and pharmacokinetics of DS-6051b in Japanese patients with non-small cell lung cancer harboring ROS1 fusions: a phase I study
- 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)
ensartinib (X-396) — Xcovery Holding Company
Preclinical data shows ensartinib has activity against ROS1+ cancer. It is in a clinical trial for pediatric ROS1+ patients.
DRUGS WITH PRECLINICAL ROS1 ACTIVITY BUT NO CLINICAL DATA
brigatinib (Alunbrig, AP26113) — Takeda Oncology (was Ariad Pharmaceuticals)
Preclinical data indicated brigatinib inhibits ROS1+ cancer. A small unpublished study of three ROS1+ NSCLC patients showed 1 partial response, 1 with stable disease, and 1 with progressive disease. It’s unlikely a larger clinical trial will be run for ROS1+ cancers. Brigatinib was approved by US FDA for ALK+ NSCLC patients who have progressed on or are intolerant to crizotinib (28-Apr-2017). Some ROS1ders with cancers other than NSCLC have anecdotally reported disappointing results on brigatinib.
- 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, 2017
IMMUNOTHERAPY for ROS1
2020 NCCN Guidelines for NSCLC say the following regarding NSCLC with targetable driving oncogene (including ROS1) and Immune Checkpoint Inhibitors (ICIs) such as nivolumab and pembrolizumab:
- Clinicians should obtain molecular testing results for actionable biomarkers before administering first-line ICI therapy.
- Patients who have metastatic NSCLC with a targeteable driver oncogene should receive first-line targeted therapy for that oncogene and not first-line ICIs (for any PD-L1 expression) because (1) targeted therapies yield higher response rates than ICIs in the first-line setting, (2) targeted therapy is better tolerated, and (3) these patients are unlikely to respond to ICIs.
Other reasons cited by NSCLC targeted therapy experts for not giving ICIs first line to NSCLC patients with targetable oncogenes are:
- Several studies (such as the ImmunoTarget trial) found patients whose cancers had driving oncogenes had poorer results on first-line ICIs than on first-line TKIs. (Progression free survival was significantly worse in the ImmunoTarget trial for patients with EGFR, ALK, ROS1, and RET compared to other oncogenic drivers.)
- First line ICIs in some lung cancer patients has caused accelerated cancer progression (hyperprogression).
- First line ICIs in patients with driving oncogenes seems to be associated with reduced effectiveness of subsequent TKIs.
- Side effects of first-line ICIs (such as pneumonitis) can make patients ineligible to take TKIs as a second-line treatment, or cause increased toxicities on subsequent TKIs.
The jury’s still out on whether and when ICI-chemo or TKI-ICI combinations might be useful for ROS1 patients. Potential toxicity of a combination versus a TKI must be considered when making treatment decisions– a Phase I/2 clinical trial for crizotinib plus nivolumab in ALK+ NSCLC was discontinued due to toxicity. Clinical trials are beginning to explore whether autologous TIL therapy may be useful for patients with oncogene-driven NSCLC who have no further TKI or chemo treatment options.
- Immune checkpoint inhibitor treatment in patients with oncogene-addicted non-small cell lung cancer (NSCLC): summary of a multidisciplinary round-table discussion
- Activating Lung Cancer Mutations Do Not Predict ICI Efficacy
- Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non–Small Cell Lung Cancer
- Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-Line Treatment of Anaplastic Lymphoma Kinase Translocation – Positive Advanced Non-Small Cell Lung Cancer (CheckMate 370)
last update 27-Feb-2020
Please send corrections and updates (ROS1-related press releases, journal articles, and conference posters) to email@example.com.