Treating ROS1+ Cancer (for Healthcare Professionals)

Evidence-based information on approved and experimental
targeted therapy drugs available for ROS1+ cancer

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ROS1+ Cancer Treatment Overview

 

Cancer research is evolving fast, and many healthcare providers are not yet familiar with ROS1+ cancer.
If you have questions about the best next step in treating your patient’s ROS1+ cancer, you may want to consult a physician who has treated several ROS1+ cancer cases and is involved in ROS1 research.

Find a ROS1 Clinician-Researcher

ROS1 gene rearrangements (also called gene fusions) result when the ROS1 gene swaps segments of DNA with another gene, such as CD74.  At least 21 different gene pairings have been identified in ROS1+ cancer (CD74-ROS1 is the most common).  When a ROS1 fusion occurs, the altered ROS1 gene creates an abnormal protein that sends signals continuously.  The signals it sends tell the cell to behave like cancer: live forever, make many copies of itself, invade neighboring tissue, and send cells out into the body to grow in different tissues.  

TKIs are the preferred first-line treatment for metastatic ROS1+ NSCLC

” …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

In clinical trials, ROS1 tyrosine kinase inhibitors (TKIs) are more effective and more tolerable than standard chemotherapy for NSCLC. The current professional version of NCCN Guidelines for NSCLC (commonly used in the USA) contains considerable discussion about ROS1 treatment options, as well as a treatment algorithm.  TKIs are also usually effective in patients who have had prior chemotherapy. Most tumor shrinkage occurs in the first few months of taking the TKI. Patients who cannot tolerate one TKI in first-line treatment may be able to switch to a different, more tolerable TKI. Due to the small population of ROS1+ cancer patients, it will always be challenging to enroll enough patients in a phase III clinical trial  to determine whether one ROS1 TKI is more effective than another, so treatment approvals and recommendations are based on Phase II clinical trial data.

ROS1 TKIs enter every cell in the body. In normal cells in the adult body, this has little effect, since ROS1 proteins are usually not expressed in adults.  In ROS1+ cancer cells, however, the TKI molecule binds to the active ROS1 protein. This inhibits the protein's ability to signal; the cell stops behaving like cancer and can undergo apoptosis (die).  However, TKIs cannot kill 100% of the cancer cells.  As such, while they may control and shrink the cancer while on therapy, they cannot cure cancer. Patients must continue to take a TKI to inhibit the cancer.  If the TKI is stopped, the cancer is no longer inhibited, and the cancer may resume growing. TKIs are generally not thought to impact the immune system as chemotherapy is known to do. 

Some ROS1 TKIs also bind to the ATP pocket on other proteins, such as ALK and NTRK.  For this reason, ROS1 TKIs have different side effect profiles.  If one first-line ROS1 TKI is not tolerable for a patient, a different first-line TKI may be more tolerable.

Stopping a TKI

 

Patients who have difficulty tolerating a TKI sometimes can stop taking the drug for a few weeks, resume the TKI at a lower dose, then either remain at the lower dose or gradually ramp back up to full dose. Many ROS1ders have stopped taking their TKI for several days before and after a procedure  (e.g., surgery) on the recommendation of their physician with no sign of cancer progression. Whether holding the drug is needed is controversial. The half-life of a TKI (e.g., 42 hours for crizotinib) is long enough that some drug will remain in the body for several days even if the patient has stopped taking it.

 

However, some patients have experienced a disease flare (known as TKI flare) if they stop taking their TKI for more than a week. Some (not all) patients who stop taking entrectinib prior to switching treatments have reported withdrawal symptoms such as extreme fatigue as well as joint and muscle aches. If a patient expresses a desire to take a long break from their TKI, please discuss the risks and benefits with them so the patient can make an informed decision.  

Acquired resistance to ROS1 TKIs

 

Eventually, all metastatic ROS1+ cancers develop acquired resistance to TKIs, and the TKI stops working. More than one mechanism of acquired resistance has been identified, and about 60% of cases appear to have a resistance mechanism that  is independent of ROS1 and will not respond to a different ROS1 TKI. The success of the next treatment depends on the mechanism driving the TKI resistance. Next generation sequencing (NGS) biomarker testing of a repeat tissue in the area of progression or a liquid biopsy may prove useful for identifying the resistance mechanism.

Preliminary research suggests a greater depth of response to targeted therapy may be associated with greater progression-free survival as well as overall survival.

Crizotinib-resistant ROS1 mutations

On-target resistance (~40% of cases)

This type of resistance arises from Changes in the ROS1 protein interfere with the TKI binding in its pocket on the protein. It will likely respond to a second-line ROS1 TKI if that TKI has been shown to overcome the resistance mutation. Mutations identified thus far are G2032R (occurring in about 33% of cases), plus D2033N, L2026M, L1951R, L2155S, S1986Y/F, L2086F, and L2000V (each occurring in about 2-4% of cases).

Off-target resistance (~60% of cases)

This may include bypass signaling, new gene alterations, or phenotypic changes.  In bypass signaling, the cell manages to activate downstream RAS, RAF, and/or MEK signaling pathways despite successful ROS1 inhibition. In new gene alterations, the cell acquires new mutations or fusions in genes such as EGFR, HER2, RET, ALK, MET, KIT, KRAS G12C, MAP2K1, or NRAS, as well as EGFR upregulation or KRAS amplification. Phenotypic changes like epithelial-mesenchymal transition have also occurred. Off-target resistance does NOT respond to switching TKIs. Combination therapies (TKI plus chemo, two TKIs targeting different biomarkers, etc.) are being explored in clinical trials to address this type of resistance.

Transformation to small cell or other neuroendocrine cancer

 

This has been seen in a few ROS1ders who had ROS1+ NSCLC--their cancer transformed to small cell lung cancer or large cell cancer neuroendocrine cancer while retaining its original ROS1 fusion. Treatment approaches vary and depend on the estnet of transformation and number of sites involved. Some cases have remained on a ROS1 TKI and added a chemotherapy typically used to treat SCLC or a neuroendocrine cancer.

resistance mutations ROS1 protein.PNG

Be careful saying “cancer free” to a patient who has metastatic ROS1+ cancer

 

Cancer patients long to hear their doctor tell them they are "cancer free."  However, please be careful using "cancer free" with metastatic ROS1+ cancer--a clean scan or liquid biopsy does not necessarily mean all the cancer has left the body.  When ROS1+ cancer cells are being effectively inhibited by a TKI, the cells don’t behave like cancer. This means the cancer cells are likely not consuming abnormally high levels of glucose. Therefore, a PET scan may show no cancer activity, even though a tumor is still visible on CT.  ROS1+ cancer cells that are being effectively inhibited by a TKI also tend to shed less circulating tumor DNA (ctDNA), so a liquid biopsy may not detect any ROS1 fusions.  Acquired resistance inevitably occurs for metastatic ROS1+ cancer treated with TKIs, and ROS1+ cancer is often quite aggressive, so most patients will see their cancer return (sometimes very quickly after a clean scan).

 

While hearing "cancer free" certainly gives a person hope, the person can feel betrayed when the cancer returns.  ROS1 Clinician-Researchers usually refer to patients who achieve a complete response to a TKI as having “No Evidence of Disease,” or NED.  This simply means current technology cannot detect the presence of cancer, but does not imply the patient is “cancer free.”


The specific gene fusion MIGHT affect ROS1 TKI efficacy

Over 20 different ROS1 gene fusion pairings have been identified by researchers (see graphic). Preclinical testing of the first ROS1 TKIs was mostly conducted using cancer model of  the most common gene pairing (CD74-ROS1).  The gene partner may affect how well a TKI works for ROS1+ cancer, but more work needs to be done before such information is clinically actionable. Analysis of lung cancer response in crizotinib and entrectinib clinical trials suggest the gene partner does not influence effectiveness, but the subgroups were very small. 

Rearrangements in ROS1+ NSCLC
Image Credit  Used with permission.

Rearrangements in ROS1+ NSCLC.PNG

ROS1 fusions in cancers other than NSCLC have responded to ROS1 TKIs

ROS1 is altered in about 5% of malignant solid tumor patients, with ROS1 mutations present in about 4% of all malignant solid tumor patients. ROS1 mutations have been found in 30 different cancers in the AACR GENIE database, but these are not necessarily ROS1 fusions that respond to ROS1 TKIs.  ROS1 fusions have been found in at least 18 cancers.  Patients who have ROS1+ cancers other than NSCLC have responded to ROS1 TKIs,  but thus far the drugs are only approved for NSCLC. The value of crizotinib for non-NSCLC ROS1+ cancer is being evaluated in basket trials such as NCI MATCH-Subprotocl G. Some members of The ROS1ders with cancers such as angiosarcoma, melanoma, pancreatic and liver cancers have reported responses to crizotinib. 
 

If you have a patient with an aggressive cancer , please consider NGS biomarker testing to determine if they have ROS1+ cancer. 

 
ROS1ders-Patterns-02-dark.png

ROS1 Treatment Algorithm

  • This algorithm reflects the current National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer (NSCLC)  for ROS1+ NSCLC (adenocarinoma, large cell, NSCLC not otherwise specified, and squamous). We've added investigational agents that preclinical and/or clinical data suggest are effective against brain metastases and/or acquired resistance for ROS1+ cancer.

  • If ROS1+ cancer is discovered during non-TKI first line systemic therapy, either

    • complete planned systemic therapy, including maintenance therapy, OR

    • interrupt therapy and follow with first-line TKI therapy.

  • Upon progression, biomarker testing should be done using broad next-generation sequencing (NGS) gene panel to identify resistance mechanisms and possible new drivers. If plasma-based biomarker testing is negative, tissue-based testing with rebiopsy material is strongly recommended.​

  • Beware of flare phenomenon in subset of patients who discontinue TKI.  If disease flare occurs, restart TKI.

Revised ROS1 algorithm (2022-02-18) final.JPG

Effective ROS1 TKIs

FIRST LINE ROS1 TKIs

 
TKI
Maker
IC50 (nmol/L)
ORR
CNS Resp
PFS (mo)
DOR (mo)
OS (mo)
Approval Status
Evidence
Rozlytrek (entrectinib)
Genentech/ Roche
2.7
77% (N=53)
74% (N=23)
19
11.4 to 34.8
N/A
approved for ROS1+ NSCLC in some countries (August 2019 in USA)
Xalkori (crizotinib)
Pfizer
5.4
72% (N=53)
no
19.3
15.2 to 45.3
51.4 (29.3-NR)
approved for ROS1+ NSCLC in many countries (April 2016 in USA)
Zykadia (ceritinib)
Novartis
16.4
62% (N=32)
63% (N=8)
9.3
17 to 25
24 (5-43)
NCCN recommended for 1st line treatment of ROS1+ NSCLC

N=number of study participants evaluated, ORR=Overall Response Rate, CNS=Central Nervous System, DOR=Duration of Response, PFS=Progression Free Survival, OS=Overall Survival, NR=not reached.

The two drugs approved in the US for first-line ROS1+ NSCLC are entrectinib and crizotinib. Their effectiveness for inhibiting ROS1+ cancer is comparable in Phase 2 clinical trial data. Here is how they differ: (1) entrectinib has much better central nervous system penetration than crizotinib, and (2) they have different side effect profiles. Some oncologists choose entrectinib as the first line treatment because it treats brain metastases that are present, and reduces the risk of developing new brain metastases .   However, less than half of ROS1+ patients develop brain metastases , and we can't predict who will develop them.  If a ROS1+ cancer patient has brain metastases , entrectinib may be preferable to  crizotinib plus stereotactic brain radiation. However, if the patient doesn't have brain metastases at the time of diagnosis, then tolerability (side effects) might influence the choice of drug more. 

 

 

Entrectinib effectively treats the brain, and is emerging as the preferred first line TKI for ROS1+ NSCLC. Treating the brain is important because nearly half of ROS1+ cancer patients will eventually develop brain metastases. However, it does have neurologic side effects that may require a dose reduction or switch to a different TKI for some patients.  These side effects are thought to occur because the drug also binds with the NTRK-2 protein.

Crizotinib does not treat the brain effectively, but many ROS1ders who were treated first-line with crizotinib have thrived for years on crizotinib with no brain metastases (some even achieved and maintained no evidence of disease) and with good quality of life.  Crizotinib is often less toxic than entrectinib and is approved in more countries than the other ROS1 TKIs.  

Ceretinib is less effective and is often less tolerable than crizotinib or entrectinib. However, it may be more accessible than the other ROS1 TKIs in some countries. 

SECOND LINE ROS1 TKIs

TKI
Maker
Treats Brain
FDA Approval Status
Resistance Mutations Targeted
Notes
Rozlytrek (entrectinib)
Genentech/ Roche
yes
approved for ROS1+ NSCLC
primarily for CNS-only progression on crizotinib
not usually effective on tumors outside CNS that progressed on other TKIs
Lobrena (lorlatinib)
Pfizer
yes
NCCN recommended for 2nd/3rd line ROS1+ NSCLC (not approved for ROS1 but approved for ALK+ NSCLC)
L2000V S1986F/L2000V (not effective against G2032R)
may treat leptomeningeal disease; compassionate use usually not available to new patients; some clinical trials available
Cabometyx, Cometriq (cabozantinib)
Exelixis
yes
not approved for ROS1 but approved for other cancers
G2032R, L2000V, L2086F, S1986F/L2000V, S1986F/L2086F, G2032R/L2086F, S1986F/G2032R/L2086F
difficult to tolerate for more than a few months
TKI
Sponsor
Trial Phase
Clinical Trial
Sites
Treats Brain
Trial Features
Repotrectinib (TPX-0005)
Turning Point Therapeutics
2
International (opened summer 2017)
yes
Targets resistance mutations G2032R, L2000V, S1986F/L2000V
Taletrectinib (DS-6051b, AB-106)
Anheart Therapeutics
2
International (opened fall 2021)
yes
Targets resistance mutations G2032R, L2026M, L1951R, and S1986F; Avoids TRKB-related CNS adverse events
NVL-520
Nuvalent
1
International (opened fall 2021)
yes
Avoids TRK-related CNS adverse events; targets resistance mutations G2032R, S1986Y/F, L2026M, D2033N

Second-line TKIs may be useful when a patient develops acquired resistance to a first line TKI. A rebiopsy may be helpful in determining which mechanism is driving the resistance. Switching TKIs is only useful if the new TKI is effective against the on-target resistance present in the patient’s tumor.  Crizotinib and ceritinib are not effective as second-line treatments. Second-line TKI options are listed in the chart below.  Additional charts summarize clinical trial data for each.

Entrectinib has been shown effective for treating CNS progression that occurs with crizotinib, but only IF crizotinib is controlling the cancer outside of the CNS. Entrectinib is not effective against on-target acquired resistance.

Lorlatinib is recommended at level 2A in the NCCN guidelines for second-line treatment for ROS1+ cancer, but does not have regulatory approval for ROS1. It tends to have serious cognitive side effects at the 100 mg dose for a significant number of patients, but patients have done well on reduced doses.  It seems particularly effective in treating progression that appears in the CNS. However, it is not  effective against on-target acquired resistance mutation G2032R. 

Cabozantinib has shown ability to overcome acquired crizotinib resistance in ROS1+ cancer in early studies, particularly for the G2032R on-target resistance mutation. However, the dosage required to treat ROS1 effectively makes the drug difficult to tolerate for more than about 2 months.

Experimental ROS1 TKIs in clinical trials such as repotrectinib, taletrectinib, and NVL-520 may be good options for second-line treatment if on-target resistance mechanisms are present. 

 

ALK TKIs Less Effective For ROS1

Alectinib preclinical studies show the drug does not inhibit ROS1. NCCN Guidelines and ROS1 Clinician-Researchers agree it should NEVER be used in ROS1+ cancer.

Alunbrig (brigatinib) preclinical data showed activity against ROS1+ cancer that has no acquired resistance. A small unpublished study of three ROS1+ NSCLC patients showed 1 partial response in a TKI naive patient, and no responses in patients previously treated with crizotinib (one had stable disease, and one had progressive disease). A retrospective chart study found brigatinib had a 29% response rate, with no complete responses.  ROS1ders have reported no responses to brigatinib.  

Ensartinib preclinical data showed activity against ROS1+ cancer.  A phase 2 clinical trial in China found it had a 27% response rate.

TKI
Manufacturer
IC50 (nmol/L) (no resistance mutations)
Effectiveness
Response Rate
Evidence
alectinib
Genentech
995.4
none
not available
brigatinib
Takeda Oncology
9.4
moderate
29% of 6 patients
ensartinib
Xcovery Holding Company
N/A
moderate
27% of 59 patients
 

ROS1 Treatment Options Other than TKIs 

Chemotherapy drugs (especially pemetrexed alone or in combination with carboplatin)  can be effective against ROS1+ cancers and are somtimes used by ROS1 Clinician-Researchers when TKIs cease to be effective or when TKIs are not available.

Radiation or Surgery
If the area of progression is limited in extent, it may be possible to stay on the same TKI and treat the area of progression with focused radiation, some other form of ablation, or even surgery.

TKI combination therapies are being explored in clinical trials in an attempt to prevent the development of off-target acquired resistance or to address cancers that have developed a second driving mutation (ALK, EGFR, RET, MET, etc.) as a resistance mechanism.  However, TKI combinations can be more toxic, so caution must be taken when prescribing TKI combinations.


 

Immunotherapy Should NOT be Used as First-Line Treatment in ROS1+ Cancer

 

Immune checkpoint inhibitors (ICIs, or immunotherapy) should only be used for ROS1+ cancer after TKIs, chemotherapy options have been exhausted (see ImmunoTarget clinical trial). NCCN Guidelines for metastatic NSCLC say patients who have a targeteable driver oncogene (e,g., EGFR, ALK, ROS1) and PD-L1 expression levels of 1% or more should receive first-line targeted therapy for that oncogene instead of first-line ICIs 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.  Anecdotally, common side effects of ICIs (such as pneumonitis) might make patients ineligible to receive a TKI as a second-line treatment.

 

The jury is still out on whether and when ICI-chemo or TKI-ICI combinations might be useful for ROS1+ patients.  Potential toxicity of an ICI-TKI combination must be considered – a Phase I/2 clinical trial for crizotinib plus nivolumab in ALK+ NSCLC was discontinued due to toxicity.

 

Clinical trials are exploring whether autologous tumor-infiltrating lymphocyte (TIL) therapy may be useful for patients with oncogene-driven NSCLC.

 
 
 
 
 
 
 
 
 
 
 
 
ROS1ders-patterns-06.png

References 

Alectinib

 

Brigatinib

 

Cabozantinib

 

Ceretinib 

 

Crizotinib

 

Ensartinib

 

Entrectinib

 

Lorlatinib

 

NVL-520
Repotrectinib

 

Taletrectinib (previously DS-6051b)

TQ-B3101

Chemotherapy

Mechanisms of ROS1 Metastatic Spread and TKI Resistance

Immunotherapy

 
 
 
 

Medically reviewed by ROS1 Clinician-Researchers
Last updated 17-Aug-2022