Title options: 100-character limit, with spaces:
- Advancing the Treatment of ROS1+ NSCLC: An Oncologist’s Perspective (70 characters)
- The Evolving Treatment Landscape for ROS1+ Lung Cancer Patients (63 characters)
- The Evolving Treatment Landscape for ROS1+ NSCLC (50 characters)
- ROS1+ NSCLC: Advancements in Care(34 characters)
Outline:
- Intro:
- Highlight approval:
- At the end of 2023, the S. Food and Drug Administration (FDA) approved a treatment option called AUGTYRO™ (repotrectinib), a next-generation tyrosine kinase inhibitor (TKI), for the treatment of adult patients with locally advanced or metastatic ROS1+ NSCLC.
- Insert W&P
- AUGTYRO is associated with the following Warnings & Precautions: central nervous system (CNS) effects, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity. Please see Important Safety Information below.
- Highlight 2024 NCCN guidelines recommendation of repotrectinib as a preferred first-line treatment option for patients with ROS1+ advanced or metastatic NSCLC. (Reference is on MS-85 in 2024 NCCN guidelines)
- Introduce the KOL: We recently spoke with XX, to get [his/her] perspective on this approved treatment option why the approval is significant.
- Highlight approval:
In November 2023, the FDA approved Augtyro (repotrectinib) for treating advanced lung cancers with a ROS1 gene fusion. The complete results of the TRIDENT-1 clinical trial, which led to this approval, have been published. The study showed that nearly 80% of participants with non-small cell lung cancer (NSCLC) who had not previously received a ROS1-targeted drug responded positively, with their tumors shrinking. Additionally, nearly 40% of those previously treated with other ROS1-targeted drugs also showed a positive response. Augtyro’s approval covers its use as an initial and second-line treatment for advanced or metastatic NSCLC with ROS1 fusions.
The TRIDENT-1 trial included 127 participants with ROS1 fusion-positive lung cancers, demonstrating that Augtyro can lead to long-term responses for these patients. The drug also showed effectiveness against brain metastases, a common issue in lung cancer. Augtyro is designed to overcome certain ROS1 mutations that cause resistance to other ROS1 inhibitors, such as crizotinib and entrectinib. In the trial, 59% of participants with the G2032R mutation responded to Augtyro. Despite its effectiveness, the trial did not directly compare Augtyro with other ROS1-targeted drugs, which is a limitation. Common side effects included dizziness, dysgeusia, and paresthesia, with a small percentage of participants discontinuing the treatment due to side effects.
AUGTYRO is associated with the following Warnings & Precautions: central nervous system (CNS) effects, interstitial lung disease (ILD)/pneumonitis, hepatotoxicity, myalgia with creatine phosphokinase elevation, hyperuricemia, skeletal fractures, and embryo-fetal toxicity. Please see Important Safety Information below.
The NCCN guidelines highlight the significance of ROS1 gene rearrangements in NSCLC, which occur in about 1-2% of patients. These rearrangements lead to ROS1 kinase dysregulation and inappropriate signaling. Various targeted therapies, initially developed for ALK-positive metastatic NSCLC, have shown efficacy in treating ROS1-positive cases. Among these, crizotinib, a first-generation tyrosine kinase inhibitor (TKI), has demonstrated high response rates of around 70-80% in several clinical trials, with significant durations of response and progression-free survival (PFS). However, while crizotinib is effective, its intracranial penetration is limited, prompting the exploration of other treatments.
The NCCN also used the TRIDENT trial data. In the phase 1 and 2 TRIDENT-1 trial, repotrectinib showed an objective response rate of 79% in patients who had not received ROS1 TKI therapy, with a median response duration of 34.1 months and a PFS of 35.7 months. The response rate for those previously treated with a ROS1 TKI was 38%, with a median response duration of 14.8 months and a PFS of 9 months. Repotrectinib exhibited a high intracranial response rate, particularly in TKI-naïve patients. Common adverse events included dizziness, dysgeusia, and paresthesia. Given its efficacy and ability to penetrate the CNS, repotrectinib presents a promising option for ROS1-positive NSCLC treatment.
Physician’s Weekly (PW) recently spoke with Luis Raez, MD, director of the Thoracic Oncology Program at Memorial Cancer Institute in Florida and an investigator of the TRIDENT trial, to better understand the significance of the approval.
PW: How do you foresee the approval of Augtyro impacting patients diagnosed with ROS1+ NSCLC? What does it mean for oncologists in terms of treatment options and patient care?
Dr. Raez: It’s never fair to compare different studies. However, if we compare the studies that led to the approval for all ROS1 agents, repotrectinib with a diagnostic odds ratio (DOR) of 83% at 1 year has the highest CNS protection. It also has the highest ORR in the TKI-naïve population.
Furthermore, it has activity against the ROS1 G2032 resistant mutation where crizotinib and entrectenib are not sensitive. With a PFS of 36 months, it has the longest PFS among 5 TKIs with ROS1 activity. The toxicity profile is similar to entrectenib, which is the current front-line drug as per standard of care.
What were the key findings from the study the approval was based on, TRIDENT-1?
In the global, pivotal phase 1/2 TRIDENT-1 trial, repotrectinib, a next-generation ROS1 and tropomyosin receptor tyrosine kinase inhibitor, demonstrated durable clinical activity in TKI-naïve and TKI-pretreated patients with ROS1+ advanced NSCLC. We observed the following results:
- In TKI-naïve patients, 78.9% (95% CI, 67.6-87.7) of patients had an objective response; 12-month landmark DOR was 86.1%.
- In patients pretreated with one prior ROS1 TKI and no prior chemo, 37.5% (95% CI, 24.9–51.5) of patients had an objective response; 6-month landmark DOR was 79.5%.
- Repotrectinib activity was also observed in additional cohorts of TKI-pretreated patients, including in patients with ROS1 G2032R resistance mutation (ORR, 58.5%; 95% CI, 32.9-81.6).
- Intracranial efficacy was observed in patients who were TKI-naïve and those pretreated with TKI.
- Repotrectinib safety is well characterized, manageable, and signals potential compatibility with long-term use; low-grade dizziness is the most common treatment-emergent adverse event.
- Stable or improved global health status was seen in both TKI-naïve and TKI-pretreated patients.
- Updated efficacy, safety, and preliminary QOL results from the ongoing TRIDENT-1 study suggest that repotrectinib could represent a potential new treatment option for patients with ROS1+ advanced NSCLC.
The 2024 NCCN guidelines recommend repotrectinib as a preferred treatment option for patients with brain metastases. Can you tell us more about that? What did the TRIDENT-1 study show in patients whose cancer had spread to their brain?
In patients with CNS metastasis, it showed an ORR of 87.5% in patients who were TKI naïve and 41.7% in patients who were pre-treated already with another TKI.
This marked the highest CNS penetration reported by any other ROS1 TKI.
Let’s talk more about TKIs. Why is Augtyro a next-generation TKI?
It is the most potent agent; the amount of drug in vitro needed to stop tumor growth (called IC50) is the lowest compared with the other 5 TKIs. We see in real life that it not only has the highest ORR but also the longest PFS reported to date (36 months), which is close to double that reported for entrectenib, the current standard of care. We are waiting for survival data to see the benefit there.
For more information about AUGTYRO, please visit www.augtyrohcp.com.
INDICATION
AUGTYROTM (repotrectinib) is indicated for the treatment of adult patients with locally advanced or metastatic
ROS1-positive non-small cell lung cancer (NSCLC).
IMPORTANT SAFETY INFORMATION
Warnings & Precautions
Central Nervous System Adverse Reactions
- Among the 426 patients who received AUGTYRO in Study TRIDENT-1, a broad spectrum of central nervous system (CNS) adverse reactions including dizziness, ataxia, and cognitive disorders occurred in 77% of patients with Grade 3 or 4 events occurring in 4.5%.
- Dizziness, including vertigo, occurred in 65%; Grade 3 dizziness occurred in 8% of patients. The median
time to onset was 7 days (1 day to 1.4 years). Dose interruption was required in 9% of patients, and 11% required dose reduction of AUGTYRO due to dizziness.
- Ataxia, including gait disturbance and balance disorder, occurred in 28% of patients; Grade 3 ataxia
occurred in 0.5%. The median time to onset was 15 days (1 day to 1.4 years). Dose interruption was required in 5% of patients, 8% required dose reduction and one patient (0.2%) permanently discontinued AUGTYRO due to ataxia.
- Cognitive impairment, including memory impairment and disturbance in attention, occurred in 25% of
patients. Cognitive impairment included memory impairment (15%), disturbance in attention (12%), and confusional state (2%); Grade 3 cognitive impairment occurred in 0.9% of patients. The median time to onset of cognitive disorders was 37 days (1 day to 1.4 years). Dose interruption was required in 2% of patients, 2.1% required dose reduction and 0.5% permanently discontinued AUGTYRO due to cognitive adverse reactions.
- Mood disorders occurred in 6% of Mood disorders occurring in >1% of patients included anxiety
(2.6%); Grade 4 mood disorders (mania) occurred in 0.2% of patients. Dose interruption was required in 0.2% of patients and 0.2% required a dose reduction due to mood disorders.
- Sleep disorders including insomnia and hypersomnia occurred in 18% of Sleep disorders observed
in >1% of patients were somnolence (9%), insomnia (6%) and hypersomnia (1.6%). Dose interruption was required in 0.7% of patients, and 0.2% required a dose reduction due to sleep disorders.
- The incidences of CNS adverse reactions reported were similar in patients with and without CNS
metastases.
- Advise patients not to drive or use machines if they are experiencing CNS adverse reactions. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on
Interstitial Lung Disease (ILD)/Pneumonitis
- Among the 426 patients treated with AUGTYRO, ILD/pneumonitis (pneumonitis [2.8%] and ILD [0.2%]) occurred in 3.1%; Grade 3 ILD/pneumonitis occurred in 1.2%. The median time to onset was 45 days (19 days to 0.9 years). Dose interruption was required in 1.4% of patients, 0.5% required dose reduction, and 1.1% permanently discontinued AUGTYRO due to ILD/pneumonitis.
- Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately
withhold AUGTYRO in patients with suspected ILD/pneumonitis and permanently discontinue AUGTYRO if ILD/pneumonitis is confirmed.
Hepatotoxicity
- Among the 426 patients treated with AUGTYRO, increased alanine transaminase (ALT) occurred in 38%, increased aspartate aminotransferase (AST) occurred in 41%, including Grade 3 or 4 increased ALT in 3.3% and increased AST in 2.9%. The median time to onset of increased ALT or AST was 15 days (range: 1 day to 1.9 years). Increased ALT or AST leading to dose interruptions or reductions occurred in 2.8% and 1.2% of patients, respectively. Hyperbilirubinemia leading to dose interruptions occurred in 0.5%.
- Monitor liver function tests, including ALT, AST and bilirubin, every 2 weeks during the first month of
treatment, then monthly thereafter and then as clinically indicated. Withhold and then resume at same or reduced dose upon improvement or permanently discontinue AUGTYRO based on the severity.
Myalgia with Creatine Phosphokinase (CPK) Elevation
- AUGTYRO can cause myalgia with or without creatine phosphokinase (CPK) elevation. Among the 426 patients treated with AUGTYRO, myalgia occurred in 13% of patients, with Grade 3 in 0.7%. Median time to onset of myalgia was 19 days (range: 1 day to 2 years). Concurrent increased CPK within a 7-day window was observed in 3.7% of patients. AUGTYRO was interrupted in one patient with myalgia and concurrent CPK elevation.
- Advise patients to report any unexplained muscle pain, tenderness, or Monitor serum CPK levels
during AUGTYRO treatment and monitor CPK levels every 2 weeks during the first month of treatment and as needed in patients reporting unexplained muscle pain, tenderness, or weakness. Initiate supportive care as clinically indicated. Based on severity, withhold and then resume AUGTYRO at same or reduced dose upon improvement.
Hyperuricemia
- Among the 426 patients treated with AUGTYRO, 21 patients (5%) experienced hyperuricemia reported as an adverse reaction, 0.7% experienced Grade 3 or 4 hyperuricemia. One patient without pre-existing gout required urate-lowering medication.
- Monitor serum uric acid levels prior to initiating AUGTYRO and periodically during Initiate
treatment with urate-lowering medications as clinically indicated. Withhold and then resume at same or reduced dose upon improvement, or permanently discontinue AUGTYRO based on severity.
Skeletal Fractures
- Among 426 adult patients who received AUGTYRO, fractures occurred in 2.3%. Fractures involved the ribs (0.5%), feet (0.5%), spine (0.2%), acetabulum (0.2%), sternum (0.2%), and ankles (0.2%). Some fractures occurred at sites of disease and prior radiation therapy. The median time to fracture was 71 days (range: 31 days to 1.4 years). AUGTYRO was interrupted in 0.3% of patients.
- Of 26 evaluable patients in an ongoing open-label study in pediatric patients, fractures occurred in one 12-
year-old patient (ankle/foot) and one 10-year-old patient (stress fracture). AUGTYRO was interrupted in both patients. AUGTYRO is not approved for use in pediatric patients less than 12 years of age.
- Promptly evaluate patients with signs or symptoms (e.g., pain, changes in mobility, deformity) of
There are no data on the effects of AUGTYRO on healing of known fractures and risk of future fractures.
Embryo-Fetal Toxicity
- Based on literature reports in humans with congenital mutations leading to changes in tropomyosin receptor tyrosine kinase (TRK) signaling, findings from animal studies, and its mechanism of action, AUGTYRO can cause fetal harm when administered to a pregnant woman.
- Advise pregnant women of the potential risk to a Advise females of reproductive potential to use
effective non-hormonal contraception during treatment with AUGTYRO and for 2 months following the last dose, since AUGTYRO can render some hormonal contraceptives ineffective.
- Advise male patients with female partners of reproductive potential to use effective contraception during
treatment with AUGTYRO and for 4 months after the last dose.
Adverse Reactions
- The safety of AUGTYRO was evaluated in 426 patients in TRIDENT-1. The most common adverse reactions (≥20%) were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, fatigue, ataxia, cognitive impairment, muscular weakness, and nausea.
Drug Interactions
Effects of Other Drugs on AUGTYRO
Strong and Moderate CYP3A Inhibitors
- Avoid concomitant use with strong or moderate CYP3A inhibitors. Concomitant use of AUGTYRO with a strong or a moderate CYP3A inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of AUGTYRO. Discontinue CYP3A inhibitors for 3 to 5 elimination half-lives of the CYP3A inhibitor prior to initiating AUGTYRO.
P-gp Inhibitors
- Avoid concomitant use with P-gp inhibitors. Concomitant use of AUGTYRO with a P-gp inhibitor may increase repotrectinib exposure, which may increase the incidence and severity of adverse reactions of
Strong and Moderate CYP3A Inducers
- Avoid concomitant use with strong or moderate CYP3A inducers. Concomitant use of AUGTYRO with a strong or moderate CYP3A inducer may decrease repotrectinib plasma concentrations, which may decrease efficacy of AUGTYRO.
Effects of AUGTYRO on other Drugs
Certain CYP3A4 Substrates
- Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates, where minimal concentration changes can cause reduced efficacy. If concomitant use is unavoidable, increase the CYP3A4 substrate dosage in accordance with approved product labeling.
- Repotrectinib is a CYP3A4 Concomitant use of repotrectinib decreases the concentration of
CYP3A4 substrates, which can reduce the efficacy of these substrates.
Contraceptives
- Repotrectinib is a CYP3A4 inducer, which can decrease progestin or estrogen exposure to an extent that could reduce the effectiveness of hormonal contraceptives.
- Avoid concomitant use of AUGTYRO with hormonal Advise females of childbearing potential
to use an effective nonhormonal contraceptive.
Please see U.S. Full Prescribing Information for AUGTYRO [insert location of PI here]