MOUNTAINEER evaluated TUKYSA® (tucatinib) + trastuzumab
THE FIRST PIVOTAL TRIAL OF PATIENTS WITH RAS WT, HER2+ mCRC1,2
MOUNTAINEER was a multicenter, open-label, phase 2 clinical trial that enrolled adult patients with unresectable or metastatic RAS WT, HER2+ colorectal cancer who had not been previously treated with anti-HER2 therapy1,2
MAJOR EFFICACY OUTCOMES
- ORR and DOR in cohorts A and B (N = 84)†
ADDITIONAL EFFICACY OUTCOMES
- PFS,† OS in cohorts A and B (N = 84)
- TUKYSA 300 mg orally, continuously, twice daily; trastuzumab 6 mg/kg intravenously, once every 21 days with an initial dose of 8 mg/kg1
- Patients were treated until disease progression or unacceptable toxicity1
Select inclusion criteria
- HER2+, as defined by HER2 overexpression or gene amplification, per local IHC, ISH, and/or NGS testing1
- RAS WT in primary or metastatic tumor tissue1,2
- Prior treatment with fluoropyrimidines, oxaliplatin, irinotecan, anti-VEGF mAb, and anti-PD-1 mAb (if tumor had dMMR proteins or was MSI-H)1
- ECOG performance status of 0-21
Select exclusion criteria
- Prior anti-HER2 therapy1
- Clinically significant cardiopulmonary disease or LVEF <50%3
- Positive for hepatitis B by surface antigen expression or had active hepatitis C infection3
- Received previous treatment with any systemic anticancer therapy, non–central nervous system radiation, or experimental agent within 3 weeks of first dose of study treatment3
*Or a non–US approved trastuzumab product.1
†Assessed by BICR according to RECIST v1.1.1,2
2L = second-line; BICR = blinded independent central review; dMMR = deficient mismatch repair; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; HER = human epidermal growth factor receptor; IHC = immunohistochemistry; ISH = in situ hybridization; LVEF = left ventricular ejection fraction; mAb = monoclonal antibody; mCRC = metastatic colorectal cancer; MSI-H = microsatellite instability-high; NGS = next-generation sequencing; ORR = overall response rate; OS = overall survival; PD-1 = programmed cell death protein-1; PFS = progression-free survival; RECIST = Response Evaluation Criteria in Solid Tumors; VEGF = vascular endothelial growth factor; WT = wild type.
Select Important Safety Information
Warnings and Precautions
- Embryo-Fetal Toxicity: TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for 1 week after the last dose.
MOUNTAINEER ASSESSED A BROAD RANGE OF 2L+ PATIENTS WITH RAS WT, HER2+ mCRC1,2
Patients evaluated in MOUNTAINEER had not received prior anti-HER2 therapy1
| Baseline patient characteristics | TUKYSA + trastuzumab | |||||
|---|---|---|---|---|---|---|
| AGE | ||||||
| Median, years (range) | 55 (24-77) | |||||
| Age ≥65 years | 14% | |||||
| GENDER | ||||||
| Male | 61% | |||||
| RACE/ETHNICITY | ||||||
| White | 77% | |||||
| Black | 4% | |||||
| Asian | 4% | |||||
| Hispanic or Latino | 4% | |||||
| PRIMARY TUMOR LOCATION | ||||||
| Left colon | 85% | |||||
| Transverse colon | 8% | |||||
| Right colon | 6% | |||||
| Multiple/overlapping sites | 1% | |||||
| ECOG PERFORMANCE STATUS | ||||||
| 0 | 60% | |||||
| 1 | 37% | |||||
| 2 | 4% | |||||
| SELECT METASTATIC SITES | ||||||
| Liver metastases | 64% | |||||
| Lung metastases | 70% | |||||
| PRIOR THERAPIES | ||||||
| Fluoropyrimidine, oxaliplatin, and irinotecan | 99% | |||||
| Anti-VEGF antibodies | 83% | |||||
| Anti-EGFR antibodies | 52% | |||||
| PRIOR LINES OF THERAPY | ||||||
| 1 | 23% | |||||
| 2 | 38% | |||||
| ≥3 | 39% | |||||
2L = second-line; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; HER = human epidermal growth factor receptor; mCRC = metastatic colorectal cancer; VEGF = vascular endothelial growth factor; WT = wild type.
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Important Safety Information
Warnings and Precautions
- Diarrhea: TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death. If diarrhea occurs, administer antidiarrheal treatment as clinically indicated. Perform diagnostic tests as clinically indicated to exclude other causes of diarrhea. Based on the severity of the diarrhea, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
In MOUNTAINEER, when TUKYSA was given in combination with trastuzumab, diarrhea occurred in 64% of patients, including Grade 3 (3.5%), Grade 2 (10%), and Grade 1 (50%). - Hepatotoxicity: TUKYSA can cause severe hepatotoxicity. Monitor ALT, AST, and bilirubin prior to starting TUKYSA, every 3 weeks during treatment, and as clinically indicated. Based on the severity of hepatotoxicity, interrupt dose, then dose reduce or permanently discontinue TUKYSA.
In MOUNTAINEER, 6% of patients had a bilirubin increase > 3 × ULN (Grade ≥3), 6% had an AST increase > 5 × ULN, and 4.7% had an ALT increase > 5 × ULN. Hepatotoxicity led to dose reduction of TUKYSA in 3.5% of patients and discontinuation of TUKYSA in 2.3% of patients. - Embryo-Fetal Toxicity: TUKYSA can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential, and male patients with female partners of reproductive potential, to use effective contraception during TUKYSA treatment and for 1 week after the last dose.
Adverse Reactions
Serious adverse reactions occurred in 22% of patients; the most common (in ≥2% of patients) were intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia, abdominal pain, and rectal perforation (2.3% each).
Adverse reactions leading to permanent discontinuation of TUKYSA occurred in 6% of patients; the most common (in ≥2% of patients) was increased ALT (2.3%). Adverse reactions leading to dosage interruption occurred in 23% of patients; the most common (in ≥3% of patients) were increased ALT and diarrhea (3.5% each). Adverse reactions leading to dose reduction occurred in 9% of patients; the most common (in ≥2% of patients) were increased ALT and diarrhea (2.3% each).
The most common adverse reactions (≥20%) in patients treated with TUKYSA and trastuzumab were diarrhea, fatigue, rash, nausea, abdominal pain, infusion-related reactions, and pyrexia.
Other adverse reactions (<10%) include epistaxis (7%), weight decreased (7%), oropharyngeal pain (5%), oral dysesthesia (1%), and stomatitis (1%).
Lab Abnormalities
In MOUNTAINEER, Grade ≥3 laboratory abnormalities reported in ≥5% of patients who received TUKYSA were decreased lymphocytes, decreased sodium, increased AST, and increased bilirubin.
The mean increase in serum creatinine was 32% within the first 21 days of treatment with TUKYSA. The serum creatinine increases persisted throughout treatment and were reversible in 87% of patients with values outside normal lab limits upon treatment completion. Consider alternative markers of renal function if persistent elevations in serum creatinine are observed.
Drug Interactions
- Strong CYP3A/Moderate CYP2C8 Inducers: Concomitant use may decrease TUKYSA activity. Avoid concomitant use of TUKYSA.
- Strong or Moderate CYP2C8 Inhibitors: Concomitant use of TUKYSA with a strong CYP2C8 inhibitor may increase the risk of TUKYSA toxicity; avoid concomitant use. Increase monitoring for TUKYSA toxicity with moderate CYP2C8 inhibitors.
- CYP3A Substrates: Concomitant use may increase the toxicity associated with a CYP3A substrate. Avoid concomitant use of TUKYSA with a CYP3A substrate, where minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP3A substrate dosage.
- P-gp Substrates: Concomitant use may increase the toxicity associated with a P-gp substrate. Consider reducing the dosage of P-gp substrates, where minimal concentration changes may lead to serious or life-threatening toxicities.
Use in Specific Populations
- Lactation: Advise women not to breastfeed while taking TUKYSA and for 1 week after the last dose.
- Hepatic Impairment: Reduce the dose of TUKYSA for patients with severe (Child-Pugh C) hepatic impairment.
REF-7647_FINAL_01/23
Indication
TUKYSA is indicated in combination with trastuzumab for the treatment of adult patients with RAS wild-type, HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Please see full Prescribing Information.
References
1. TUKYSA [Prescribing Information]. Bothell, WA: Seagen Inc. January 2023. 2. Strickler JH, Cercek A, Siena S, et al; MOUNTAINEER investigators.Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 2023;24(5):496-508. doi:10.1016/S1470-2045(23)00150-X 3. Strickler JH, Cercek A, Siena S, et al; MOUNTAINEER investigators. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 2023;24(5):496-508. Supplementary appendix. doi:10.1016/S1470-2045(23)00150-X