TUKYSA + trastuzumab
38% ORR AND >1 YEAR (12.4 MONTHS) mDOR IN 2L+ PATIENTS WITH RAS WT, HER2+ mCRC1
Durable and confirmed response1
The longest mDOR reported in 2L+ patients with RAS WT, HER2+ mCRC1-4
Exploratory analysis
DISEASE CONTROL RATE WAS 71%5
DCR, which includes SD, was an exploratory post-hoc calculation and not a prespecified endpoint. Unlike in a randomized trial, the interpretation and clinical relevance of some endpoints are unclear in a single-arm trial without a comparable control arm. It's unknown if SD is a result of a natural disease progression or treatment with TUKYSA® (tucatinib) + trastuzumab.
DCR was defined as the total ORR, which is the sum of CR and PR, plus SD. Per RECIST v1.1, SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.6
*Based on Kaplan-Meier method.1
†Based on observed duration of response.1
2L = second-line; CI = confidence interval; CR = complete response; DOR = duration of response; DCR = disease control rate; HER = human epidermal growth factor receptor; mCRC = metastatic colorectal cancer; mDOR = median duration of response; ORR = overall response rate; PD = progressive disease; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease; WT = wild type.
SAFETY PROFILE IN MOUNTAINEER
Of the most common adverse reactions, a majority were Grade 1 or 21
| Adverse reactions in ≥10% of patients | ||||||||
|---|---|---|---|---|---|---|---|---|
| TUKYSA + trastuzumab (N = 86*) | ||||||||
| All grades (%) | Grade 3 (%) | |||||||
| GASTROINTESTINAL DISORDERS | ||||||||
| Diarrhea | 64 | 3.5 | ||||||
| Nausea | 35 | 0 | ||||||
| Vomiting | 16 | 0 | ||||||
| Abdominal pain† | 21 | 2.3 | ||||||
| Constipation | 14 | 1.2 | ||||||
| GENERAL DISORDERS | ||||||||
| Fatigue | 44 | 2.3 | ||||||
| Pyrexia | 20 | 0 | ||||||
| Chills | 19 | 1.2 | ||||||
| SKIN AND SUBCUTANEOUS DISORDERS | ||||||||
| Rash‡ | 37 | 0 | ||||||
| INJURY, POISONING, AND PROCEDURAL COMPLICATIONS | ||||||||
| Infusion-related reaction | 21 | 0 | ||||||
| METABOLISM AND NUTRITION DISORDERS | ||||||||
| Decreased appetite | 19 | 0 | ||||||
| BLOOD AND LYMPHATIC SYSTEM DISORDERS | ||||||||
| Anemia | 10 | 0 | ||||||
| VASCULAR DISORDERS | ||||||||
| Hypertension | 17 | 7 | ||||||
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS | ||||||||
| Back pain | 17 | 2.3 | ||||||
| Arthralgia | 16 | 1.2 | ||||||
| Myalgia | 13 | 0 | ||||||
| RESPIRATORY, THORACIC, AND MEDIASTINAL DISORDERS | ||||||||
| Cough | 16 | 0 | ||||||
| Dyspnea | 14 | 0 | ||||||
| PSYCHIATRIC DISORDERS | ||||||||
| Anxiety | 10 | 0 | ||||||
*Includes 1 patient who only received trastuzumab.1
†Abdominal pain includes abdominal discomfort, abdominal pain, and abdominal pain upper.1
‡Rash includes acne, dermatitis acneiform, dermatitis contact, erythema, erythema multiforme, rash, rash macular, rash maculo-papular, rash papular, rash pustular, skin exfoliation, and urticaria.1
- Serious adverse reactions that occurred in ≥2% of patients were intestinal obstruction (7%), urinary tract infection (3.5%), pneumonia (2.3%), abdominal pain (2.3%), and rectal perforation (2.3%)1
- The most common laboratory abnormalities reported in ≥20% of patients were increased creatinine, increased glucose, increased ALT, decreased hemoglobin, increased AST, increased bilirubin, increased alkaline phosphatase, decreased lymphocytes, decreased albumin, decreased leukocytes, and decreased sodium1
- 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 observed1
No Grade 5 adverse reactions were reported in the trial5
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
TUKYSA + trastuzumab
ADVERSE REACTIONS OF CLINICAL INTEREST1
The Prescribing Information for TUKYSA contains warnings and precautions for diarrhea, hepatotoxicity, and embryo-fetal toxicity, some of which may be severe or fatal. Please see full Important Safety Information for more details.
Diarrhea
- TUKYSA can cause severe diarrhea including dehydration, hypotension, acute kidney injury, and death
- 64% of patients experienced diarrhea, with 3.5% experiencing a Grade 3 event
- Diarrhea led to dose interruption in 3.5% of patients and dose reduction in 2.3% of patients
- If diarrhea occurs, administer antidiarrheal treatment and perform diagnostic tests to exclude other causes, as clinically indicated. Based on the severity, interrupt dose and then dose reduce or permanently discontinue TUKYSA® (tucatinib)
Hepatotoxicity
- TUKYSA can cause severe hepatotoxicity
- 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
- 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
For information on how to manage select adverse reactions associated with TUKYSA and trastuzumab, please refer to the respective Prescribing Information for each agent
ULN = upper limit of normal.
DOSE ADJUSTMENTS IN MOUNTAINEER1
Dose interruptions, reductions, and discontinuations due to adverse reactions
- The adverse reaction which resulted in permanent discontinuation of TUKYSA in ≥2% of patients was increased ALT (2.3%)
- Adverse reactions which required dose reductions in ≥2% of patients were increased ALT (2.3%) and diarrhea (2.3%)
- Adverse reactions which required dose interruption in ≥3% of patients were increased ALT (3.5%) and diarrhea (3.5%)
6% of patients discontinued and 9% of patients dose reduced TUKYSA due to adverse reactions
To learn about dose modifications for TUKYSA and trastuzumab, please refer to the respective Prescribing Information for each agent.
ALT = alanine aminotransferase.
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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. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(6):738-746. doi:10.1016/S1470-2045(16)00150-9 3. Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019;20(4):518-530. doi:10.1016/S1470-2045(18)30904-5 4. Yoshino T, Di Bartolomeo M, Raghav KPS, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2022;40(suppl 4):119. doi:10.1200/JCO.2022.40.4_suppl.119 5. 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 6. Villaruz LC, Socinski MA. The clinical viewpoint: definitions, limitations of RECIST, practical considerations of measurement. Clin Cancer Res. 2013;19(10):2629-2636. doi:10.1158/1078-0432.CCR-12-2935