Avmapki Fakzynja Drug Information
Generic name: AVUTOMETINIB POTASSIUM AND DEFACTINIB HYDROCHLORIDE
Uses of Avmapki Fakzynja
AVMAPKI FAKZYNJA CO-PACK is indicated for the treatment of adult patients with KRAS -mutated recurrent low-grade serous ovarian cancer (LGSOC) who have received prior systemic therapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Dosage & Administration of Avmapki Fakzynja
Patient Selection
Select patients for the treatment of recurrent LGSOC with AVMAPKI FAKZYNJA CO-PACK based on the presence of a KRAS mutation in tumor specimens. An FDA-approved test for the detection of a KRAS mutation in LGSOC for selecting patients for treatment with AVMAPKI FAKZYNJA CO-PACK is not available.
Eye Exams and Prophylactic Skin Medications Ophthalmic Exams Conduct a comprehensive ophthalmic exam at baseline, prior to cycle 2, and every three cycles thereafter regardless of baseline exam findings, and as clinically indicated. Prophylactic Medications for Skin Reactions With initiation of and during at least the first 2 cycles of AVMAPKI FAKZYNJA CO-PACK administer: Topical corticosteroid (applied to the face, scalp, neck, upper chest and upper back) Systemic oral antibiotics
Recommended Dosage and Administration AVMAPKI Capsules
The recommended dosage of AVMAPKI capsules is 3.2 mg (four 0.8 mg capsules) taken orally twice weekly (Day 1 and Day 4) for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Take AVMAPKI at the same time with each dose. AVMAPKI should be taken with food.
Swallow capsules whole. Do not chew, break, or open the capsules. If a dose of AVMAPKI is missed by more than 24 hours, skip the missed dose and take the next scheduled dose as prescribed.
Do not take two doses at the same time to make up for a missed dose. If vomiting occurs after taking AVMAPKI, do not take an additional dose. Take the next scheduled dose as prescribed.
FAKZYNJA Tablets The recommended dosage of FAKZYNJA tablets is 200 mg (one tablet) taken orally twice daily for the first 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Take each dose of FAKZYNJA with food. Swallow tablets whole.
Do not chew, break or crush the tablets.
Dosage Modifications for Adverse Reactions
Dose reductions due to adverse reactions due to AVMAPKI FAKZYNJA CO-PACK are summarized in Table 1. Table 2 AVMAPKI FAKZYNJA CO-PACK Dosage Modifications Retinal Pigment Epithelial (RPE) Detachment Increased Blood Creatine Phosphokinase (CPK)
| Dose Level | AVMAPKI Capsule | FAKZYNJA Tablet |
|---|---|---|
| Starting dose | 3.2 mg twice weekly for first 3 weeks of each 4-week cycle | 200 mg twice daily for first 3 weeks of each 4-week cycle |
| Dose reduction | 2.4 mg twice weekly for first 3 weeks of each 4-week cycle | 200 mg once daily for first 3 weeks of each 4-week cycle |
| Permanently discontinue both AVMAPKI and FAKZYNJA in patients unable to tolerate after one dose reduction of both products. | ||
| Adverse Reaction | Severity Severity as defined by National Center Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0 | Dose Modification |
|---|---|---|
| N/A: Not applicable | ||
| Keratitis [see Warnings and Precautions (5.1) ] | Confluent superficial keratitis, a cornea epithelial defect, or 3-line or more loss in best corrected distance visual acuity | Withhold AVMAPKI FAKZYNJA CO-PACK until resolved to nonconfluent superficial keratitis, then resume at same dose. |
| Corneal ulcer or stromal opacity or best corrected distance visual acuity 20/200 or worse Corneal perforation | Withhold AVMAPKI FAKZYNJA CO-PACK until resolved to nonconfluence superficial keratitis, then resume at reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK. | |
| Blurred vision [see Warnings and Precautions (5.1) ] | BCVA worse than baseline but no worse than 20/200 | Withhold AVMAPKI FAKZYNJA CO-PACK until resolution to baseline or 20/40, whichever is worse, then resume treatment at same dose. |
| BCVA 20/200 or worse | Withhold AVMAPKI FAKZYNJA CO-PACK until resolution to baseline or 20/40, whichever is worse, then resume at reduced dose. | |
| Conjunctivitis [see Warnings and Precautions (5.1) ] | Confluent superficial punctate staining, moderate to severe vasodilation | Withhold AVMAPKI FAKZYNJA CO-PACK until resolution to nonconfluent superficial keratitis, then resume at same dose. |
| Conjunctival ulcer or neovascularization | Withhold AVMAPKI FAKZYNJA CO-PACK until resolution to nonconfluent superficial keratitis, then resume at reduced dose. | |
| Retinal Pigment Epithelial (RPE) Detachment [see Warnings and Precautions (5.1) ] | N/A | First occurrence Repeat Optical Coherence Tomography (OCT) examination in two weeks. First follow-up OCT examination and RPE present Reduce dose of AVMAPKI FAKZYNJA CO-PACK Repeat OCT examination in two weeks. Second follow-up OCT examination and RPE present and/or loss of 1 line in BCVA: Withhold AVMAPKI FAKZYNJA CO-PACK Repeat OCT examination in two weeks. Third follow-up OCT examination RPE resolving/resolved, resume at reduced dose. No resolution, permanently discontinue AVMAPKI FAKZYNJA CO-PACK |
| Rash [see Warnings and Precautions (5.2) ] | Grade ≤ 2 | Consider withholding AVMAPKI FAKZYNJA CO-PACK if rash does not respond to supportive care or recurs after resolution to Grade ≤1. Dose reduce AVMAPKI FAKZYNJA CO-PACK for intolerable Grade 2. |
| Grade 3 | Withhold AVMAPKI FAKZYNJA CO-PACK until resolved to Grade 2 then resume at reduced dose. Resume at same dose if resolved to Grade ≤1. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for recurrent Grade 3 despite dose reduction. | |
| Grade 4 | Permanently discontinue AVMAPKI FAKZYNJA CO-PACK. | |
| Hepatotoxicity [see Warnings and Precautions (5.3) ] | Grade 2 | Withhold AVMAPKI FAKZYNJA CO-PACK for Grade 2 hyperbilirubinemia (without Gilbert's syndrome) with Grade ≤1 increase in AST and/or ALT until hyperbilirubinemia Grade ≤1, then resume at same dose. Grade 2 hyperbilirubinemia with Grade 2 increase in AST and/or ALT until hyperbilirubinemia Grade ≤1 or baseline, then resume at same dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for Grade 2 hyperbilirubinemia associated with Grade >2 increase in AST and/or ALT. |
| Grade 3 | Withhold AVMAPKI FAKZYNJA CO-PACK if Grade 3 hyperbilirubinemia is associated with Grade ≤1 increase in AST and/or ALT until hyperbilirubinemia Grade ≤1 or at baseline, then resume at same dose. if recurrent Grade 3 hyperbilirubinemia is associated with Grade ≤1 increase in AST and/or ALT until hyperbilirubinemia Grade ≤2 or at baseline, then resume at reduced dose. if Grade 3 increased AST and/or ALT is not associated with hyperbilirubinemia until Grade ≤2 or at baseline, then resume at reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for Grade 3 hyperbilirubinemia associated with Grade ≥2 increase in AST and/or ALT. | |
| Grade 4 | Withhold AVMAPKI FAKZYNJA CO-PACK for Grade 4 hyperbilirubinemia associated with Grade ≤1 increase in AST and/or ALT and if resolves within one week resume at reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for Grade 4 increase in AST and/or ALT. Grade 4 hyperbilirubinemia associated with Grade ≤1 increase in AST and/or ALT that does not resolve within 1 week. Grade 4 hyperbilirubinemia associated with Grade ≥2 increase in AST and/or ALT. | |
| Increased Blood Creatine Phosphokinase (CPK) [see Warnings and Precautions (5.4) ] | Grade 3 | Withhold AVMAPKI FAKZYNJA CO-PACK, if improves to Grade ≤1 within three weeks resume at same dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for CPK elevation longer than three weeks. |
| Grade 4 | Withhold AVMAPKI FAKZYNJA CO-PACK, if improves to Grade ≤1 within three weeks resume at reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for CPK elevation longer than three weeks. | |
| Any grade CPK elevation with rhabdomyolysis or other event related to CPK elevation | Permanently discontinue AVMAPKI FAKZYNJA CO-PACK | |
| Other Adverse Reactions | Grade 2 | Consider withholding AVMAPKI FAKZYNJA CO-PACK if adverse reaction does not respond to supportive care or recurs after resolution to Grade ≤1. |
| Grade 3 | First occurrence: Withhold AVMAPKI FAKZYNJA CO-PACK until resolved to baseline or Grade ≤1 then resume at same dose. Second occurrence: Withhold AVMAPKI FAKZYNJA CO-PACK until resolved to baseline or Grade ≤1 then resume at reduced dose. Permanently discontinue AVMAPKI FAKZYNJA CO-PACK for recurrent Grade 3 despite dose reduction. | |
| Grade 4 | Permanently discontinue AVMAPKI FAKZYNJA CO-PACK. | |
Side Effects of Avmapki Fakzynja
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The pooled safety population described in Warnings and Precautions reflect exposure to the AVMAPKI FAKZYNJA CO-PACK (combination of AVMAPKI 3.2 mg twice weekly and FAKZYNJA 200 mg twice daily) for the first 3 weeks in a 4-week cycle until disease progression or unacceptable toxicity in 136 adult patients with recurrent LGSOC treated on RAMP-201 and FRAME (NCT03875820). The median duration of treatment was 10 months (range 0 to 51 months).
RAMP-201 The safety of AVMAPKI FAKZYNJA CO-PACK was evaluated in RAMP-201, a single-arm multicenter trial in 57 patients with KRAS- mutated recurrent LGSOC. The median duration of treatment was 12 months (range 0.03-40). Serious adverse reactions occurred in 32% of patients who received AVMAPKI FAKZYNJA CO-PACK.
Fatal adverse reactions occurred in 3.6% of patients who received AVMAPKI FAKZYNJA CO-PACK, including intestinal obstruction (1.8%) and perforation (1.8%). Permanent discontinuation of AVMAPKI FAKZYNJA CO-PACK due to an adverse reaction occurred in 14% of patients. The adverse reactions leading to permanent discontinuation included elevations in creatine phosphokinase, dyspnea, malaise, decreased glomerular filtration rate, hyperbilirubinemia, increased alanine aminotransferase, and abdominal pain (1.8% each).
Dosage interruptions of AVMAPKI FAKZYNJA CO-PACK due to an adverse reaction occurred in 84% of patients. Dose reductions of AVMAPKI FAKZYNJA CO-PACK due to an adverse reaction occurred in 44% of patients. The most common (≥25%) adverse reactions, including laboratory abnormalities, were increased creatine phosphokinase, nausea, fatigue, increased aspartate aminotransferase, rash, diarrhea, musculoskeletal pain, edema, decreased hemoglobin, increased alanine aminotransferase, vomiting, increased blood bilirubin, increased triglycerides, decreased lymphocyte count, abdominal pain, dyspepsia, dermatitis acneiform, vitreoretinal disorders, increased alkaline phosphatase, stomatitis, pruritus, visual impairment, decreased platelet count, constipation, dry skin, dyspnea, cough, urinary tract infection, and decreased neutrophil count.
Table 3 summarizes the adverse reactions in RAMP-201. Table 3 Adverse Reactions (≥10%) in Patients with KRAS-Mutated Recurrent LGSOC who Received AVMAPKI FAKZYNJA CO-PACK in RAMP-201 Severity as defined by National Center Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. 0 Clinically relevant adverse reactions in < 10% of patients who received AVMAPKI FAKZYNJA CO-PACK included urticaria and decreased ejection fraction. Table 4 summarizes the laboratory abnormalities in RAMP-201.
Table 4 Select Laboratory Abnormalities (≥ 10%) in Patients with KRAS-Mutated Recurrent LGSOC who Received Clinically relevant laboratory abnormalities in < 10% of patients who received AVMAPKI FAKZYNJA CO-PACK included increased INR and prolonged activated partial thromboplastin time.
| Adverse Reaction | AVMAPKI FAKZYNJA CO-PACK N = 57 | |
|---|---|---|
| All Grades % | Grade 3 or 4 No Grade 4 treatment-emergent adverse events occurred. % | |
| Gastrointestinal disorders | ||
| Nausea | 74 | 1.8 |
| Diarrhea | 68 | 7 |
| Vomiting | 49 | 3.5 |
| Abdominal pain Includes multiple terms | 39 | 1.8 |
| Dyspepsia | 37 | 0 |
| Stomatitis | 35 | 3.5 |
| Constipation | 30 | 0 |
| Dry mouth | 18 | 0 |
| Decreased Weight | 11 | 0 |
| General disorders and administration site condition | ||
| Fatigue | 72 | 3.5 |
| Edema | 67 | 1.8 |
| Skin and subcutaneous tissue disorders | ||
| Rash Includes: butterfly rash, dermatitis, drug eruption, erythema, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, and rash pruritic | 72 | 3.5 |
| Dermatitis acneiform Includes: acne, dermatitis acneiform, folliculitis, perioral dermatitis, and rash pustular | 37 | 5.3 |
| Pruritus | 35 | 1.8 |
| Dry skin | 30 | 0 |
| Alopecia | 23 | 0 |
| Photosensitivity | 16 | 0 |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain | 68 | 1.8 |
| Joint swelling | 11 | 0 |
| Eye disorders | ||
| Vitreoretinal disorders Includes: chorioretinopathy, detachment of retinal pigment epithelium, macular fibrosis, macular hole, maculopathy, retinal detachment, retinal drusen, retinal vein occlusion, retinopathy, serous retinal detachment, serous retinopathy, subretinal fluid, vitreous detachment, and vitreous floaters | 37 | 3.5 |
| Visual impairment Includes: asthenopia, astigmatism, halo vision, metamorphopsia, photophobia, photopsia, vision blurred, visual field defect, and visual impairment | 35 | 0 |
| Dry eye | 12 | 0 |
| Respiratory disorders | ||
| Dyspnea | 26 | 5.3 |
| Cough | 25 | 0 |
| Nervous system disorders | ||
| Dizziness | 23 | 1.8 |
| Headache | 16 | 0 |
| Neuropathy peripheral | 14 | 0 |
| Dysgeusia | 11 | 0 |
| Vascular disorders | ||
| Hemorrhage | 23 | 0 |
| Hypertension | 16 | 5.3 |
| Venous thromboembolism | 14 | 5.3 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 18 | 1.8 |
| Infections and infestations | ||
| Urinary tract infection | 25 | 3.5 |
| Paronychia | 14 | 1.8 |
| Upper respiratory tract infection | 11 | 0 |
| Laboratory Abnormality | AVMAPKI FAKZYNJA CO-PACK | |
|---|---|---|
| All Grades (%) The denominator used to calculate the rate varied from 45 to 57 based on the number of patients with a baseline value and at least one post-treatment value. | Grade 3 or 4 (%) | |
| Chemistry | ||
| Increased creatine phosphokinase | 82 | 19 |
| Increased aspartate aminotransferase | 70 | 3.5 |
| Decreased albumin | 70 | 0 |
| Increased alanine aminotransferase | 58 | 3.5 |
| Increased blood bilirubin | 48 | 3.5 |
| Increased triglycerides | 46 | 3.5 |
| Increased alkaline phosphatase | 37 | 1.8 |
| Decreased potassium | 23 | 9 |
| Hematology | ||
| Decreased hemoglobin | 65 | 5 |
| Decreased lymphocyte count | 40 | 1.8 |
| Decreased platelet count | 35 | 0 |
| Decreased neutrophil count | 25 | 1.8 |
| Urine | ||
| Proteinuria | 22 | 4.4 |
Warnings & Cautions for Avmapki Fakzynja
Ocular Toxicities AVMAPKI FAKZYNJA CO-PACK can cause ocular adverse reactions, including visual impairment and vitreoretinal disorders. Ocular adverse reactions occurred in 68% of patients with recurrent LGSOC treated with AVMAPKI FAKZYNJA CO-PACK. Thirty-five patients (26%) experienced vitreoretinal disorders, including retinal detachment (9%), and retinal vein occlusion (0.7%).
Eighteen patients (13%) experienced an ocular adverse reaction that resulted in dose interruption of AVMAPKI FAKZYNJA CO-PACK and one patient experienced an ocular adverse reaction that resulted in dose reduction. The median time to onset of retinal detachment was 27 days (range 2 to 535 days). Of the patients who experienced ocular adverse reactions, 29% had ongoing ocular events at last follow-up.
Refer patients to a qualified eye care professional for a comprehensive ophthalmic exam at baseline, prior to cycle 2, every three cycles thereafter, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs or symptoms. Monitor for ocular adverse reactions and withhold, reduce, or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and persistence of ocular adverse reactions.
Serious Skin Toxicities AVMAPKI FAKZYNJA CO-PACK can cause serious skin toxicities, including Severe Cutaneous Adverse Reactions (SCARs). Cases of acute generalized exanthematous pustulosis, erythema multiforme and drug reaction with eosinophilia and systemic symptoms have been reported in clinical trials of avutometinib (a drug in AVMAPKI FAKZYNJA CO-PACK). Skin toxicities occurred in 94% of patients with recurrent LGSOC treated with AVMAPKI FAKZYNJA CO-PACK.
Thirteen patients (10%) developed bacterial skin infections. Skin toxicity led to dose interruption of AVMAPKI FAKZYNJA CO-PACK in 10%, to dose reduction in 7%, and to permanent discontinuation in 0.7% of patients. The median time to onset of the first skin toxicity was 14 days (range 1 to 500 days).
At last follow-up, 66% of patients had ongoing skin toxicity. Patients in RAMP-201 used topical corticosteroids (applied to the face, scalp, neck, upper chest and upper back) and systemic oral antibiotics for prophylaxis of skin adverse reactions. These medications were initiated at the start of AVMAPKI FAKZYNJA CO-PACK and administered during at least the first two cycles of treatment.
Limit unnecessary exposure to sunlight and apply daily sunscreen (sun protection factor ≥ 30). Monitor for skin toxicity and withhold, reduce dose, or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and persistence.
Hepatotoxicity AVMAPKI FAKZYNJA CO-PACK can cause hepatotoxicity. Elevations in one or more liver related laboratory values led to dose interruption for 20%, dose reduction for 2.2%, and permanent discontinuation for 0.7% of patients. Increased blood bilirubin may be attributed to defactinib (a component of AVMAPKI FAKZYNJA CO-PACK) due to the inhibition of enzymes responsible for metabolizing (uridine diphosphate-glucuronosyltransferase (UGT)1A1) and transporting (Organic Anion Transporting Polypeptides (OATP)1B1/1B3) bilirubin.
Monitor liver related laboratory values prior to the start of each cycle, on day 15 of the first four cycles, and as clinically indicated. Withhold, reduce dose, or permanently discontinue AVMAPKI FAKZYNJA CO-PACK based on severity and duration of these adverse reactions.
Rhabdomyolysis AVMAPKI FAKZYNJA CO-PACK can cause increased creatine phosphokinase (CPK). Increased CPK occurred in 75% of patients with recurrent LGSOC treated with AVMAPKI FAKZYNJA CO-PACK, including Grade 3-4 elevations in 18% of patients. Among the patients who experienced an elevation in CPK, concurrent increase in creatinine occurred in 19% (n=19/102) and myalgia occurred in 10% (n=10/102).
Elevation of CPK >10 times the baseline value with a concurrent increase in serum creatinine of ≥1.5 times the baseline value occurred in 0.7% of patients. Increased CPK resulted in dose interruption for 22%, in dose reduction for 7%, and in discontinuation for 2.9% of patients. Rhabdomyolysis has occurred in a patient with LGSOC treated with AVMAPKI FAKZYNJA CO-PACK at the recommended dosage in a clinical trial.
If increased CPK occurs, evaluate patients for rhabdomyolysis or other causes.
Embryo-Fetal Toxicity Based on the mechanisms of action, AVMAPKI FAKZYNJA CO-PACK can cause fetal harm when administered to a pregnant woman. Inhibition of either molecular pathway has been associated with embryo-fetal anomalies and lethality in animals. Advise pregnant women and females of reproductive potential of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with AVMAPKI FAKZYNJA CO-PACK and for 1 month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AVMAPKI FAKZYNJA CO-PACK and for 4 months after the last dose.
Drug Interactions with Avmapki Fakzynja
Effect of Other Drugs on AVMAPKI FAKZYNJA CO-PACK Strong and Moderate CYP3A4 Inhibitors Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with strong or moderate CYP3A4 inhibitors. Defactinib is a CYP3A4 substrate. Concomitant use of defactinib with a strong CYP3A4 inhibitor increases defactinib exposure, which may increase the risk of AVMAPKI FAKZYNJA CO-PACK adverse reactions.
Concomitant use of defactinib with a strong CYP3A4 inducer decreases defactinib exposure, which may reduce the effectiveness of FAKZYNJA. Gastric Acid Reducing Agents Avoid concomitant use of AVMAPKI FAKZYNJA CO-PACK with proton pump inhibitors (PPIs) or H2 receptor antagonists. If concomitant use of an acid-reducing agent cannot be avoided, administer FAKZYNJA 2 hours before or 2 hours after the administration of a locally acting antacid.
Concomitant use of FAKZYNJA with gastric acid reducing agents decreases defactinib exposure, which may reduce the effectiveness of AVMAPKI FAKZYNJA CO-PACK.
Effect of AVMAPKI FAKZYNJA CO-PACK on Other Drugs Warfarin
For patients requiring anticoagulation, an alternative to warfarin is recommended. If concomitant use is unavoidable, monitor INR frequently during treatment with AVMAPKI FAKZYNJA CO-PACK. Cases of bleeding and increased INR occurred in patients taking FAKZYNJA concomitantly with warfarin in clinical trials.
Pregnancy Safety for Avmapki Fakzynja
Pregnancy Risk Summary Based on the mechanisms of action, AVMAPKI FAKZYNJA CO-PACK can cause fetal harm when administered to a pregnant woman. There are no available data on the use of AVMAPKI FAKZYNJA CO-PACK in pregnant women to inform a drug-associated risk. Animal reproductive and developmental toxicity studies have not been conducted with avutometinib or defactinib; however, inhibition of either molecular pathway has been associated with embryo-fetal anomalies and lethality in animals.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.
Pediatric Use of Avmapki Fakzynja
Pediatric Use The safety and effectiveness of AVMAPKI FAKZYNJA CO-PACK in pediatric patients has not been established.
Clinical Studies of Avmapki Fakzynja
The efficacy of AVMAPKI FAKZYNJA CO-PACK was evaluated in RAMP-201 (NCT04625270), an open-label, multicenter study that included 57 adult patients with measurable KRAS -mutated recurrent LGSOC. Patients were required to have received at least one prior systemic therapy, including a platinum-based regimen. KRAS mutation status was determined by prospective local testing using next generation sequencing (NGS) or polymerase chain reaction of tumor tissue specimens.
Patients were excluded if they were candidates for debulking surgery, were on treatment with warfarin, had an active skin disorder requiring systemic therapy within the past year, or had an ocular disorder (including a history of retinal pathology, an active or chronic visually significant corneal disorder, or a history of glaucoma). Patients received AVMAPKI 3.2 mg orally twice weekly for the first 3 weeks out of a 4-week cycle and FAKZYNJA 200 mg orally twice daily for the first 3 weeks out of a 4-week cycle until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) assessed by blinded independent review committee (BIRC) according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.
An additional efficacy outcome measure was duration of response (DoR). Tumor response assessments occurred every 8 weeks for the first 72 weeks and every 12 weeks thereafter. All patients had received prior platinum-based chemotherapy, 84% received prior hormonal therapy (as maintenance or treatment), 40% received prior bevacizumab and 21% received a prior MEK inhibitor.
Efficacy results are presented in Table 5. Table 5 Efficacy Results in RAMP-201 The tumor KRAS mutations observed in the 25 responders were A146V, G12D, G12R, G12V, and Q61H.
| AVMAPKI FAKZYNJA CO-PACK N = 57 | |
|---|---|
| Confirmed Overall Response Rate (95% CI) ORR 95% CI calculated using Clopper-Pearson method | 44% (31,58) |
| Complete response | 3.5% |
| Partial response | 40% |
| Duration of Response (DoR) | |
| Range (months) | 3.3, 31.1 |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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