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First-line Advanced RCC

Overview

Efficacy Measures: OS, PFS, & ORR

Safety & Tolerability Profile

Dosing

Therapy Management Strategies

MOAs – INLYTA and pembrolizumab

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Second-line Advanced RCC

Overview

Efficacy Measures: PFS, ORR, OS, & Subset
​​​​​​​Analyses

Safety & Tolerability Profile

Patient Characteristics & Treatment
Considerations 

Oral Dosing

VEGFR Pathway & INLYTA® (axitinib) MOA

NCCN Recommendation

​​​​​​​Professional Resources

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VEGFR Pathway & INLYTA® (axitinib) MOA

​​​​​​​INLYTA® (axitinib) for 2nd-Line Treatment of Advanced RCC

VEGFR pathway

THE VEGFR PATHWAY IS A PRIMARY DRIVER IN RCC1,2

    • VEGF plays an important role in RCC, in which it is constitutively upregulated1,2
    • VEGF acts on 3 receptors: VEGFR-1, -2, and -3, which are implicated in pathologic angiogenesis, lymphangiogenesis, tumor growth, and cancer progression3-6
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  • Preclinical evidence demonstrates that the VEGFR pathway plays a key role in continued RCC tumor growth and spread3,7
  • Preclinical activity does not necessarily correlate with clinical outcomes

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INLYTA mechanism of action (MOA)​​​​​​​

INLYTA WAS DESIGNED TO INHIBIT RECEPTOR TYROSINE KINASES, INCLUDING VEGFR-1, -2, AND -3

    • INLYTA has been shown to inhibit receptor tyrosine kinases, including VEGFR-1, -2, and -3, in vitro and in preclinical models
    • Preclinical models suggest that the VEGFR pathway contributes to tumor growth and cancer progression by stimulating pathological angiogenesis and impacting immune cell activity in the tumor microenvironment8
    • Preclinical activity does not necessarily correlate with clinical outcomes
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References

  1. Brieger J, Weidt EJ, Schirmacher P, Störkel S, Huber C, Decker HJ. Inverse regulation of vascular endothelial growth factor and VHL tumor suppressor gene in sporadic renal cell carcinomas is correlated with vascular growth: an in vivo study on 29 tumors. J Mol Med (Berl). 1999;77(6):505-510.
  2. Linehan WM, Vasselli J, Srinivasan R, et al. Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res. 2004;10(18, pt 2):6282S-6289S.
  3. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14(22):7272-7283.
  4. Alitalo A, Detmar M. Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene. 2012;31(42):4499-4508.
  5. Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2012;2(7):a006502.
  6. Duignan IJ, Corcoran E, Pennello A, et al. Pleiotropic stromal effects of vascular endothelial growth factor receptor 2 antibody therapy in renal cell carcinoma models. Neoplasia. 2011;13(1):49-59.
  7. Han KS, Raven PA, Frees S, et al. Cellular adaptation to VEGF-targeted antiangiogenic therapy induces evasive resistance by overproduction of alternative endothelial cell growth factors in renal cell carcinoma. Neoplasia. 2015;17(11):805-816.
  8. Yuan H, Cai P, Li Q, et al. Axitinib augments antitumor activity in renal cell carcinoma via STAT3-dependent reversal of myeloid-derived suppressor cell accumulation. Biomed Pharmacother. 2014;68(6):751-756.

INLYTA for 2nd-Line Treatment of Advanced RCC

  • Overview
  • Efficacy Measures: PFS, ORR, OS, & Subset Analyses
  • Safety & Tolerability Profile​​​​​​​
  • Patient Characteristics & Treatment Considerations
  • Oral Dosing
  • VEGFR Pathway & INLYTA® (axitinib) MOA
  • NCCN Recommendation
  • Professional Resources

Efficacy Measures

Including PFS, ORR, and OS, as well as prespecified subset analysis

View the data

Safety & Tolerability Profile

Including Warnings & Precautions, most common adverse events, duration of treatment, and real-world dosing data

Examine the profile

Patient Characteristics & Treatment Considerations

Patient characteristics and clinical factors to consider when selecting a 2nd-line treatment for advanced RCC

Explore considerations
Hypertension including hypertensive crisis has been observed. Blood pressure should be well controlled prior to initiating INLYTA. Monitor for hypertension and treat as needed. For persistent hypertension despite use of antihypertensive medications, reduce the dose. Discontinue INLYTA if hypertension is severe and persistent despite use of antihypertensive therapy and dose reduction of INLYTA, and discontinuation should be considered if there is evidence of hypertensive crisis.

Arterial and venous thrombotic events have been observed and can be fatal. Use with caution in patients who are at increased risk for, or who have a history of, these events.

Hemorrhagic events, including fatal events, have been reported. INLYTA has not been studied in patients with evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. If any bleeding requires medical intervention, temporarily interrupt the INLYTA dose.

Cardiac failure has been observed and can be fatal. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require permanent discontinuation of INLYTA.

Gastrointestinal perforation and fistula, including death, have occurred. Use with caution in patients at risk for gastrointestinal perforation or fistula. Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment.

Hypothyroidism requiring thyroid hormone replacement has been reported. Monitor thyroid function before initiation of, and periodically throughout, treatment.

INLYTA has the potential to adversely affect wound healing. Withhold INLYTA for at least 2 days prior to elective surgery. Do not administer INLYTA for at least 2 weeks following major surgery and until adequate wound healing. The safety of resuming INLYTA after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) has been observed. If signs or symptoms occur, permanently discontinue treatment.

Monitor for proteinuria before initiation of, and periodically throughout, treatment. For moderate to severe proteinuria, reduce the dose or temporarily interrupt treatment with INLYTA.

Liver enzyme elevation has occurred during treatment with INLYTA as a single agent. INLYTA in combination with pembrolizumab can cause hepatotoxicity with higher than expected frequencies of Grades 3 and 4 alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation. Monitor ALT, AST, and bilirubin before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are used for monotherapy. Consider withholding INLYTA and/or pembrolizumab, initiating corticosteroid therapy, and/or permanently discontinuing the combination for severe or life-threatening hepatotoxicity.

For patients with moderate hepatic impairment, the starting dose of INLYTA should be decreased. INLYTA has not been studied in patients with severe hepatic impairment.

INLYTA can cause fetal harm. Advise patients of the potential risk to the fetus and to use effective contraception. When INLYTA is used in combination with pembrolizumab, refer to the full Prescribing Information of pembrolizumab for pregnancy and contraception information.

Avoid strong CYP3A4/5 inhibitors. If unavoidable, reduce the dose of INLYTA. Grapefruit or grapefruit juice may also increase INLYTA plasma concentrations and should be avoided.

Avoid strong CYP3A4/5 inducers and, if possible, avoid moderate CYP3A4/5 inducers.

Fatal adverse reactions (ARs) occurred in 3.3% of patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC. These included 3 cases of cardiac arrest, 2 cases of pulmonary embolism, and 1 case each of cardiac failure, death due to unknown cause, myasthenia gravis, myocarditis, Fournier’s gangrene, plasma cell myeloma, pleural effusion, pneumonitis, and respiratory failure.


The most common (≥20%) ARs (all grades, vs sunitinib) occurring in patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC were diarrhea (56% vs 45%), fatigue/asthenia (52% vs 51%), hypertension (48% vs 48%), hepatotoxicity (39% vs 25%), nausea (28% vs 32%), constipation (21% vs 15%), hypothyroidism (35% vs 32%), decreased appetite (30% vs 29%), palmar-plantar erythrodysesthesia (28% vs 40%), stomatitis/mucosal inflammation (27% vs 41%), rash (25% vs 21%), dysphonia (25% vs 3.3%), and cough (21% vs 14%).

The most common (≥20%) Grade 3/4 ARs (vs sunitinib) occurring in patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC were hypertension (24% vs 20%) and hepatotoxicity (20% vs 4.9%).

The most common (≥20%) lab abnormalities (all grades, vs sunitinib) occurring in patients receiving INLYTA in combination with pembrolizumab as first-line treatment for advanced RCC included hyperglycemia (62% vs 54%), increased ALT (60% vs 44%), increased AST (57% vs 56%), increased creatinine (43% vs 40%), hyponatremia (35% vs 29%), hyperkalemia (34% vs 22%), hypoalbuminemia (32% vs 34%), hypercalcemia (27% vs 15%), hypophosphatemia (26% vs 49%), increased alkaline phosphatase (26% vs 30%), hypocalcemia (22% vs 29%), increased blood bilirubin (22% vs 21%), prolonged activated partial thromboplastin time (22% vs 14%), lymphopenia (33% vs 46%), anemia (29% vs 65%), and thrombocytopenia (27% vs 78%).

The most common (≥20%) ARs (all grades, vs sorafenib) in patients receiving INLYTA as second-line treatment for advanced RCC were diarrhea (55% vs 53%), hypertension (40% vs 29%), fatigue (39% vs 32%), decreased appetite (34% vs 29%), nausea (32% vs 22%), dysphonia (31% vs 14%), palmar-plantar erythrodysesthesia syndrome (27% vs 51%), weight decreased (25% vs 21%), vomiting (24% vs 17%), asthenia (21% vs 14%), and constipation (20% vs 20%).

The most common (≥10%) Grade 3/4 ARs (vs sorafenib) occurring in patients receiving INLYTA as second-line treatment for advanced RCC were hypertension (16% vs 11%), diarrhea (11% vs 7%), and fatigue (11% vs 5%).

The most common (≥20%) lab abnormalities (all grades, vs sorafenib) occurring in patients receiving INLYTA as second-line treatment for advanced RCC included increased creatinine (55% vs 41%), decreased bicarbonate (44% vs 43%), hypocalcemia (39% vs 59%), decreased hemoglobin (35% vs 52%), decreased lymphocytes (absolute) (33% vs 36%), increased ALP (30% vs 34%), hyperglycemia (28% vs 23%), increased lipase (27% vs 46%), increased amylase (25% vs 33%), increased ALT (22% vs 22%), and increased AST (20% vs 25%).

INLYTA® (axitinib) in combination with pembrolizumab is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

INLYTA as a single agent is indicated for the treatment of advanced RCC after failure of one prior systemic therapy.
Please see full Prescribing Information for INLYTA.

INDICATIONS

INLYTA® (axitinib) in combination with pembrolizumab is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

​​​​​​​INLYTA as a single agent is indicated for the treatment of advanced RCC after failure of one prior systemic therapy.​​​​​​​

Please see  full Prescribing Information.

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