Efficacy Measures: OS, PFS, & ORR

INLYTA® (axitinib) + pembrolizumab for 1st-Line Treatment of Advanced RCC

Trial design – KEYNOTE-426

A phase 3, randomized, multicenter, open-label trial conducted in patients who had not received systemic therapy for advanced RCC (N=861)

•        KEYNOTE-426 has the longest available follow-up of any phase 3 TKI/IO combination trial to date, with a median patient follow-up of 37.7 months (range: 0.1 to 50.6 months)2-4

*North America vs Western Europe vs “Rest of the World.”

Until RECIST v1.1-defined progression of disease or unacceptable toxicity.

As assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

§As measured by BICR.
BICR=Blinded Independent Central Review; IMDC=International Metastatic RCC Database Consortium; RECIST=Response Evaluation Criteria in Solid Tumors.

SELECTED BASELINE CHARACTERISTICS

Among all patients included in the study (N=861)

  • Median age of 62 years (range: 26-90)
    • 38% aged ≥65 years
  • 73% male
  • 79% White
  • 80% baseline KPS score of 90 to 100
    • 19% baseline KPS score of 70 to 80
    • 1% missing data

Patients were enrolled in the study regardless of PD-L1 tumor expression status.

  • 60.5% PD-L1 ≥11
  • 39.5% PD-L1 <11

IMDC PROGNOSTIC RISK CATEGORY1,5,6

Among all patients included in the study (N=861)

IMDC risk score is determined by the total number of the following 6 risk factors that are present5:

  • KPS score <80
  • Time from initial diagnosis to randomization <1 year
  • Hemoglobin level below the lower limit of the normal range
  • Corrected serum calcium level above the upper limit of the normal range
  • Absolute neutrophil count above the upper limit of the normal range
  • Platelet count above the upper limit of the normal range

IMDC=International Metastatic RCC Database Consortium; KPS=Karnofsky Performance Status; PD-L1=programmed death-ligand 1.

Efficacy results
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INLYTA® (axitinib) + pembrolizumab was the first TKI/IO combination to demonstrate efficacy vs sunitinib across 3 key endpoints1

​​​​​​​KEYNOTE-426: A phase 3, randomized, multicenter, open-label trial conducted in patients who had not received systemic therapy for advanced RCC (N=861)
Data shown here are based on a median follow-up of 12.8 months (range: 0.1 to 22.0 months)


Powerful efficacy: Overall survival (OS—primary endpoint)

INLYTA® (axitinib) + pembrolizumab demonstrated superior OS compared with sunitinib1

  • HR for OS for INLYTA + pembrolizumab vs sunitinib was 0.53 (95% CI: 0.38, 0.74); P<0.0001
  • Median OS was not reached in either group
  • Consistent results were observed across prespecified subgroups, IMDC prognostic risk categories, and PD-L1 tumor expression status
  • The median duration of treatment with INLYTA + pembrolizumab was 10.4 months (range: 1 day to 21.2 months)​​​​​​​​​​​​​​

*Based on the stratified Cox proportional hazard model.

Based on stratified log-rank test.

P value (1-sided) is compared with the allocated alpha of 0.0001 for this interim analysis (with 39% of the planned number of events for the extended follow-up analysis).
IMDC=International Metastatic RCC Database Consortium; OS=overall survival; PD-L1=programmed death-ligand 1.


​​​​​​​Extended follow-up analysis

Data shown here are based on a median follow-up of 37.7 months (range: 0.1 to 50.6 months)2
LIMITATIONS: Although the extended follow-up analysis was prespecified, no formal hypothesis testing was performed given that the endpoints of OS, PFS, and ORR were met in the initial interim analysis. Therefore, no conclusions can be drawn from the extended follow-up analysis.2

Extended follow-up analysis: Overall survival (primary endpoint)2

  • HR for OS for the INLYTA® (axitinib) + pembrolizumab arm vs the sunitinib arm was 0.73 (95% CI: 0.60, 0.88)2*
  • Median OS was 45.7 months for the INLYTA + pembrolizumab arm (95% CI: 43.6, NR) vs 40.1 months for the sunitinib arm (95% CI: 34.3, 44.2)2

*Based on the stratified Cox proportional hazard model.
NR=not reached.

 

Efficacy results

​​​​​​​

KEYNOTE-426: A phase 3, randomized, multicenter, open-label trial conducted in patients who had not received systemic therapy for advanced RCC (N=861)
Data shown here are based on a median follow-up of 12.8 months (range: 0.1 to 22.0 months)

Powerful efficacy: Progression-free survival (PFS—primary endpoint)

INLYTA® (axitinib) + pembrolizumab demonstrated superior PFS vs sunitinib​​​​​​​1

  • ~4-month improvement in median PFS with INLYTA + pembrolizumab vs sunitinib

*Based on the stratified Cox proportional hazard model.

Based on stratified log-rank test.

P value (1-sided) is compared with the allocated alpha of 0.0013 for this interim analysis (with 81% of the planned number of events for the extended follow-up analysis).
mPFS=median progression-free survival; PFS=progression-free survival.

Extended follow-up analysis

Data shown here are based on a median follow-up of 37.7 months (range: 0.1 to 50.6 months)2
​​​​​​​
LIMITATIONS: Although the extended follow-up analysis was prespecified, no formal hypothesis testing was performed given that the endpoints of OS, PFS, and ORR were met in the initial interim analysis. Therefore, no conclusions can be drawn from the extended follow-up analysis.2

Extended follow-up analysis: Progression-free survival (primary endpoint)2

  • HR for PFS for the INLYTA® (axitinib) + pembrolizumab arm vs the sunitinib arm was 0.68 (95% CI: 0.58, 0.80)2*
  • Median PFS was 15.7 months for the INLYTA + pembrolizumab arm (95% CI: 13.6, 20.2) vs 11.1 months for the sunitinib arm (95% CI: 8.9, 12.5)2

*Based on the stratified Cox proportional hazard model.
PFS=progression-free survival. 

Efficacy results


KEYNOTE-426: A phase 3, randomized, multicenter, open-label trial conducted in patients who had not received systemic therapy for advanced RCC (N=861)
Data shown here are based on a median follow-up of 12.8 months (range: 0.1 to 22.0 months)

Powerful efficacy: Overall confirmed response rate (ORR—secondary endpoint)

INLYTA® (axitinib) + pembrolizumab demonstrated significantly higher ORR vs sunitinib1

Per RECIST v1.1 guidelines7:

  • Complete response is evaluated as the disappearance of all target lesions
  • Partial response is evaluated as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter

*Confirmed ORR (CR + PR) is based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as defined by BICR with 2 measurements at least 4 weeks apart.
 

Based on Miettinen and Nurminen method stratified by IMDC risk group and geographic region.
BICR=Blinded Independent Central Review; CR=complete response; IMDC=International Metastatic RCC Database Consortium;
ORR=overall response rate; PR=partial response.

 

Extended follow-up analysis

Data shown here are based on a median follow-up of 37.7 months (range: 0.1 to 50.6 months)2​
​​​​
LIMITATIONS: Although the extended follow-up analysis was prespecified, no formal hypothesis testing was performed given that the endpoints of OS, PFS, and ORR were met in the initial interim analysis. Therefore, no conclusions can be drawn from the extended follow-up analysis.2

Extended follow-up analysis: Overall confirmed response rate* (secondary endpoint)2

*Confirmed ORR (CR + PR) is based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as defined by BICR with 2 measurements at least 4 weeks apart. 

  BICR=Blinded Independent Central Review; CR=complete response; IMDC=International Metastatic RCC Database Consortium; ORR=overall response rate; PR=partial response.
 


References

  • Rini BI, Plimack ER, Stus V, et al; for KEYNOTE-426 Investigators. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127.
  • Data on file. Pfizer Inc., New York, NY.
  • Choueiri TK, Motzer RJ, Rini BI, et al. Updated efficacy results from the JAVELIN Renal 101 trial: first-line avelumab plus axitinib versus sunitinib in patients with advanced renal cell carcinoma. Ann Oncol. 2020;31(8):1030-1039.
  • Choueiri TK, Powles T, Burotto M, et al. 696O_PR - Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. September 19, 2020. Accessed January 15, 2021. https://oncologypro.esmo.org/meeting-resources/esmo-virtual-congress-2020/nivolumab-cabozantinib-vs-sunitinib-in-first-line-treatment-for-advanced-renal-cell-carcinoma-first-results-from-the-randomized-phase-iii-checkmate-9er-trial
  • Heng DY, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor–targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794-5799.
  • International mRCC Database Consortium. IMDC criteria. Updated May 2020. Accessed May 16, 2020. https://www.imdconline.com​​​​​​​
  • ​​​​​​​Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.

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INLYTA + pembrolizumab for 1st-Line Treatment of Advanced RCC

  • Overview
  • Efficacy Measures: OS, PFS, & ORR 
  • Safety & Tolerability Profile 
  • Dosing 
  • Therapy Management Strategies 
  • MOAs - INLYTA and pembrolizumab 
  • NCCN Recommendation
  • Publications
  • Health Care Provider Videos
  • Professional Resources

SAFETY & TOLERABILITY PROFILE

WARNINGS, PRECAUTIONS, & ADVERSE REACTIONS

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THERAPY MANAGEMENT STRATEGIES

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PATIENT FINANCIAL SUPPORT 
& RESOURCES

PFIZER ONCOLOGY TOGETHER™, CO-PAY CARD, & RESOURCES

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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.​​​​​​​