In HR+, HER2- MBC

Verzenio: The ONLY CDK4 & 6 inhibitor to achieve significant OS improvement in combination with fulvestrant regardless of menopausal status1,2

9.4 months increase in median OS with Verzenio plus fulvestrant vs fulvestrant alone1

OS IN ITT POPULATION1,3

  • Results are based on a preplanned interim analysis and considered to be definitive due to the occurrence of 77% (338/441) of the planned OS events needed for the final analysis1,4
  • The percentage of deaths at the time of analysis was 47.3% (n=211) and 57.0% (n=127) in the Verzenio plus fulvestrant and fulvestrant alone arms, respectively1,4
  • Primary endpoint of median PFS was met: 16.4 months (95% CI: 14.4-19.3) with Verzenio + fulvestrant vs 9.3 months (95% CI: 7.4-12.7) with fulvestrant alone (HR=0.553; 95% CI: 0.449-0.681; P<0.0001)3
  • The percentage of events at the time of PFS analysis was 49.8% (n=222) and 70.4% (n=157) in the Verzenio plus fulvestrant and fulvestrant alone arms, respectively3

In HR+, HER2- MBC

Even women with visceral disease achieved overall survival results consistent with the overall study population1

Anna has visceral disease*

*Visceral disease: ≥1 lesion on an internal organ or in the third space (including lung, liver, pleural, or peritoneal metastatic involvement).5

OS IN PATIENTS WITH VISCERAL DISEASE

  • Prespecified subgroup analyses of PFS and OS were performed for stratification factors of disease site, including visceral disease
  • Risk reduction reflective of the median. Analyses were not adjusted for multiplicity, and the study was not powered to test the effect of Verzenio plus fulvestrant among subgroups

Verzenio reduced risk of death by 33% in women with visceral disease1


In HR+, HER2- MBC

Even women with primary ET resistance achieved overall survival results consistent with the overall study population1

Pam has primary ET resistance

In MONARCH 2, primary ET resistance was defined as3:

  • Relapse within 2 years of adjuvant ET
  • Progressive disease within 6 months of first-line ET for MBC

OS IN PATIENTS WITH PRIMARY ET RESISTANCE1

  • Prespecified subgroup analyses of PFS and OS were performed for the stratification factor of endocrine resistance (including primary ET resistance)
  • Risk reduction reflective of the median. Analyses were not adjusted for multiplicity, and the study was not powered to test the effect of Verzenio plus fulvestrant among subgroups

Verzenio reduced risk of death by 31% in women with primary ET resistance1

Select Important Safety Information

Diarrhea occurred in 81% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 90% of patients receiving Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 20% of patients receiving Verzenio alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.

Diarrhea incidence was greatest during the first month of Verzenio dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.

Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose.

In HR+, HER2- MBC

Verzenio delayed time to chemotherapy1,6

EXPLORATORY ANALYSIS: TIME TO CHEMOTHERAPY (IN ITT POPULATION)1,6

  • Time to chemotherapy: time from randomization to initiation of first post-discontinuation chemotherapy. Patients who died prior to receiving chemotherapy (n=111) did not contribute an event to this analysis1
  • This analysis was not controlled for type I error, and the study was not powered to test this endpoint1
  • Risk reduction reflective of the median

Verzenio reduced risk of progression to chemotherapy by 38% in the ITT population1

In HR+, HER2- MBC

Verzenio significantly improved median PFS in the ITT population7

PFS IN ITT POPULATION3

  • The percentage of events at the time of PFS analysis was 49.8% (n=222) and 70.4% (n=157) in the Verzenio plus fulvestrant and fulvestrant alone arms, respectively3

Verzenio reduced risk of progression or death by 45% in the ITT population7


In HR+, HER2- MBC

Even women with visceral disease achieved improved median PFS consistent with the overall study population7,8

PREPLANNED SUBGROUP ANALYSIS: PFS IN WOMEN WITH VISCERAL DISEASE8

  • The percentage of events at the time of PFS analysis in the ITT population was 49.8% (n=222) and 70.4% (n=157) in the Verzenio plus fulvestrant and fulvestrant alone arms, respectively3
  • Prespecified subgroup analyses of PFS were performed for the stratification factor of disease site, including visceral disease7,8
  • Risk reduction reflective of the median. Analyses were not adjusted for multiplicity and the study was not powered to test the effect of Verzenio plus fulvestrant among subgroups8

Verzenio reduced risk of progression or death by 52% in women with visceral disease8


In HR+, HER2- MBC

Even women with primary resistance achieved improved median PFS consistent with the overall study population7,8

PREPLANNED SUBGROUP ANALYSIS: PFS IN WOMEN WITH PRIMARY RESISTANCE8

  • The percentage of events at the time of PFS analysis in the ITT population was 49.8% (n=222) and 70.4% (n=157) in the Verzenio plus fulvestrant and fulvestrant alone arms, respectively3
  • Prespecified subgroup analyses of PFS were performed for the stratification factor of endocrine resistance7,8
  • Risk reduction reflective of the median. Analyses were not adjusted for multiplicity and the study was not powered to test the effect of Verzenio plus fulvestrant among subgroups8

Verzenio reduced risk of progression or death by 55% in women with primary ET resistance7

MONARCH 2 trial design

MONARCH 2 included women with worse prognoses1,3,9*

All patients in the trial had prior endocrine therapy:

  • 59% had ET in the adjuvant or neoadjuvant setting and had progressed from early-stage disease to metastatic7
  • 38% had ET in the first-line metastatic setting and had progressed on first-line treatment7

*Patients with disease progression following ET who were at "higher risk" (defined as the presence of visceral disease or primary ET resistance, which are associated with decreased overall survival) were included in the MONARCH 2 clinical trial.1,7,10-12
Visceral disease: ≥1 lesion on an internal organ or in the third space (including lung, liver, pleural, or peritoneal metastatic involvement).5
Primary resistance: relapse within the first 2 years of adjuvant ET or progressive disease within the first 6 months of first-line ET for MBC.3
§ET history was not available for 12 patients in the Verzenio arm and 5 patients in the placebo arm.7


Verzenio + fulvestrant: Phase III, randomized, double-blind, placebo-controlled trial (N=669)3,7

MONARCH 2 was a phase III, randomized, double-blind, placebo-controlled trial that enrolled 669 patients with HR+, HER2- MBC who progressed on or after ET. Pre/perimenopausal women (17%) were rendered postmenopausal prior to the study. Patients had received no chemotherapy and no more than 1 prior ET in the metastatic setting. Patients were randomized 2:1 to Verzenio + fulvestrant (n=446) or placebo + fulvestrant (n=223). Verzenio and placebo were dosed PO BID on a continuous dosing schedule until disease progression or unacceptable toxicity. 500 mg fulvestrant was administered by IM injection on days 1, 15, and 29 of the first month and once monthly thereafter. The primary endpoint was PFS. Key secondary endpoints were ORR, OS, and DoR.





References: 1. Sledge GW Jr, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial [published online September 29, 2019]. JAMA Oncol. 2020;6(1):116-124. doi:10.1001/jamaoncol.2019.4782. 2. Turner NC, Slamon DJ, Ro J, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N Engl J Med. 2018;379:1926-1936. 3. Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020. 4. Data on file. Lilly USA, LLC. DOF-AL-US-0088. 5. Data on file. Lilly USA, LLC. ONC20171128a. 6. Supplement to: Sledge GW Jr, Toi M, Neven P, et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor–positive, ERBB2-negative breast cancer that progressed on endocrine therapy—MONARCH 2: a randomized clinical trial [published online September 29, 2019]. JAMA Oncol. 2020;6(Suppl2):1-7. doi:10.1001/jamaoncol.2019.4782. 7. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35:2875-2884. 8. Data on file. Lilly USA, LLC. ONC20180103a. 9. Goetz MP, Toi M, Campone M, et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35:3638-3646. 10. Yamamura J, Kamigaki S, Fujita J, Osato H, Komoike Y. The difference in prognostic outcomes between de novo stage IV and recurrent metastatic patients with hormone receptor-positive, HER2-negative breast cancer. In Vivo. 2018;32(2):353-358. 11. Gong Y, Liu Y-R, Ji P, Hu X, Shao ZM. Impact of molecular subtypes on metastatic breast cancer patients: a SEER population-based study. Sci Rep. 2017;7:45411. 12. Wang R, Zhu Y, Liu X, et al. The clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer. BMC Cancer. 2019;19:1091.

Indication & Important Safety Information
Indication

Verzenio is indicated for the treatment of hormone receptor–positive (HR+), human epidermal growth factor receptor 2−negative (HER2–) advanced or metastatic breast cancer (MBC)1:

  • In combination with fulvestrant for women with disease progression following endocrine therapy
  • In combination with an aromatase inhibitor (AI) for postmenopausal women as initial endocrine-based therapy
  • As a single agent for adult patients with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting
Important Safety Information

Diarrhea occurred in 81% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 86% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 90% of patients receiving Verzenio alone in MONARCH 1. Grade 3 diarrhea occurred in 9% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 13% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 20% of patients receiving Verzenio alone in MONARCH 1. Episodes of diarrhea have been associated with dehydration and infection.

Diarrhea incidence was greatest during the first month of Verzenio dosing. In MONARCH 3, the median time to onset of the first diarrhea event was 8 days, and the median duration of diarrhea for Grades 2 and 3 were 11 and 8 days, respectively. In MONARCH 2, the median time to onset of the first diarrhea event was 6 days, and the median duration of diarrhea for Grades 2 and 3 were 9 days and 6 days, respectively. In MONARCH 3, 19% of patients with diarrhea required a dose omission and 13% required a dose reduction. In MONARCH 2, 22% of patients with diarrhea required a dose omission and 22% required a dose reduction. The time to onset and resolution for diarrhea were similar across MONARCH 3, MONARCH 2, and MONARCH 1.

Instruct patients that at the first sign of loose stools, they should start antidiarrheal therapy such as loperamide, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose.

Neutropenia occurred in 41% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 46% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and 37% of patients receiving Verzenio alone in MONARCH 1. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 22% of patients receiving Verzenio plus an aromatase inhibitor in MONARCH 3, 32% of patients receiving Verzenio plus fulvestrant in MONARCH 2 and in 27% of patients receiving Verzenio alone in MONARCH 1. In MONARCH 3, the median time to first episode of Grade ≥3 neutropenia was 33 days, and in MONARCH 2 and MONARCH 1, was 29 days. In MONARCH 3, median duration of Grade ≥3 neutropenia was 11 days, and for MONARCH 2 and MONARCH 1 was 15 days.

Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Febrile neutropenia has been reported in <1% of patients exposed to Verzenio in the MONARCH studies. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.

Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with Verzenio and other CDK4/6 inhibitors. Across clinical trials (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated patients had ILD/pneumonitis of any grade, 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations.

Dose interruption or dose reduction is recommended in patients who develop persistent or recurrent Grade 2 ILD/pneumonitis. Permanently discontinue Verzenio in all patients with grade 3 or 4 ILD/pneumonitis.

Grade ≥3 increases in alanine aminotransferase (ALT) (6% versus 2%) and aspartate aminotransferase (AST) (3% versus 1%) were reported in the Verzenio and placebo arms, respectively, in MONARCH 3. Grade ≥3 increases in ALT (4% versus 2%) and AST (2% versus 3%) were reported in the Verzenio and placebo arms respectively, in MONARCH 2.

In MONARCH 3, for patients receiving Verzenio plus an aromatase inhibitor with Grade ≥3 increases in ALT or AST, median time to onset was 61 and 71 days, respectively, and median time to resolution to Grade <3 was 14 and 15 days, respectively. In MONARCH 2, for patients receiving Verzenio plus fulvestrant with Grade ≥3 increases in ALT or AST, median time to onset was 57 and 185 days, respectively, and median time to resolution to Grade <3 was 14 and 13 days, respectively.

For assessment of potential hepatotoxicity, monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or Grade 3 or 4, hepatic transaminase elevation.

Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus an aromatase inhibitor as compared to 0.6% of patients treated with an aromatase inhibitor plus placebo in MONARCH 3. Venous thromboembolic events were reported in 5% of patients treated with Verzenio plus fulvestrant in MONARCH 2 as compared to 0.9% of patients treated with fulvestrant plus placebo. Venous thromboembolic events included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. Across the clinical development program, deaths due to venous thromboembolism have been reported. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate.

Verzenio can cause fetal harm when administered to a pregnant woman based on findings from animal studies and the mechanism of action. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Verzenio and for at least 3 weeks after the last dose. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential.

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were diarrhea (81% vs 30%), neutropenia (41% vs 2%), fatigue (40% vs 32%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 2 for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 3%), thrombocytopenia (16% vs 3%), alopecia (16% vs 2%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs <1%), rash (11% vs 4%), pyrexia (11% vs 6%), and weight decreased (10% vs 2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), leukopenia (17%), constipation (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 2%), diarrhea (9% vs 1%), leukopenia (8% vs <1%), ALT increased (7% vs 2%), and anemia (6% vs 1%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (27% vs 2%), diarrhea (13% vs <1%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (6% vs 3%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were neutropenia (24%), diarrhea (20%), fatigue (13%), infections (7%), leukopenia (6%), anemia (5%), and nausea (5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥10% for Verzenio plus anastrozole or letrozole and ≥2% higher than placebo plus anastrozole or letrozole vs placebo plus anastrozole or letrozole were increased serum creatinine (98% vs 84%; 2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs <1%), anemia (82% vs 28%; 2% vs 0%), decreased neutrophil count (80% vs 21%; 22% vs 3%), decreased lymphocyte count (53% vs 26%; 8% vs 2%), decreased platelet count (36% vs 12%; 2% vs <1%), increased ALT (48% vs 25%; 7% vs 2%), and increased AST (37% vs 23%; 4% vs <1%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥10% for Verzenio plus fulvestrant and ≥2% higher than placebo plus fulvestrant vs placebo plus fulvestrant were increased serum creatinine (98% vs 74%; 1% vs 0%), decreased white blood cells (90% vs 33%; 23% vs 1%), decreased neutrophil count (87% vs 30%; 33% vs 4%), anemia (84% vs 33%; 3% vs <1%), decreased lymphocyte count (63% vs 32%; 12% vs 2%), decreased platelet count (53% vs 15%; 2% vs 0%), increased ALT (41% vs 32%; 5% vs 1%), and increased AST (37% vs 25%; 4% vs 4%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1 with Verzenio were increased serum creatinine (98%; <1%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 27%), anemia (68%; 0%), decreased lymphocyte count (42%; 14%), decreased platelet count (41%; 2%), increased ALT (31%; 3%), and increased AST (30%; 4%).

Strong and moderate CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of the strong CYP3A inhibitor ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the Verzenio dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the Verzenio dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the Verzenio dose in 50 mg decrements. Patients should avoid grapefruit products.

Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents. Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity.

With severe hepatic impairment (Child-Pugh Class C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min).

Please see full Prescribing Information for Verzenio.

AL HCP ISI 17SEP2019

Reference: 1. Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020.