Lilly Announces Updated Verzenio® (abemaciclib) Phase 3 monarchE Trial Data Presented at ESMO Virtual Plenary and Simultaneously Published in the Annals of Oncology

• Adjuvant Verzenio in combination with endocrine therapy (ET) continued to demonstrate a significant improvement in reducing the risk of recurrence in patients with HR+ HER2-, node-positive, high risk early breast cancer
• With additional follow up, the treatment benefit of Verzenio plus ET was maintained over time and extended beyond the two-year treatment period; mature safety analysis was also consistent with previous results
• Consistent Verzenio treatment benefit in reducing risk of recurrence observed in patients regardless of Ki-67 score

TORONTO, Oct. 18, 2021 /CNW/ - Eli Lilly and Company announced updated data from the positive Phase 3 monarchE trial evaluating the investigational use of Verzenio® (abemaciclib) in combination with standard adjuvant endocrine therapy (ET) for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), node-positive, high risk early breast cancer (EBC). These data were presented at ESMO's Virtual Plenary (October 14, 2021) and simultaneously published in the Annals of Oncology.

As previously published in the Journal of Clinical Oncology,ⁱ monarchE met its primary endpoint of a statistically significant improvement in invasive disease-free survival (IDFS) in the intent-to-treat (ITT) population for patients treated with adjuvant Verzenio plus ET compared to those treated with ET alone. Consistent with expert guidelines, IDFS was defined as the length of time before breast cancer comes back, any new cancer develops, or death.

The trial included women and men with HR+ HER2-, node-positive EBC who had a high risk of disease recurrence based on clinical and pathological features (N=5,637). Patients were assigned to one of two cohorts. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALN), or 1-3 positive ALN and either Grade 3 disease or tumour size ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALN and centrally determined Ki-67 score of ≥20 per cent (defined in the study as "Ki-67 high"). Ki-67 is a marker of cellular proliferation. Ki-67 score was also determined centrally in Cohort 1 patients with a suitable sample, but Ki-67 determination was not required for enrollment in this cohort. The ITT population included both Cohort 1 and Cohort 2.

Data in the presentation and publication include updated results reflecting median follow-up of 27 months. In the updated analysis, the benefit of Verzenio on IDFS and distant relapse-free survival (DRFS) was maintained (Table 1 below). At three years, the absolute improvement rates in IDFS and DRFS were 5.4 per cent and 4.2 per cent, respectively. Exploratory piecewise analyses of the IDFS and DRFS hazard ratio (HR) estimates within each year were also conducted, which demonstrated increasing magnitude of IDFS effect size over time: from the first year (0-1yr HR = 0.80, 95 per cent CI: 0.59, 1.03) to the second year (1-2yr HR = 0.68, 95 per cent CI: 0.52, 0.87), and strengthened beyond the two-year study treatment period (2+yr HR = 0.60, 95 per cent CI: 0.40, 0.86). Similarly, the DRFS HR estimates strengthened from the first year (0-1yr HR = 0.73, 95 per cent CI: 0.52, 0.99) to the second year (1-2yr HR = 0.68, 95 per cent CI: 0.51, 0.88), and persisted beyond the two-year study treatment period (2+yr HR = 0.69, 95 per cent CI: 0.45, 1.03). The impact of Ki-67 score on prognosis and likelihood of benefit from Verzenio was also analyzed. As expected, a high Ki-67 score of ≥20 per cent was prognostic of increased recurrence risk among patients with high-risk clinical and pathological features. However, Verzenio conferred consistent benefit in reducing risk of recurrence regardless of having a low (<20 per cent) or high (≥20 per cent) Ki-67 score among patients with high-risk clinical and pathological features (Table 2 below). With 90 per cent of patients now having completed the two-year treatment period or discontinued early, safety data are considered mature and remain consistent with the known profile of Verzenio. All patients in monarchE will continue to be followed to assess overall survival and other endpoints. Overall survival data were not yet mature.

"The results from monarchE are truly impressive and we are encouraged by the consistency of the treatment benefit and increasing magnitude of effect observed over time in reducing the risk of recurrence and development of metastatic disease," said Joyce A. O'Shaughnessy, M.D., Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center, Texas Oncology, US Oncology, Dallas Texas, monarchE investigator and presenter at  the October 14, 2021 ESMO Virtual Plenary. "These data suggest that the addition of adjuvant Verzenio to endocrine therapy in the high risk early breast cancer setting has the potential to change the way we treat these patients and may address a significant unmet need for those with clinical and pathological risk features who are in need of new treatment options."

The following table shows the evolution of IDFS and DRFS data in the ITT population.

Table 1.

	Primary Outcome^i		Additional Follow-Up
Data cut-off date	July 8, 2020		April 1, 2021
Patients off study treatment period	41.0%		89.6%
Efficacy Results	Verzenio + ET	ET alone	Verzenio + ET	ET alone
Median follow-up, months	19.1		27.1
Invasive disease-free survival (IDFS)
Events, n	163	232	232	333
IDFS rates, % (95% CI)
2-year	92.3 (90.9, 93.5)	89.3 (87.7, 90.7)	92.7 (91.6, 93.6)	90.0 (88.8, 91.1)
3-year	Not estimable	Not estimable	88.8 (87.0, 90.3)	83.4 (81.3, 85.3)
HR (95% CI) p-value	0.71 (0.58, 0.87) *Nominal p-value = 0.0009		0.70 (0.59, 0.82) *Nominal p-value <0.0001
Distant relapse-free survival (DRFS)
Events, n	131	193	191	278
DRFS rates, % (95% CI)
2-year	93.8 (92.6, 94.9)	90.8 (89.3, 92.1)	94.1 (93.2, 95.0)	91.6 (90.5, 92.6)
3-year	Not estimable	Not estimable	90.3 (88.6, 91.8)	86.1 (84.2, 87.9)
HR (95% CI)	0.69 (0.55, 0.86)		0.69 (0.57, 0.83)
^i Johnston SRD, Harbeck N, Hegg R, et al; monarchE Committee Members and Investigators. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE) [published online ahead of print, September 20, 2020]. J Clin Oncol. doi:10.1200/JCO.20.02514.   *The primary efficacy endpoint was statistically significant at interim analysis 2

The following table shows IDFS in Cohort 1 according to centrally determined Ki-67 score [low (<20 per cent), high (≥20 per cent)].*

Table 2.

	Verzenio + ET	ET alone	HR (95% CI)
Cohort 1 Ki-67 High, N = 2003
Patients, N	1017	986	0.626 (0.488, 0.803)
Events, n	104	158
3-Year IDFS Rates	86.1%	79.0%
Cohort 1 Ki-67 Low, N = 1914
Patients, N	946	968	0.704 (0.506, 0.979)
Events, n	62	86
3-Year IDFS Rates	91.7%	87.2%

*Data from Additional Follow-up analysis with a data cut-off date of April 1, 2021

"We are extremely pleased with the consistency of the landmark results from monarchE and are excited to see these important data shared with the breast cancer community," said David Hyman, M.D., chief medical officer, oncology at Lilly. "Verzenio treatment benefit observed at the primary outcome analysis was maintained with 27 months of median follow-up, including beyond the Verzenio treatment period, reinforcing our confidence in the observed treatment effect."

Adverse reactions from monarchE were consistent with the known safety profile for Verzenio.  A higher incidence of Grade ≥3 adverse events (AEs) and serious adverse events was observed with Verzenio plus ET compared to ET alone (50 per cent vs. 16 per cent and 15 per cent vs. 9 per cent, respectively). The most frequent AEs were diarrhea, neutropenia, and fatigue in the Verzenio plus ET arm, and arthralgia, hot flush, and fatigue in the ET alone arm.

About the monarchE Study
monarchE is a global, randomized, open-label, two cohort, multicenter Phase 3 study in adult women and men with HR+ HER2-, node-positive resected EBC with clinical and pathological features consistent with a high risk of disease recurrence. A total of 5,637 patients were randomized (1:1) to receive two years of Verzenio 150 mg twice daily plus physician's choice of standard endocrine therapy, or standard endocrine therapy alone. Patients in both treatment arms were instructed to continue to receive adjuvant endocrine therapy for up to 5-10 years as recommended by their clinician. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALN), or 1-3 positive ALN and either Grade 3 disease or tumor size ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALN and centrally determined Ki-67 score of ≥20%. The primary endpoint was IDFS in the ITT population (Cohorts 1 & 2). Secondary endpoints were IDFS in patients with high Ki-67 score (in the ITT population and in the Cohort 1 population), DRFS, overall survival, and safety.^i,ii

About Early Breast Cancer and Risk of Recurrence
It is estimated that 90 per cent of all breast cancers are detected at an early stage. Although the prognosis for HR+ HER2- EBC is generally positive, 20 per cent of patients will experience recurrence potentially to incurable metastatic disease.  Risk of recurrence is greatest within the initial two to three years post-diagnosis, particularly in patients with node-positive, high risk EBC.  Factors associated with high risk of recurrence include: positive nodal status, large tumor size (≥5 cm), high tumor grade (Grade 3), and high rate of cellular proliferation [Ki-67 score (≥20 per cent)].ⁱⁱ

Node-positive means that cancer cells from the tumor in the breast have been found in the lymph nodes in the armpit area. Although the breast cancer is removed through surgery, the presence of cancer cells in the lymph nodes signifies that there is a higher chance of the cancer returning and spreading.

About Verzenio^®
Verzenio® (abemaciclib) is a targeted treatment known as a CDK4/6 inhibitor. Verzenio is a non-chemotherapy oral tablet. In estrogen receptor-positive (ER+) breast cancer cell lines, cyclin D1 and CDK4 & 6 promote phosphorylation of the retinoblastoma protein (Rb), cell cycle progression, and cell proliferation.

In vitro, continuous exposure to Verzenio inhibited Rb phosphorylation and blocked progression from G1 to S phase of the cell cycle, resulting in senescence and apoptosis (cell death). Preclinically, Verzenio dosed daily without interruption resulted in reduction of tumor size. Inhibiting CDK4 & 6 in healthy cells can result in side effects, some of which may be serious. Clinical evidence also suggests that Verzenio crosses the blood-brain barrier. In patients with advanced cancer, including breast cancer, concentrations of Verzenio and its active metabolites (M2 and M20) in cerebrospinal fluid are comparable to unbound plasma concentrations.

Verzenio is Lilly's first solid oral dosage form to be made using a faster, more efficient process known as continuous manufacturing. Continuous manufacturing is a new and advanced type of manufacturing within the pharmaceutical industry, and Lilly is one of the first companies to use this technology.

Indication
In Canada, Verzenio^® (abemaciclib) is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer:

• in combination with an aromatase inhibitor in postmenopausal women as initial endocrine based therapy.
• in combination with fulvestrant in women with disease progression following endocrine therapy. Pre- or perimenopausal women must also be treated with a gonadotropin-releasing hormone (GnRH) agonist.
• as a single agent in women with disease progression following endocrine therapy and at least 2 prior chemotherapy regimens. At least one chemotherapy regimen should have been administered in the metastatic setting, and at least one should have contained a taxane.

Please consult the Verzenio Product Monograph for important information on contraindications, warnings, precautions, adverse reactions, interactions and dosing. The product monograph is also available by calling us at 1-888-545-5972.

About Lilly Oncology
For more than 50 years, Lilly has been dedicated to delivering life-changing medicines and support to people living with cancer and those who care for them. Lilly is determined to build on this heritage and continue making life better for all those affected by cancer around the world.

About Lilly Canada
Eli Lilly and Company is a global healthcare leader that unites caring with discovery to make life better for people around the world. We were founded more than a century ago by Colonel Eli Lilly, who was committed to creating high quality medicines that meet people's needs, and today we remain true to that mission in all our work. Lilly employees work to discover and bring life-changing medicines to people who need them, improve the understanding and management of disease, and contribute to our communities through philanthropy and volunteerism.

Eli Lilly Canada was established in 1938, the result of a research collaboration with scientists at the University of Toronto which eventually produced the world's first commercially available insulin. Our work focuses on oncology, diabetes, autoimmunity, neurodegeneration, and pain. To learn more about Lilly Canada, please visit us at www.lilly.ca.

For our perspective on issues in healthcare and innovation, follow us on twitter @LillyPadCA.

Lilly Forward-Looking Statement
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about Verzenio (abemaciclib) as a treatment for patients with early breast cancer and reflects Lilly's current beliefs and expectations. However, as with any pharmaceutical product, there are substantial risks and uncertainties in the process of development and commercialization. Among other things, there can be no guarantee that future study results will be consistent with the results to date or that Verzenio will receive additional regulatory approvals or be commercially successful. For further discussion of these and other risks and uncertainties, see Lilly's most recent Form 10-K and Form 10-Q filings with the United States Securities and Exchange Commission. Except as required by law, Lilly undertakes no duty to update forward-looking statements to reflect events after the date of this release.

REFERENCES

___________________________

ⁱ Johnston SRD, Harbeck N, Hegg R, et al; monarchE Committee Members and Investigators. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2-, node-positive, high-risk, early breast cancer (monarchE) [published online ahead of print, September 20, 2020]. J Clin Oncol. doi:10.1200/JCO.20.02514.
ⁱⁱ Verzenio [package insert]. Indianapolis, IN: Eli Lilly and Company.

SOURCE Eli Lilly Canada Inc.

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