Presented at the Society of Hematologic Oncology (SOHO) Annual Meeting, Virtual Format, September 9–12, 2020

Aims

Impact of Prolonged Dose Delays on Response With Belantamab Mafodotin (Belamaf;

GSK2857916) Treatment in DREAMM-2 Study: 13-Month Follow-up

Poster No. MM-250

Adam D Cohen1, Hans C Lee2, Suzanne Trudel3, Al-Ola Abdallah4, Natalie Callander5,

Edward Libby6, Lionel Karlin7, Sagar Lonial8, Lynsey Womersley9, January Baron10,

Eric Lewis11, Kaytlyn Nungesser10, Ira Gupta10, Joanna Opalinska10

1Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA; 2MD Anderson Cancer Center, Houston, TX, USA; 3Princess

Margaret Cancer Centre, Toronto, ON, Canada; 4University of Kansas Cancer Center, Fairway, KS, USA; 5University of Wisconsin, Carbone

Cancer Center, Madison, WI, USA; 6Division of Medical Oncology, University of Washington, Seattle, WA, USA; 7Haematology Department,

Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Benite, France; 8Emory University, Winship Cancer Institute, Atlanta, GA,

USA; 9GlaxoSmithKline, Stockley Park, Uxbridge, UK; 10GlaxoSmithKline, Upper Providence, PA, USA; 11GlaxoSmithKline, Research

Triangle Park, NC, USA

Conclusions

In DREAMM-2, it was common for patients receiving single-agent belamaf to experience

keratopathy (MECs, an eye examination finding) requiring dose modifications, including

prolonged dose delays.

Clinical responses were maintained in over 80% of patients whose AEs were managed with

the first prolonged dose delays.

Grade 3/4 keratopathy (MECs, an eye examination finding) events improved to Grade ≤2

events in over 80% of patients with their first prolonged dose delays, supporting the use of

dose delays as a corneal event management strategy.

For questions, please contact: Adam.Cohen@pennmedicine.upenn.edu

To present findings on the impact of dose delays on responses in

patients receiving 13 months of single-agent belamaf in a post hoc

analysis of DREAMM-2 (NCT03525678).

Treatment

At the data cut-off date (January 31, 2020), patients in both the 2.5- and 3.4-mg/kg groups

received a median of 3 treatment cycles (range: 1–17).

The median dose intensity was more consistent with the planned dose intensity for the

2.5-mg/kg group (median: 2.39 mg/kg [range: 0.5–2.6]) compared with the 3.4-mg/kg group

(median: 2.95 mg/kg [range: 0.8–3.7]).

Dose modifications in the overall population

In the 2.5- and 3.4-mg/kg groups, 41% (39/95) and 48% (48/99) of patients, respectively, had a

dose delay.

• In patients with dose delays in the 2.5-mg/kg group, 36% (14/39) of patients had a single dose

delay, 31% (12/39) had two dose delays, and 33% (13/39) of patients had ≥3 dose delays.

• In patients with dose delays in the 3.4-mg/kg group, 48% (23/48) of patients had a single dose

delay, 13% (6/48) had two dose delays, and 40% (19/48) of patients had ≥3 dose delays.

The median duration of dose delays was 42 days (range: 4–212) for the 2.5-mg/kg group and

23 days (range: 4–149) for the 3.4-mg/kg group.

Dose modifications due to AEs in the overall population

Keratopathy (MECs, an eye examination finding) was the most frequent reason for dose

delays and reductions (Table 1).

• A total of 3% of patients (3 each in the 2.5- and 3.4-mg/kg groups) discontinued treatment

due to corneal events (keratopathy [MECs], change in BCVA, or blurred vision).

Table 1. Dose delays, reductions, and discontinuations due to AEs

n (%)Belamaf

2.5 mg/kg (N=95)

Belamaf

3.4 mg/kg (N=99)

Patients with AEs leading to dose delays*

Dose delays due to keratopathy (MECs†)7

51 (54)

45 (47)

61 (62)

52 (53)

Patients with AEs leading to dose reductions

Dose reductions due to keratopathy (MECs†)7

33 (35)

24 (25)

44 (44)

30 (30)

Patients with AEs leading to permanent treatment

discontinuation

Discontinuations due to keratopathy (MECs†)7

Discontinuations due to patient-reported AEs/symptoms7

9 (9)

1 (1)

2 (2)‡

12 (12)

3 (3)

0

*Dose delays of any duration, including but not limited to delays >63 days; †an eye examination finding; ‡blurred vision or change in BCVA (n=1 each).

Figure 1. Clinical responses and corneal event grade over time in patients with dose delays >63 days (post hoc analysis)

Clinical response in patients with prolonged dose delays

In the 31 patients with ≥partial response (≥PR) in the 2.5-mg/kg cohort, 16 had prolonged dose

delays (>63 days; Figure 1A); 19 of the 35 patients with ≥PR in the 3.4-mg/kg cohort had

prolonged dose delays (Figure 1B)

• Most of these patients (88% and 84% in the 2.5- and 3.4-mg/kg cohorts, respectively)

continued to experience a clinical benefit during the first prolonged delay, with some of these

patients (38% and 32%, respectively) deepening their clinical response during dose delay

(Table 2). Few (13% and 16%, respectively) developed progressive disease.

Corneal event outcomes in patients with prolonged dose delays

• Keratopathy (MECs, an eye examination finding) was also the most frequent reason for dose

delays in patients with prolonged delays (Figure 1).

• In patients with Grade 3/4 keratopathy (MECs, an eye examination finding) at the beginning

of the first prolonged dose delay, 80% (8/10) in the 2.5-mg/kg group and 100% (11/11) in the

3.4-mg/kg group improved to Grade ≤2 at the end of this delay.

• The 2 patients in the 2.5-mg/kg group who had Grade 3 events at the end of the first

prolonged delay are still in follow-up as of this analysis.

Background

Belamaf (GSK2857916) is a first-in-class, monomethyl auristatin F

(MMAF)–containing antibody-drug conjugate (ADC) that binds to B-cell

maturation antigen (BCMA) and eliminates multiple myeloma cells by a

multimodal mechanism of action.1,2

• MMAF delivered to BCMA-expressing malignant cells inhibits

microtubule polymerization resulting in immune-independent apoptosis

that is accompanied by release of markers of immunogenic cell death,

which may contribute to an adaptive immune response. The antibody

component of belamaf enhances antibody-dependent cellular

cytotoxicity and phagocytosis.

In patients with heavily pretreated relapsed/refractory multiple myeloma

(RRMM) who historically have a poor prognosis (overall survival [OS] 6–9

months),3–6 deep and durable responses with single-agent belamaf were

sustained over 13 months’ follow-up in the Phase II DREAMM-2 study

(estimated OS of 13.7 months in patients receiving the 2.5-mg/kg dose;

see SOHO poster MM-219).7

Corneal events are commonly reported with MMAF-containing ADCs.8 In

DREAMM-2, corneal events including keratopathy (microcyst-like

epithelial changes [MECs], an eye examination finding with/without

symptoms), change in best-corrected visual acuity (BCVA), or symptoms

(blurred vision and dry eye) were the most common adverse events

(AEs) reported during belamaf treatment. 7

• Belamaf-related corneal events were adequately managed with dose

modifications (delays or reductions) in DREAMM-2. No permanent loss

of vision has been reported.9

• Other studies have also shown improvement in, or resolution of,

corneal changes with dose modifications during treatment with other

ADCs containing MMAF.10

Table 2. Clinical outcomes with first prolonged dose delays (>63 days)

Belamaf

2.5 mg/kg (n=16)

Belamaf

3.4 mg/kg (n=19)

Maintained a clinical benefit, n (%)

Deepened clinical response

Maintained the same response category

Did not meet progression criteria*

14 (88)

6 (38)

6 (38)

2 (13)

16 (84)

6 (32)

8 (42)

2 (11)

Developed progressive disease, n (%) 2 (13)† 3 (16)‡

Percentages do not add up to 100% due to rounding. *Indicates patients with elevated paraproteins reported during the delays,

though these elevated paraproteins did not meet progressive disease criteria; †1 patient developed progressive disease 6 weeks

into delay and 1 patient developed progressive disease 3 weeks after delay; ‡1 patient developed progressive disease 6 weeks into

the delay, 1 patient developed progressive disease 15 weeks into the delay, and 1 patient developed progressive disease 6 weeks

after delay.

References

1. Tai YT, et al. Blood 2014;123:3128–38.

2. Tai YT, Anderson KC. Immunotherapy 2015;7:1187.

3. Sonneveld P, et al. Blood 2016;127:2955–62.

4. Verelst SGR, et al. HemaSphere 2018;2:4.

5. Gandhi UH, et al. Leukemia 2019;33:2266–75.

6. Chari A, et al. N Engl J Med 2019;381:727–38.

Disclosures

ADC has received grant funding from Bristol-Myers Squibb, GlaxoSmithKline (GSK),

and Novartis; personal fees from Janssen, Kite Pharma, Oncopeptides, Seattle

Genetics, and Takeda; and personal fees and other association with Celgene and

GSK. HCL has received grant funding and personal fees from Amgen, Celgene,

Janssen, and Takeda; personal fees from GSK and Sanofi; and grant funding from

Daiichi Sankyo. ST received consulting fees from Amgen, Celgene, and GSK; honoraria

from Amgen Canada, Celgene, Janssen, Karyopharm, Sanofi, and Takeda; and

research funding from Amgen, Celgene, Genentech, GSK, and Janssen.

A-OA declares no competing interests. NC received research funding from Cellectar.

ELibby has received personal fees from AbbVie and Janssen, and research funding

from Amgen, Celgene, Genentech, and GSK. LK has received personal fees for

participation in advisory boards from Amgen, Celgene, GSK, Janssen, and Takeda, and

travel support from Amgen and Janssen. SL has received grant funding and personal

fees from Celgene and Takeda, and personal fees from Amgen, Bristol-Myers Squibb,

GSK, Janssen, Merck, and Novartis. LW, JB, ELewis, KN, and JO are employees of

and hold stocks and shares in GSK. IG is an employee of and holds stocks/shares in

GlaxoSmithKline and holds stocks/shares in Novartis.

Acknowledgments

Editorial assistance was provided by Crystal Kraft and Sarah

Hauze of Fishawack Indicia Ltd and funded by GSK. This study

was funded by GSK (205678). Drug linker technology licensed

from Seattle Genetics; monoclonal antibody produced using

POTELLIGENT Technology licensed from BioWa.

Figure 1A was previously presented at ASCO 2020.7

7. Lonial S, et al. ASCO 2020, Poster 436.

8. Farooq A, et al. Ophthalmol Ther 2020

[accepted manuscript].

9. Lonial S, et al. Lancet Oncol 2020;21:207–21.

10. Kumar S, et al. Lancet Oncol 2016;17:e328–46.

DREAMM-2 is an ongoing, open-label, two-arm, randomized, multicenter

study of single-agent belamaf (2.5 or 3.4 mg/kg, intravenously every 3

weeks until disease progression or unacceptable toxicity) in patients with

RRMM.9

• Objective response (International Myeloma Working Group [IMWG]

criteria 2016)10 was assessed by an independent review committee

every 3 weeks, regardless of treatment delays.

• In a post hoc analysis, the impact of prolonged dose delays (defined

as >63 days; equivalent to ≥3 treatment cycles) on clinical response

was assessed.

Dose modifications (delays or reductions) were permitted to manage

AEs, or for medical or surgical and logistical reasons unrelated to

treatment. For corneal events, dose modifications were based on a

combination of eye examination findings (ie, keratopathy [MECs]) and

change in BCVA from baseline.

Methods

Results

Figure shows response at each time point assessed by independent review committee using IMWG 2016 criteria8 every 3 weeks regardless of dose delay. Only patients who had a dose-hold >63 days at any point are shown in this figure. The reason for dose delay (keratopathy [MECs, an eye examination finding], indicated by the eye icons; all other reasons written out

with the maximum grade of the event per CTCAE v4.03), belamaf dose (3.4, 2.5, or 1.92 mg/kg), and keratopathy (MEC) grade (0–4 based on corneal examination findings and changes in BCVA) are also indicated. These clinical outcomes are also summarized in Table 2.

CPK, creatinine phosphokinase; CR, complete response; CTCAE v4.03, Common Terminology Criteria for Adverse Events, version 4.03; ECG T-wave/MVD, electrocardiogram T-wave inversion/mitral valve disease; Gr, grade; IOP, intraocular pressure; MR, minimal response; NE, not evaluable; sCR, stringent complete response; SD, stable disease; URTI, upper

respiratory tract infection; VGPR, very good partial response.

Further analyses of DREAMM-2 are presented at

this meeting (posters MM-209 and MM-219).