ADC Therapeutics SA (NYSE: ADCT) today announced a voluntary pause
in the enrollment of new patients in the Phase 2 LOTIS-9 clinical
trial (ClinicalTrials.gov Identifier: NCT05144009) evaluating
ZYNLONTA® (loncastuximab tesirine-lpyl) and rituximab (Lonca-R) in
unfit or frail patients with previously untreated diffuse large
B-cell lymphoma (DLBCL).
The voluntary action was taken by the Company
after a recent review of aggregate data of the 40 patients enrolled
in the trial and consultation with the Data Monitoring Committee
(DMC) which signaled potentially excessive respiratory-related
events. These respiratory-related treatment-emergent adverse events
(TEAEs) included seven Grade 5 fatal events and five Grade 3 or
Grade 4 respiratory-related TEAEs. As per investigator assessment,
eleven of the twelve events (including six of the seven Grade 5
fatal events) were individually assessed as unlikely or unrelated
to study drug. Four out of the five Grade 3 or Grade 4 events have
since resolved and the patients have completed treatment per
protocol. The cause of these events remains under further
investigation.
All patients with fatal events had one or more
significant active underlying respiratory and/or cardiac
co-morbidities including severe chronic obstructive pulmonary
disease (COPD), pulmonary edema, chronic bronchiectasis, idiopathic
pulmonary fibrosis and recent COVID-19 infection and all were
greater than or equal to 80 years of age. The mean age was 82.7
years and the mean number of days from the last dose to death was
51 days, with a range of 19 to 86 days. It is important to note
that all twelve of the patients with Grade 3-5 TEAEs in the LOTIS-9
study would have been excluded from the LOTIS-5 trial.
The Company’s decision to pause enrollment
enables time to evaluate data around the TEAEs and determine next
steps. The Company has notified all study investigators and
regulatory authorities including the U.S. Food and Drug
Administration (FDA) and the European Medicines Agency (EMA) of the
Company’s decision to pause enrollment. The Company does not expect
to report additional data from the trial by the end of the
year.
“Our top priority is the safety of every patient
who participates in our clinical trials,” said Ameet Mallik, Chief
Executive Officer of ADC Therapeutics. “Given the aggregate of the
respiratory-related events seen in the trial, we implemented a
voluntary pause of enrollment to allow for a thorough investigation
of the data set. This trial includes a very difficult-to-treat
patient population with limited treatment options, and we will
provide an update on next steps when available.”
LOTIS-9 Baseline Characteristics, Safety
and Efficacy (as of May 10, 2023 data cutoff)
The tables below illustrate preliminary data
from the LOTIS-9 clinical trial with a data cut-off date of May 10,
2023. These data are reflective of the 30 patients who were
enrolled by that point; since this time an additional 10 patients
have enrolled and received treatment as part of the study.
Table 1 – Baseline
Characteristics
Variable |
Cohort A (Unfit) |
Cohort B (Frail or cardiac comorbidities) |
Total |
(N=13) |
(N=17) |
(N=30) |
|
|
|
Age (years) |
|
|
|
n |
13 |
17 |
30 |
Mean |
83.4 |
82.2 |
82.7 |
std |
2.69 |
6.26 |
5 |
Median |
83 |
82 |
82 |
Min,
Max |
80, 89 |
72, 92 |
72, 92 |
|
|
|
|
Sex, [n(%)] |
Female |
3 (23.1) |
7 (41.2) |
10 (33.3) |
Male |
10 (76.9) |
10 (58.8) |
20 (66.7) |
|
|
|
|
Stage of Disease at Study
Entry, n (%) |
|
|
|
Stage I |
1 (7.7) |
1 (5.9) |
2 (6.7) |
Stage II |
3 (23.1) |
4 (23.5) |
7 (23.3) |
Stage III |
6 (46.2) |
7 (41.2) |
13 (43.3) |
Stage IV |
3 (23.1) |
5 (29.4) |
8 (26.7) |
Table 2 – Treatment-Emergent Adverse
Events with Fatal Outcome
|
Cohort A (Unfit) |
Cohort B (Frail or cardiac comorbidities) |
Total |
|
(N=13) |
(N=17) |
(N=30) |
|
|
|
|
|
Patients with any fatal
TEAE |
3 (23.1) |
3 (17.6) |
6 (20.0) |
|
Infections and
infestations |
0 |
1 (5.9) |
1 (3.3) |
Pneumonia |
0 |
1 (5.9) |
1 (3.3) |
|
Respiratory, thoracic and
mediastinal disorders |
3 (23.1) |
2 (11.8) |
5 (16.7) |
Acute respiratory
failure |
1 (7.7) |
0 |
1 (3.3) |
Chronic
obstructive pulmonary disease |
0 |
1 (5.9) |
1 (3.3) |
Dyspnoea |
1 (7.7) |
0 |
1 (3.3) |
Hypoxia |
0 |
1 (5.9) |
1 (3.3) |
Respiratory
failure |
1 (7.7) |
0 |
1 (3.3) |
Since the data cut-off date of May 10, 2023,
there has been one additional Grade 5 event for a total of seven
Grade 5 events. Two out of seven patients died within 30 days from
the last doses of study medication, the remaining 5 patients died
more than 30 days after the last dose of study drug ranging from 41
to 86 days. Adverse events are coded using MedDRA version 24.1 and
graded using CTCAE v5.0. Only treatment-emergent adverse events are
summarized. For each system organ class and preferred term,
patients are included only once.
Table 3 – Treatment-Emergent Grade 3 or
4 Adverse Events – Cardiac, Infections / Infestations, Respiratory,
Thoracic and Mediastinal Disorders and Others ≥5%
Total Occurrence*
|
Cohort A (Unfit) |
Cohort B (Frail or cardiac comorbidities) |
Total |
|
(N=13) |
(N=17) |
(N=30) |
|
|
|
|
Patients with any grade >=3
TEAE |
2 (15.4) |
7 (41.2) |
9 (30.0) |
|
Cardiac disorders |
1 (7.7) |
1 (5.9) |
2 (6.7) |
|
Infections and
infestations |
0 |
2 (11.8) |
2 (6.7) |
Pneumonia |
0 |
2 (11.8) |
2 (6.7) |
COVID-19
pneumonia |
0 |
1 (5.9) |
1 (3.3) |
Influenza |
0 |
1 (5.9) |
1 (3.3) |
Sepsis |
0 |
1 (5.9) |
1 (3.3) |
|
Respiratory, thoracic and
mediastinal disorders |
1 (7.7) |
3 (17.6) |
4 (13.3) |
Acute respiratory
failure |
1 (7.7) |
1 (5.9) |
2 (6.7) |
Pleural
effusion |
1 (7.7) |
1 (5.9) |
2 (6.7) |
Dyspnoea |
1 (7.7) |
0 |
1 (3.3) |
Respiratory
distress |
0 |
1 (5.9) |
1 (3.3) |
|
Vascular disorders |
1 (7.7) |
1 (5.9) |
2 (6.7) |
Since the data cut-off date of May 10, 2023,
there has been one additional Grade 3 or 4 cardiac event, one
additional Grade 3 or 4 infection, and one additional Grade 3 or 4
respiratory event.
*Numbers represent distinct TEAEs; patients may
have experienced more than one event
Table 4 – Overall Response Rate as
Determined by the Investigator
|
Cohort A (Unfit) |
Cohort B (Frail or cardiac comorbidities) |
Total |
(N=10) |
(N=7) |
(N=17) |
|
|
|
Best Overall Response |
|
|
|
Complete response |
5 (50.0) |
5 (71.4) |
10 (58.8) |
Partial response |
5 (50.0) |
1 (14.3) |
6 (35.3) |
Stable disease |
0 |
1 (14.3) |
1 (5.9) |
Not evaluable |
0 |
0 |
0 |
Progressive
disease |
0 |
0 |
0 |
|
|
|
|
ORR (CR+PR), n (%) |
10 (100) |
6 (85.7) |
16 (94.1) |
95% CI for ORR |
(69.2, 100) |
(42.1, 99.6) |
(71.3, 99.9) |
95% CI for CR |
(18.7, 81.3) |
(29.0, 96.3) |
(32.9, 81.6) |
Best overall response (BOR) by investigator.
Based on efficacy population, i.e., patients with baseline and at
least one post-baseline disease assessment.ORR=Overall Response
Rate. CI=Confidence Interval.
About ZYNLONTA® (loncastuximab
tesirine-lpyl)
The U.S. Food and Drug Administration (FDA) and
the European Medicines Agency have approved ZYNLONTA (loncastuximab
tesirine-lpyl) for the treatment of adult patients with relapsed or
refractory (r/r) large B-cell lymphoma after two or more lines of
systemic therapy, including DLBCL not otherwise specified, DLBCL
arising from low-grade lymphoma and also high-grade B-cell
lymphoma. The trial included a broad spectrum of heavily
pre-treated patients (median three prior lines of therapy) with
difficult-to-treat disease, including patients who did not respond
to first-line therapy, patients refractory to all prior lines of
therapy, patients with double/triple hit genetics and patients who
had stem cell transplant and CAR-T therapy prior to their treatment
with ZYNLONTA. This indication is approved by the FDA under
accelerated approval and in the European Union under conditional
approval based on overall response rate and continued approval for
this indication may be contingent upon verification and description
of clinical benefit in a confirmatory trial. Please see full
prescribing information including important safety information
about ZYNLONTA at www.ZYNLONTA.com.
About ADC Therapeutics
ADC Therapeutics (NYSE: ADCT) is a
commercial-stage global leader and pioneer in the field of antibody
drug conjugates (ADCs). The Company is advancing its proprietary
ADC technology to transform the treatment paradigm for patients
with hematologic malignancies and solid tumors.
ADC Therapeutics’ CD19-directed ADC ZYNLONTA
(loncastuximab tesirine-lpyl) received accelerated approval by the
FDA and conditional approval from the European Commission for the
treatment of relapsed or refractory diffuse large B-cell lymphoma
after two or more lines of systemic therapy. ZYNLONTA is also in
development in combination with other agents and in earlier lines
of therapy. In addition to ZYNLONTA, ADC Therapeutics has multiple
ADCs in ongoing clinical and preclinical development.
ADC Therapeutics is based in Lausanne (Biopôle),
Switzerland and has operations in London, the San Francisco Bay
Area and New Jersey. For more information, please visit
https://www.adctherapeutics.com/ and follow the company on Twitter
and LinkedIn.
ZYNLONTA® is a registered trademark of ADC
Therapeutics SA.
Forward-Looking Statements
This press release contains forward-looking
statements within the meaning of the safe harbor provisions of the
Private Securities Litigation Reform Act of 1995, including
statements concerning the investigation of the causes of the
pulmonary adverse events, anticipated communications and
interactions with regulatory authorities and any actions taken by
regulatory authorities or us relating to next steps for our LOTIS-9
or other clinical trials which could include protocol
modifications, clinical suspensions or other actions; and
statements relating to the development of products and product
candidates, and the timing, conduct and results of clinical trials.
In some cases you can identify forward-looking statements by
terminology such as “may”, “will”, “should”, “would”, “expect”,
“intend”, “plan”, “anticipate”, “believe”, “estimate”, “predict”,
“potential”, “seem”, “seek”, “future”, “continue”, or “appear” or
the negative of these terms or similar expressions, although not
all forward-looking statements contain these identifying words.
Forward-looking statements are subject to certain risks and
uncertainties that can cause actual results to differ materially
from those described. Factors that may cause such differences
include, but are not limited to: the nature, frequency and severity
of adverse events; the ability to complete clinical trials on
expected timelines, if at all; the outcome of clinical trials or
the sufficiency of results from such clinical trials; the timing
and results of the Company’s or its partners’ research projects or
clinical trials including LOTIS 5, 7 and 9, ADCT 901, 601 and 602;
and the timing and outcome of regulatory submissions and actions by
the FDA or other regulatory agencies with respect to the Company’s
products or product candidates. Additional information concerning
these and other factors that may cause actual results to differ
materially from those anticipated in the forward-looking statements
is contained in the “Risk Factors” section of the Company's Annual
Report on Form 20-F and in the Company's other periodic reports and
filings with the Securities and Exchange Commission. The Company
cautions investors not to place undue reliance on the
forward-looking statements contained in this document. The Company
undertakes no obligation to revise or update these forward-looking
statements to reflect events or circumstances after the date of
this press release, except as required by law.
CONTACTS:
InvestorsEugenia LitzADC
TherapeuticsEugenia.Litz@adctherapeutics.com+44 7879 627205+1
908-723-2350
Media Nicole RileyADC Therapeutics
Nicole.Riley@adctherapeutics.com+1 862-926-9040
ADC Therapeutics (NYSE:ADCT)
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