Therapy of Small-cell Lung Cancer (SCLC) With a Topoisomerase-I … · 2017. 7. 4. · 1 Therapy of Small-cell Lung Cancer (SCLC) With a Topoisomerase-I-inhibiting Antibody-Drug Conjugate

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Therapy of Small-cell Lung Cancer (SCLC) With a Topoisomerase-I-

inhibiting Antibody-Drug Conjugate (ADC) Targeting Trop-2,

Sacituzumab Govitecan

Jhanelle E. Gray1*, Rebecca S. Heist2*, Alexander N. Starodub3*, D. Ross Camidge4*,

Ebenezer Kio3, Gregory Masters5, W. Thomas Purcell4, Michael J. Guarino5, Jamal

Misleh5, Charles J. Schneider5, Bryan J. Schneider6, Allyson J. Ocean6, Tirrell

Johnson7, Leena Gandhi2, Kevin Kalinsky8, Ronald J. Scheff6, Wells A. Messersmith4,

Serengulam V. Govindan9, Pius Maliakal9, Boyd Mudenda9, William A. Wegener9,

Robert M. Sharkey9, and David M. Goldenberg9

1H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; 2Massachusetts

General Hospital Cancer Center, Harvard Medical School, Boston, MA; 3Indiana

University Health Center for Cancer Care, Goshen, IN; 4University of Colorado Cancer

Center, Aurora, CO; 5Helen F. Graham Cancer Center & Research Institute, Newark,

DE; 6Weill Cornell Medicine, New York, NY; 7UF Health Cancer Center, Orlando, FL; 8Columbia University Medical Center-Herbert Irving Comprehensive Cancer Center,

New York, NY; 9Immunomedics, Inc., Morris Plains, NJ

*These authors contributed equally.

Corresponding author: Jhanelle E. Gray, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, FOB 1, Tampa, FL 33612. 813-745-6895 (phone); 813-745-3027 (Fax); [email protected] (email), or David M. Goldenberg, Immunomedics, Inc., 300 The American Road, Morris Plains, NJ 07950. 973-605-8200 (phone); 973-605-8311 (fax), [email protected] (email).

Running Title: Sacituzumab Govitecan for Small-cell Lung Cancer

Disclosure of Potential Conflicts of Interest: D.M. Goldenberg has stock (including

patents) in Immunomedics, Inc., and is a Board member. S.V. Govindan, P, Maliakal, B.

Mudenda, W.A. Wegener, and R.M. Sharkey are employees of Immunomedics, Inc.,

with stock options.

Presented in part at the Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 3-7, 2016, and at the Annual Meeting of the American Association for Cancer Research, Washington, D.C., April 1-5, 2017.

Clinical Trial Identifier: NCT01631552

Statement of significance: A novel antibody-drug conjugate has been tested for safety and efficacy in patients with metastatic small-cell lung cancer after receiving a median of two prior therapies. The results indicate that this is an active agent in this very advanced patient population, warranting further clinical development.

Research. on February 16, 2021. © 2017 American Association for Cancerclincancerres.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on July 5, 2017; DOI: 10.1158/1078-0432.CCR-17-0933

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Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/)




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Translational Relevance

No new therapeutic has been approved for the treatment of metastatic (stage IV)

small-cell lung cancer (mSCLC) in twenty years. In this trial, we evaluated a novel

antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132), comprised of an

antibody targeting Trop-2 and containing the active metabolite of irinotecan, SN-38 (a

topoisomerase-I inhibitor). Repeated treatment cycles had manageable toxicity with

tumor reduction in the majority of patients, including objective responses in 17% at the

optimal dose schedule and with a median response duration of 5.7 months, based on

an intention-to-treat analysis. These patients had a median of two prior therapies.

Activity was observed in patients who were chemosensitive or chemoresistant to first-

line chemotherapy, and also in patients who failed second-line topotecan therapy. Thus,

sacituzumab govitecan is a promising new therapeutic for advanced mSCLC.




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Abstract

Purpose: We evaluated a Trop-2-targeting antibody conjugated with SN-38 in

metastatic small-cell lung cancer (mSCLC) patients.

Experimental Design: Sacituzumab govitecan was studied in patients with

pretreated (median, 2; range, 1-7) mSCLC who received either 8 or 10 mg/kg i.v. on

days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective

response rate (ORR); duration of response, progression-free survival (PFS), and overall

survival (OS) were secondary endpoints.

Results: Sixty percent of patients showed tumor shrinkage from baseline CTs.

On an intention-to-treat basis (N= 50), the ORR was 14% (17% for 10 mg/kg group); the

median response duration, 5.7 months; the clinical benefit rate (CBR>4 months), 34%;

median PFS, 3.7 months; median OS, 7.5 months. There was a suggested

improvement in PR, CBR, and PFS with sacituzumab govitecan in second-line patients

who were sensitive to frontline therapy, but no difference between frontline

chemosensitive vs chemoresistant patients in the overall population. There was a

statistically significant higher OS in those patients who received prior topotecan vs no

topotecan therapy in a small subgroup. Grade >3 adverse events included neutropenia

(34%), fatigue (13%), diarrhea (9%), and anemia (6%). Trop-2 tumor staining was not

required for patient selection. No antibodies to the drug conjugate or its components

were detected on serial blood collections.

Conclusions: Sacituzumab govitecan appears to have a safe and effective

therapeutic profile in heavily-pretreated, mSCLC patients, including those who are

chemosensitive or chemoresistant to frontline chemotherapy. Additional studies as a

monotherapy or combination therapy are warranted.




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Introduction

Small-cell lung cancer (SCLC), originating from neuroendocrine progenitor cells,

comprises approximately 15% of all lung cancers, yet has one of the lowest 5-year

survival rates at 6% (1, 2). This is because of its highly aggressive nature, with about

two-thirds of patients already having metastatic disease at diagnosis (3). While palliative

first-line therapy of stage IV SCLC (mSCLC) has a high initial response rate of 60-75%,

the outcome is poor, with a median progression-free survival (PFS) of only 5.5 months

and a median overall survival (OS) of <10 months with platinum-based chemotherapy

(3). Responses to second-line therapy have been poorer, such as <10%, with a median

survival of only 4 to 5 months following second- or third-line chemotherapy (1, 3-5).

Unfortunately, those patients with platinum-resistant mSCLC (i.e., response duration <3

months) fare even worse (6). In the USA, the only approved drug in this second-line

setting of chemosensitive patients (duration of response >3 months), since 1998, is

topotecan, indicated for recurrent patients who were sensitive (duration of response

exceeding 3 months) (7-9). Still, irinotecan, taxanes, vinorelbine, gemcitabine, and

pemetrexed also are given frequently to patients with chemosensitive recurrent disease

(10-14). A review of recent randomized phase II and III clinical trials, including

topotecan in a control arm, showed 13 to 17% responses in second-line with topotecan,

but with as much as a 20% response rate among patients with chemosensitive disease,

while only 4% for those whose tumors were chemoresistant (15). However, these

responses and/or disease stabilization in second-line do not translate into improved

survival. For example, Hagmann and colleagues (16) reported a 22.5% response, a

median PFS of 2.4 months, and a median OS of 5 months with topotecan. In a third-line

setting, no objective responses were achieved, while a median PFS of 1.3 months and

a median OS of 2.5 months were reported (16). Other established single-agent

chemotherapies or retreatment with platinum plus etoposide combinations also have

been disappointing, yielding similar survival outcomes as topotecan alone (16). A

possible exception is amrubicin, a topoisomerase II inhibitor that was approved in Japan

in 2002, where studies reported a median survival of 7 to 12 months when given in

second-line, and appears to be useful in the therapy of relapsed SCLC (17-19). A




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phase III trial conducted in the US, Europe, and Australia showed that while amrubicin

did not improve survival, it demonstrated activity and an acceptable safety profile

compared to topotecan (20). Thus, progress in the management of patients with SCLC,

especially those with metastatic disease, has been quite modest over the past 20 years.

Nearly all patients relapse early and succumb to their disease within a year.

The purpose of this study was to evaluate a novel antibody-drug conjugate

(ADC), comprising a topoisomerase-I-inhibiting camptothecin, SN-38 (7-ethyl-10-

hydroxycamptothecin, the active metabolite of irinotecan), linked to a humanized

antibody targeting Trop-2, a glycoprotein that is elevated in many epithelial cancers and

shown to be an attractive and selective target for antibody-based therapy (21). The

prodrug of SN-38, irinotecan, has been studied already in patients with SCLC, but

clinical trials in the USA and Europe have not demonstrated a benefit compared to an

etoposide-containing regimen (12, 22, 23). Therefore, developing an ADC to target the

thousand-fold more active metabolite of irinotecan, SN-38, was hypothesized as being

more active and potentially having a better therapeutic index (21). Also, preclinical

studies in human tumor xenografts indicated that a much higher dose of SN-38 could be

delivered to the tumor via this ADC compared to irinotecan (24). This improved

therapeutic index and encouraging activity were corroborated in the phase I “basket”

trial of sacituzumab govitecan given to patients with diverse metastatic cancers (25), as

well as other phase II trials in triple-negative breast cancer (TNBC) (26), urothelial

cancer (27), and non-small-cell lung cancer (28). We now report that sacituzumab

govitecan (IMMU-132) has activity and manageable toxicity in patients with advanced

and heavily-pretreated mSCLC.




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Patients and Methods

Patients

Patients >18 years of age with mSCLC who had relapsed or were refractory to at

least one prior standard line of therapy for metastatic disease, and with measurable

tumors by CT, were enrolled. They were required to have Eastern Cooperative

Oncology Group (ECOG) performance status of 0 or 1, adequate bone marrow, hepatic

and renal function, and other eligibility as described in the phase I trial (25). Previous

therapy had to be completed at least 2 weeks before enrollment.

Study Design and Treatment

The overall objective of this portion of the study was to evaluate safety and

antitumor activity of sacituzumab govitecan in patients with mSCLC. Sacituzumab

govitecan was administered intravenously at an initial infusion rate of 50 mg/h that was

escalated progressively to be completed within 3 h (subsequent infusions completed

within 60-90 min). Premedications (e.g., diphenhydramine, acetaminophen, and

dexamethasone) were prescribed optionally to reduce the risk of infusion reactions.

Doses of 8 or 10 mg/kg were given on days 1 and 8 of a 21-day cycle, with

contingencies to delay (maximum of 3 weeks). Toxicities were managed by supportive

hematopoietic growth-factor therapy for blood cell reduction at any time during

treatment, dose delays and/or modification as specified in the protocol (e.g., 25% of

prior dose), or by standard medical practice. Treatment was continued until disease

progression, initiation of alternative anticancer therapy, unacceptable toxicity, or

withdrawal of consent.

Study Oversight

The protocol and amendments were approved by each institution’s review board

and conducted in accordance with the Declaration of Helsinki and the International

Conference on Harmonization of Good Clinical Practice Guidelines. All patients gave

prior written informed consent. All authors confirmed their adherence to the protocol,

and vouched for the accuracy of the data and analyses.




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Study Assessments and Outcome

The primary endpoint was the proportion of patients with an objective response,

assessed by CT imaging (or MRI if contrast-allergic) approximately every 8 weeks until

disease progression, by each institution’s radiology group or a contracted local

radiology service. Objective responses were assessed by Response Evaluation Criteria

in Solid Tumors, version 1.1 (RECIST 1.1) (29). Partial (PR) or complete responses

(CR) required radiologic confirmation within 4 to 6 weeks after the initial response.

Clinical benefit rate (CBR) is defined as the percentage of patients with an objective

response or stable disease (SD) ≥4 months. Survival was monitored every 3 months

until death or withdrawal of consent.

Safety evaluations were conducted during scheduled visits or more frequently if

warranted. Blood count and serum chemistries were checked routinely before

administration of sacituzumab govitecan and when clinically indicated.

Adverse events (AEs) were coded by MedDRA Preferred Term and System

Organ Class (SOC) version 10, with severity assessed by NCI-CTCAE v4.03. All

patients who received sacituzumab govitecan were evaluated for toxicities.

Statistical Analyses

The protocol provided that objective response rates (ORR) were determined for

patients who received ≥2 doses (1 cycle) and had their initial 8-week CT assessment.

Subset analyses were performed based on patients meeting these requirements, while

overall response assessments are reported on an ITT basis. Duration of response is

defined according to RECIST 1.1 criteria, with those having an objective response

measured from time of the first evidence of response until progression, while stable

disease duration is measured from the start of treatment until progression. PFS and OS

are defined from the start of treatment until an objective assessment of progression was

determined (PFS) or death (OS). Duration of response, PFS, and OS were estimated by

Kaplan-Meier methods, with 95% confidence intervals (CI), using MedCalc Statistical

Software, version 16.4.3 (Ostend, Belgium).




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Approximately 50 assessable patients were to be enrolled to provide adequate

safety and efficacy data for evaluation, with an objective response rate ≥15%, based

upon protocol-defined assessability, considered sufficient clinical activity to warrant

further investigation. After initial review of both 8 and 10 mg/kg dosing, 10 mg/kg doses

were selected for further clinical development and received by the majority of patients in

this study, as also was used in the TNBC and non-small-cell lung cancer investigations

(22, 24).

Tumor Trop-2 Immunohistochemistry (IHC) and Immunogenicity of Sacituzumab

Govitecan and Components

Available archival tumor specimens were stained for Trop-2 by IHC, as reported

previously (25, 26). Positivity required at least 10% of the tumor cells to be stained, with

an intensity scored as 1+ (weak), 2+ (moderate), and 3+ (strong). Antibody responses

to sacituzumab govitecan, the IgG antibody, and SN-38 were monitored in serum

samples taken at baseline and then prior to each even-numbered cycle by enzyme-

linked immunosorbent assays performed by the sponsor (25). Assay sensitivity is 50

ng/mL for the ADC and the IgG, and 170 ng/mL for anti-SN-38 antibody.

Results

Patients

A total of 53 mSCLC patients were enrolled between November 2013 and June

2016 after receiving a median of 2 prior lines of therapy (range, 1 to 7). All patients had

received cisplatin or carboplatin plus etoposide, and were considered chemosensitive

(N=27, 51%) or chemoresistant (N=26, 49%) to their platinum-containing frontline

therapy, based on a duration of response of >3 months or <3 months, respectively

(Table 1). While 22 (42%) had only one prior line of therapy, 14 (26%) and 17 (32%)

received 2 and >3 prior lines of therapy, respectively, including topotecan and/or

irinotecan (N=18, 34%), taxanes (N=9, 17%), and immune checkpoint inhibitors (N= 5,

9%). Most patients had extensive disease, with metastases to multiple organs, including

lungs (66%), liver (59%), lymph nodes (76%), chest (34%), adrenals (25%), bone

(23%), and pleura (6%) (Table 1). Other sites of disease included pancreas (N = 4),




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pelvis (N = 2), brain (N = 2), skin (N = 2), and esophageal wall, ovary, and sinus (1

each).

Treatment Exposure, Safety and Tolerability

Of the 53 patients, 15 were treated at 8 mg/kg and 38 at 10 mg/kg. As of the

cutoff date for this report, 51 patients have now discontinued treatment, while two

started treatment about 7 months ago and are still continuing. More than 590 doses

(over 295 cycles) have been administered, with a median of 10 doses (≥ 5 cycles) per

patient, including 2 patients who received >60 doses (>30 cycles), and a median

treatment duration of 2.5 months (range, 1 to 23). No infusion-related reactions were

reported. Ten patients received hematopoietic cytokine support for neutropenia (five

only once, five repeatedly), but only after grade 3 events had occurred, so this use did

not influence the neutropenia or febrile neutropenia rates reported here. Neutropenia

was also the primary indication for dose reductions, which occurred in 18 patients (15 at

10 mg/kg, 3 at 8 mg/kg), and once reduced by 25%, additional reductions were

infrequent. No treatment-related deaths were observed.

The most frequent AEs (all grades) included gastrointestinal toxicity (diarrhea,

nausea/vomiting, abdominal pain, anorexia, constipation), fatigue, neutropenia, anemia,

and alopecia (Table 2). Although 18 patients (34%) had grade ≥3 neutropenia, only

one patient (2%) had febrile neutropenia. Other grade 3 or 4 AEs were limited to fatigue

(N=7, 13%), diarrhea (N=5, 9%), anemia (N=3, 6%), and hypoxia (N=2, 4%).

Efficacy

Three patients were disqualified after receiving their first dose due to protocol

violations, because further review found previously undiagnosed brain metastases in

two and a mixed NSCLC and SCLC histology in the other patient. Therefore, the

intention-to-treat (ITT) population included 50 patients. Of these, 43 patients received

≥2 treatment doses (1 cycle) and had at least one post-baseline CT response

assessment. The remaining 7 left the study prior to their first response assessment, six

patients during cycle one (4 unrelated adverse events, withdrew consent, disease




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progression) and one patient with concurrent multiple comorbidities after cycle 2

(sudden death).

Treatment outcomes for the 43 patients with CT response assessments are

graphed in Fig. 1, including a waterfall plot of the best percentage change in the

diameter sum of the target lesions, showing 26 (60%) experienced a reduction of tumor

size from baseline (Fig. 1A), a graph showing the duration of the responses for those

achieving PR or SD status (Fig. 1B), and a plot tracking the response changes of the

patients with PR and SD over time (Fig. 1C).

Seven patients had partial responses (PR; ≥30% reduction, confirmed), resulting

in an overall ORR of 14% (7/50) based on ITT, and 17% (6/36) for patients in the 10

mg/kg dose group (Table 3). The median time to response was 2.0 months (range, 1.8

to 3.6 months) and the Kaplan-Meier estimated median duration of response was 5.7

months (95% CI: 3.6, 19.9), with 2 responses still ongoing 7.2 and 8.7 months after

starting treatment (Fig. 1B). Twenty-one patients had stable disease (SD) as best

response (21/50, 42%), including 6 patients with >30% tumor reduction at one response

assessment but not maintained on the subsequent CT, and 3 other patients with ≥20%

tumor reduction at one or more response assessments. The Kaplan-Meier estimated

median duration of SD was 5.6 months (95% CI: 5.2, 9.7), including 10 patients with SD

≥4 months, resulting in a clinical benefit rate (CBR: PR+SD≥4 months) of 34% (17/50)

(Table 3). On an ITT basis (N=50), the median PFS and OS were 3.7 months (95% CI:

2.1, 4.3) and 7.5 months (95% CI: 6.2, 8.8), respectively (Table 3, Fig. 2). Interestingly,

the median PFS for the 10 patients with SD ≥4 months was close to that obtained by the

7 PR patients (5.6 vs 7.9 months, respectively), and the median OS was also

comparable (8.3 vs 9.2 months, respectively).

Of 4 patients who received prior treatment with an immune checkpoint inhibitor

(CPI) and had CT-assessable responses, one progressed, but the other 3 achieved

stable disease, including one patient with 54% tumor reduction at first assessment who

withdrew consent without additional treatment or assessments, one who achieved 17%

tumor shrinkage lasting 8.7 months, and a third whose tumor size remained unchanged

for 3.7 months.




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Table 3 summarizes other subgroups from the 43 CT-assessable patients. For

example, there was no substantial difference in ORR, PFS or OS between those

patients who were chemosensitive vs chemoresistant to their frontline platinum-based

chemotherapy, but the CBR was 50% and 26%, respectively, when all patients given

sacituzumab govitecan in different therapy lines were analyzed. However, when studied

in second-line in a small subgroup, there was a suggestion of improved outcome in PR,

CBR, and PFS for frontline chemosensitive vs chemoresistant patients. There was no

substantial difference in these metrics for those treated in this study in the 2nd- vs 3rd-

line or higher setting. Interestingly there was a statistically significant higher OS with

other response metrics compared in a small subset of patients who received prior

topoisomerase-I inhibitor therapy vs no such prior therapy.

Significant tumor reduction in a patient given sacituzumab govitecan after

relapsing to frontline carboplatin plus etoposide therapy is presented in Fig. 3, showing

shrinkage of the adrenal metastasis by CT and 2+ Trop-2 staining of the SCLC archival

specimen by IHC. Another example with considerable tumor reduction is given in

Supplementary Fig. S1.

Immunohistochemical Staining of Tumor Specimens

Archival tumor specimens were obtained from 29 patients, but four were

inadequate for review, leaving 25 assessable tumors, of which 92% were positive, with

two (8%) having strong (3+) and thirteen (52%) moderate (2+) staining. Twenty-three of

these 25 patients had an objective response assessment. Five patients had PR as their

best response, four with 2+ staining, while the other was 1+ (Supplementary Table

S1). An analysis of PFS and OS vs IHC score showed no clear relationship

(Supplementary Fig. S2 A and B), with Kaplan-Meier estimates for PFS and OS for

patients with IHC scores of 0 and 1+ combined (N = 10) vs 2+ and 3+ combined (N =

13), indicating no significant differences (PFS, P = 0.27; OS, P = 0.72) based on IHC

score (Supplementary Fig. S2C and D).




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Immunogenicity of ADC, SN-38, or hRS7 Antibody

No neutralizing antibodies to sacituzumab govitecan, the antibody, or SN-38

were detected in patients who maintained treatment for even up to 22 months.

Discussion

The relapse of SCLC to frontline chemotherapy continues to be divided into two

categories, resistant relapse, occurring within three months of the first platinum-based

therapy, and sensitive relapse, which occurs after at least 3 months post treatment (5,

6, 22, 23). Although there is still some ambiguity regarding the best management of

recurrent SCLC, topotecan, a topoisomerase-I inhibitor similar to the SN-38 used in the

ADC studied here, is the only product approved for 2nd-line chemosensitive relapse in

the USA, as supported by numerous trials (7-9). However, the efficacy and adverse

events of topotecan have varied considerably in prior studies, as demonstrated in a

meta-analysis of over a thousand patients contained in 14 articles, reporting that

topotecan had an objective response rate of 5% in chemoresistant frontline patients and

17% in chemosensitive patients (15). This review found grade >3 neutropenia,

thrombocytopenia, and anemia in 69%, 1%, and 24% of patients, respectively;

approximately 2% of patients died from this chemotherapy (15). Thus, topotecan shows

some promise in this second-line setting in patients who relapsed after showing

sensitivity to a platinum-based chemotherapy, but with considerable hematological

toxicity. However, even this conclusion was challenged recently by Lara et al. (30),

asserting that platinum-sensitivity is not strongly associated with improved PFS and OS

following treatment with topotecan, which is its currently-approved indication.

It is in this setting that the results reported here with sacituzumab govitecan in

advanced-disease patients (stage IV) following a median of 2 (range, 1 to 7) prior

therapies are promising. Sixty percent of the 43 CT-assessable patients showed a

reduction of tumor measurements from baseline, according to RECIST 1.1, with an ITT-

based ORR of 14% (7/50) and a median duration of response of 5.7 months (95% CI:

3.6, 19.9). Stable disease was found in 42% of patients, where 12% of these SD

patients had >30% tumor shrinkage as best response, although not confirmed on the




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second scan. The clinical benefit rate at >4 months was 34% (17/50). Median PFS and

OS were 3.7 and 7.5 months, respectively. It is interesting that the median OS for the

ten patients with SD ≥4 months was 8.3 months (95% CI: 7.5, 22.4), which is not

statistically different from the median OS of 9.2 months (95% CI: 6.2, 20.9) for patients

with a PR (P=0.56).

In the group receiving 10 mg/kg as their starting dose (N = 36), there was a

confirmed objective response in six (17%), with an additional five patients having a

single CT showing >30% tumor reduction. Also, the clinical benefit rate for this group at

the 10 mg/kg dose was 39%. This supports the preferred dose of 10 mg/kg also found

in other cancer types treated with this ADC (22, 24). Noteworthy also is the lack of

patient selection based on immunohistochemical staining of tumor Trop-2, although

there may be a suggestion that stronger staining correlated with better response, but no

significant difference in PFS or OS was found with regard to IHC score (Fig. S2).

Clearly, more studies correlating tumor expression of Trop-2 and clinical outcome are

needed.

As mentioned, PFS and OS did not differ substantially between patients with SD

>4 months or PR. Patients with >30% tumor reduction on one CT or with SD generally

are not considered in ORR assessments. However, the results here indicate no

difference in duration of response between patients with confirmed PR or SD lasting for

more than 4 months (Fig. 1B). Indeed, the dynamic tracking of the individual patient

responses for PR or SD (especially when the SD last ≥4 months, which is a similar time

frame for confirming PR) suggests a clinical benefit for both groups by remaining below

the baseline tumor size for several months (Fig. 1C). Although there was a trend for the

PFS of patients with confirmed PR to be longer than the group of patients with SD

lasting ≥4 months (P = 0.16), the OS for these 2 groups was not significantly different (P

= 0.56). Therefore, while the number of patients in this initial analysis is relatively small,

the data suggest that more consideration should be given to disease stabilization as an

important indicator of clinical activity when an appropriate duration is achieved. This is

consistent with a report of SCLC patients enrolled into phase II trials by the Southwest

Oncology Group, showing that disease control rate at 8 weeks is a better predictor of




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subsequent survival than RECIST tumor response findings (31). Cesano et al. also

emphasized that disease stabilization is a useful predictor of survival following second-

line chemotherapy in SCLC patients (32).

Evaluating patients with a CT assessment of response based on prior platinum-

regimen chemosensitivity (N = 24) or chemoresistance (N = 19) showed no response

differences with sacituzumab govitecan treatment; ORR was 17% and 16%,

respectively (Table 3), for the entire study population. PFS and OS results were 3.8 and

8.3 months for patients who were chemosensitive in frontline, compared to a PFS and

OS of 3.6 months and 6.2 months, respectively, for the chemoresistant group. In a small

population of patients given sacituzumab in second-line, however, evidence of improved

results in those who were chemosensitive to frontline therapy is suggested (Table 3),

but these results need to be confirmed in a larger study. If confirmed, this would differ

from topotecan, which is indicated in the USA only in those SCLC patients who showed

a >3-month response to frontline cisplatin and etoposide chemotherapy (6, 12, 22, 23).

Although both topotecan and SN-38 are inhibitors of the DNA topoisomerase I

enzyme, which is responsible for relaxing a supercoiled DNA helix when DNA is

synthesized by stabilizing the DNA complex and causing accumulation of single strand

DNA breaks (33), sacituzumab govitecan showed activity in a small group of patients

who relapsed after topotecan therapy (7/15 showed target lesion shrinkage, with 2 PR).

Thus, if corroborated in future trials, topotecan resistance or relapse may not be a

contraindication for administering sacituzumab govitecan, and because of being

similarly active in patients who were chemoresistant to cisplatin and etoposide (ORR of

16%), may be of particular value as a second-line therapeutic in patients with metastatic

SCLC regardless of chemosensitivity status.

In the twenty years since the approval of topotecan in the second-line setting, no

new agent has been licensed for metastatic SCLC therapy in second-line or later

therapy in the USA and Europe. However, there has been progress more recently with

inhibitors of the T-cell checkpoint receptors programmed cell-death protein (PD-1) and

cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (34). Antonia et al. conducted a

phase I-II trial of nivolumab with or without CTLA-4 antibody ipilimumab in patients with




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recurrent SCLC. Nivolumab alone achieved a 10% response rate, while the combination

had response rates of 19 to 23%, and a disease-control rate of 32% (34). However, a

recent study of ipilimumab with or without chemotherapy in SCLC failed to confirm an

advantage of combining this anti-CTLA4 antibody with chemotherapy (35). Since we

observed that sacituzumab govitecan may have activity in patients whose cancer has

progressed on therapy with immune checkpoint inhibitors, we are studying this further,

especially because of evidence showing such responses after relapse or

unresponsiveness to therapy with an immune checkpoint inhibitor in patients with other

cancer types (26, 27, 36, 37).

Despite recent progress in immunotherapy, this still is a lethal disease, especially

in the population that is chemoresistant to first-line therapy. The current results of

sacituzumab govitecan in heavily-pretreated patients with advanced, relapsed, stage IV,

SCLC, despite the limitations of a one-arm trial, suggest that this ADC may gain a role

in the therapy of both chemosensitive and chemoresistant SCLC patients, both before

or after topotecan, and thus needs to be studied further in such settings. It is

encouraging that another ADC, rovalpituzumab tesirine, an investigational DLL3-

targeting conjugate, also has shown activity in recurrent SCLC (38).




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Disclosure of Potential Conflicts of Interest

D.M. Goldenberg has stock (including patents) in Immunomedics, Inc., and is a

Board member. S.V. Govindan, P, Maliakal, B. Mudenda, W.A. Wegener, and R.M.

Sharkey are employees of Immunomedics, Inc., with stock options.

Authors’ Contributions

Conception and design: A.N. Starodub, D.R. Camidge, W.A. Wegener, D.M.

Goldenberg

Development of methodology: S.V. Govindan, P. Maliakal, W.A. Wegener

Acquisition of data (acquired and managed patients, provided facilities, etc.): J.E. Gray,

R.S. Heist, A.N. Starodub, D.R. Camidge, E. Kio, G. Masters, W.T. Purcell, M.J.

Guarino, J. Misleh, C.J. Schneider, B.J. Schneider, A.J. Ocean, T. Johnson, L. Gandhi,

K. Kalinsky, R.J. Scheff, W.A. Messersmith

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational

analysis): P. Maliakal, B. Mudenda, W.A. Wegener, R.M. Sharkey, J.E. Gray, R.S.

Heist, K. Kalinsky, A.N. Starodub, D.R. Camidge

Writing, review, and/or revision of the manuscript: All authors

Administrative, technical, or material support (i.e., reporting or organizing data,

constructing databases): P. Maliakal, B. Mudenda, W.A. Wegener, R.M. Sharkey

Study supervision: D.M. Goldenberg

Acknowledgments

We thank the patients and their families for participating, the clinical support

staffs at the investigational sites, and Heather Horne and the data management team at

Immunomedics for their contributions.

Funding

This study was supported by Immunomedics, Inc.




18

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23

Table 1. Baseline demographics and disease characteristics (N = 53)

Age Years (median; range) 63 (44 - 82)

Gender, N (%) Female 30 (56) Male 23 (44)

Race, N (%) White 47(88) Black 3 (6) Other 3 (6)

ECOG, N (%) 0 6 (11) 1 47(89)

Sites of metastases, N (%) Lung 35 (66) Liver 31 (59) Lymph nodes 40 (76) Chest 18 (34) Adrenals 13 (25) Bone 12 (23) Pleural effusion 3 (6) Pancreas 4 (7) Pelvis 2 (4) Brain 2 (4) Skin 2 (4) Others 3 (6)

Prior Lines of Therapy, N (%) 1 22 (42) 2 14 (26) ≥3 17 (32)

Sensitivity to 1st -line chemotherapy, N (%) Sensitive 27 (51) Resistant 26 (49)

Prior Therapy, N (%) Platinum and Etoposide 53 (100) Topotecan and/or

Irinotecan 18 (34)

Taxanes 9 (17) Checkpoint inhibitors (CPI) 5 (9)




24

Table 2. Adverse events (N=53)*

All Grades Grades 3 and 4

N % N %

Diarrhea 28 53 5 9

Nausea 27 51 - -

Fatigue 25 47 7 13

Neutropenia 23 43 18 34

Vomiting 18 34 - -

Abdominal pain 16 30 - -

Anorexia 15 28 - -

Anemia 14 26 3 6

Alopecia 12 23 - -

Constipation 11 21 - -

Hypomagnesemia 10 19 - -

Dehydration 9 17 - -

Dyspnea 9 17 - -

Cough 8 15 - -

Hypoxia 3 6 2 4

Febrile neutropenia 1 2 1 2

*Patients with adverse events, regardless of causality, occurring in >15%

(all grades) or ≥2% (grade ≥3) of patients.




25

Table 3. IMMU-132 response assessment for ITT population (N = 50) or subset analyses in patients who had ≥2 IMMU-132 doses with at least one CT response determination (N = 43)

All patients (N = 50) 10 mg/kg (N = 36) 8 mg/kg (N = 14) Best overall response, N (%) PR 7 (14%) 6 (17%) 1 (7%) SD 21 (42%) 17 (47%) 4 (29%) PD 15 (30%) 7 (19%) 8 (57% IE 7 (14%) 6 (17%) 1 (7%) Duration of response, months, median (95% CI) 5.7 (3.6, 19.9) 4.0 (3.6, 5.7) 19.9 (N = 1) CBR (PR+SD ≥4 months), N (%) 17 (34%) 14 (39%) 3 (21%) PFS, months, median (95%CI) 3.7 (2.1, 4.3) 3.7 (2.8, 5.3) 2.0 (1.7. 3.8) OS, months, median (95% CI 7.5 (6.2, 8.8) 6.2 (5.0, 8.3) 8.1 (7.0, 22.4)

Subgroup analyses Response to Frontline Therapy (all patients) Sensitive (N = 24) Resistant (N = 19)

PR, N (%) 4 (17%) 3 (16%)

CBR (PR+SD ≥4 months), N (%) 12 (50%) 5 (26%)

PFS, months, median (95% CI) 3.8 (2.8, 6.0) 3.6 (1.8, 3.8) NS

OS, months, median (95% CI) 8.3 (7.0, 13.2) 6.2 (4.0, 10.5) NS

Response to Frontline Therapy (IMMU-132 as 2nd line) Sensitive (N = 10) Resistant (N = 9)

PR, N (%) 2 (20%) 1 (11%)

CBR (PR+SD ≥4 months), N (%) 5 (50%) 2 (22%)


OS, months, median (95% CI) 8.1 (7.5, 10.5) 8.0 (4.0, 10.5) NS

IMMU-132 Line of Therapy Received

2nd Line (N = 19) ≥3 Lines (N = 24)

PR, N (%) 3 (16%) 4 (17%)

CBR (PR+SD ≥4 months), N (%) 7 (37%) 9 (38%)


OS, months, median (95% CI) 8.1 (7.5, 10.5) 7.0 (6.2, 20.9 NS

≥3 Lines Pts Treated with Prior TPI

Prior TPI (N = 15) No Prior TPI (N = 9)

PR, N (%) 2 (13%) 1 (11%)

CBR (PR+SD ≥4 months), N (%) 6 (40%) 3 (33%) PFS, months, median (95% CI) 3.6 (3.3, 5.5) 3.7 (1.7, 4.3) NS

OS, months, median (95% CI) 8.8 (6.2, 20.9) 5.5 (3.2, 8.3) P = 0.04

Abbreviations: PR, partial response; SD, stable disease; PD, progressive disease; CI, confidence interval. PFS, progression-free survival; OS, overall survival, CBR, clinical benefit rate (PR+SD ≥4 months); TPI, topoisomerase I inhibitors, topotecan and irinotecan; IE, inevaluable; NS, not statistically significant.




26

Figure Legends

Fig. 1. Graphic representation of anti-tumor response and duration in response-

assessable patients. A. Best percentage change in the sum of the diameters for the

selected target lesion and best overall response descriptor according to RECIST 1.1

criteria. Patients are identified with respect to the sacituzumab govitecan starting dose

and whether they were sensitive or resistant to prior first-line therapy. B. Duration of

response from the start of treatment for those patients who achieved stable disease or

better. Timing when tumor shrinkage achieved ≥30% is shown, along with sacituzumab

govitecan starting dose and sensitivity to first-line therapy. C. Dynamics of response for

patients who achieved stable disease or better. Two patients with confirmed partial

responses who are continuing treatment are shown with dashed line.

Fig. 2. Kaplan-Meier curves for 50 patients (ITT). A: Progression-free survival with 41

patients having progressed, 7 lost to follow-up while progression-free, and 2 currently

continuing progression-free. B: Overall survival with 37 deaths, 8 patients currently

alive, and 5 patients lost to follow-up.

Fig. 3. This 64-year-old male diagnosed with advanced SCLC received carboplatin as

1st line therapy from July 2013 to November 2013, with etoposide added in November

and December 2013. The disease relapsed in May 2014. Prior to starting sacituzumab

govitecan, the tumor lesions at baseline (May 2014) included subcarinal lymph node (20

mm) and right adrenal gland tumors (A: 43 x 34 mm diameter adrenal mass), as well as

multiple unmeasurable lesions in the right and left lobes of the liver, thickening of the

right hilum, a left upper lobe pulmonary nodule, and esophageal thickening. The

response evaluation after 2 months of therapy showed 50% reduction according to

RECIST 1.1 (B, adrenal mass shrinks to 14 mm, subcarinal lymph node shrinks to 17

mm). By the second response assessment, the adrenal mass was no longer visible,

while the subcarinal node experienced its maximum shrinkage ~11 months from the

start of treatment (to 11 mm), yielding maximum shrinkage of 82%. The patient

experienced a 21-month duration of response (July 2014 to March 2016). C.

Immunohistology of a biopsy from the adrenal mass stained for Trop-2 and scored as




27

2+, but with sparse distribution among the tumor cells. Arrow shows group of cells with

3+ membrane staining.




Figure 1




Figure 2




Figure 3




Published OnlineFirst July 5, 2017.Clin Cancer Res Jhanelle E. Gray, Rebecca S. Heist, Alexander N Starodub, et al. Targeting Trop-2, Sacituzumab GovitecanTopoisomerase-I-inhibiting Antibody-Drug Conjugate (ADC) Therapy of Small-cell Lung Cancer (SCLC) With a

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