trastuzumab emtansine (t-dm1) in patients with previously ......sep 11, 2018 · author manuscripts...

Trastuzumab Emtansine (T-DM1) in Patients with Previously Treated HER2-

Overexpressing Metastatic Non-Small Cell Lung Cancer: Efficacy, Safety and

Biomarkers

Solange Peters1, Rolf Stahel2, Lukas Bubendorf3, Philip Bonomi4, Augusto Villegas5,

Dariusz M. Kowalski6, Christina S. Baik7, Dolores Isla8, Javier De Castro Carpeno9, Pilar

Garrido10, Achim Rittmeyer11, Marcello Tiseo12, Christoph Meyenberg13, Sanne de

Haas14, Lisa H. Lam15, Michael W. Lu15, and Thomas E. Stinchcombe16

1Oncology Department, Lausanne University Hospital, Lausanne, Switzerland; 2Cancer

Center Zürich, University Hospital of Zürich, Zürich, Switzerland; 3Institute of Pathology,

University Hospital Basel, Basel, Switzerland; 4Section of Medical Oncology, Rush

University Medical Center, Chicago, IL, USA; 5Florida Cancer Specialists and Research

Institute, Fleming Island, FL, USA; 6Center of Oncology, Maria Skłodowska Curie

Memorial Cancer Centre, Warsaw, Poland; 7Seattle Cancer Center Alliance, University

of Washington, Seattle, WA, USA; 8Medical Oncology Section, Hospital Clinico

Universitario Lozano Blesa, Zaragoza, Spain; 9Medical Oncology Section, Hospital

Universitario La Paz, Madrid, Spain; 10Medical Oncology Department, Hospital

Universitario Ramon y Cajal, Madrid, Spain; 11Department of Thoracic Oncology,

Fachklinik für Lungenerkrankungen, Immenhausen, Germany; 12Medical Oncology Unit,

Azienda Ospedaliero-Universitaria di Parma, Italy; 13Biostatistics, F. Hoffmann-La

Roche, Basel, Switzerland; 14Oncology Biomarker Development, F. Hoffmann-La

Roche, Basel, Switzerland; 15Product Development Oncology, Genentech, Inc, South

San Francisco, CA, USA; 16Duke Cancer Institute, Duke University School of Medicine,

Durham, NC, USA

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Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on September 11, 2018; DOI: 10.1158/1078-0432.CCR-18-1590

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Running title: T-DM1 in HER2-overexpressing metastatic NSCLC

Abbreviations: AE, adverse event; ALK, anaplastic lymphoma kinase; C, treatment

cycle; CBR, clinical benefit rate; CI, confidence interval; CNA, copy number alteration;

CR, complete response; DoR, duration of response; ECOG, Eastern Cooperative

Oncology Group; EGFR, epidermal growth factor receptor; FISH, fluorescence in situ

hybridization; FMI, Foundation Medicine, Inc.; HER, human epidermal growth factor

receptor; IHC, immunohistochemistry; ISH, in situ hybridization; T-DM1, trastuzumab

emtansine; TKI, tyrosine kinase inhibitor; NCI CTCAE, National Cancer Institute

Common Terminology Criteria for Adverse Events; ND, not done; NE, not evaluable;

NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; OS, overall

survival; ORR, overall response rate; PD, progressive disease; PFS, progression-free

survival; PR, partial response; RA, rearrangement; RECIST, Response Evaluation

Criteria in Solid Tumors; SD, stable disease; SV, short variant; U, unknown HER2

amplification; UNK, unknown.

Corresponding author: Dr Solange Peters, Oncology Department, Centre Hospitalier

Universitaire Vaudois (CHUV), Rue du Bugnon 46, 1011 Lausanne, Switzerland,

Telephone: +41795560192, E-mail: [email protected]




Disclosures

SP has received honoraria from and served as a consultant for F. Hoffmann-La

Roche/Genentech, Inc., Bristol-Myers Squibb, Novartis, Pfizer, MSD, Janssen, Amgen,

Merck Serono, Eli Lilly, Regeneron, and AstraZeneca, and she has received funding for

travel from F. Hoffmann-La Roche and Bristol-Myers Squibb.

RS has received honoraria from Astellas, AstraZeneca, Lilly, MSD, Novartis, and F.

Hoffmann-La Roche, and has served as a consultant for AbbVie, AstraZeneca, BMS,

Boehringer Ingelheim, Eli Lilly, MSD, Pfizer, and F. Hoffmann-La Roche.

LB has received honoraria from and served as a consultant for F. Hoffmann-La

Roche/Genentech, Inc., Bristol-Myers Squibb, Novartis, Pfizer, MSD, and AstraZeneca,

and he has received research support from and owns stock in F. Hoffmann-La Roche.

PB has served as a consultant for and received honoraria from F. Hoffmann-La

Roche/Genentech, Inc., AstraZeneca, Biodesix, Helsinn, Merck, and Pfizer, and his

institution has received research funding from F. Hoffmann-La Roche/Genentech, Inc.,

AstraZeneca, Biodesix, and Merck.

AV has served on speakers’ bureaus and received honoraria and funding for travel from

BMS, Celgene, and Alexion, and has served as a consultant for BMS.

CSB has served as a consultant for Novartis and received research funding from

Celgene, AstraZeneca, Novartis, Clovis, Loxo, Pfizer, and Genentech, Inc.

JDCC has served as a consultant for AstraZeneca, F. Hoffmann-La Roche, Lilly,

Boehringer Ingelheim, and MSD.




PG has served as a consultant for F. Hoffmann-La Roche, Pfizer, Novartis, and BMS;

has served on speakers’ bureaus for MSD, BMS, and Boehringer Ingelheim; and has

received funding for travel from F. Hoffmann-La Roche, AstraZeneca, and Boehringer

Ingelheim.

AR has served as a consultant for AstraZeneca, Lilly, F. Hoffmann-La

Roche/Genentech, Inc., Boehringer Ingelheim, MSD, Pfizer, and Bristol-Myers Squibb.

MT has served as a consultant for AstraZeneca, Pfizer, Eli-Lilly, BMS, Novartis, Roche,

MSD, Boehringer Ingelheim, Otsuka, and Pierre Fabre.

CM is an employee of CRO KOEHLER-eClinical, Freiburg, Germany, which was

contracted to work on behalf of F. Hoffmann-La Roche.

SdH is a salaried employee of F. Hoffmann-La Roche.

LHL and ML are salaried employees of Genentech, Inc. and own stock in F. Hoffmann-

La Roche.

TES has served as a consultant for AstraZeneca, Takeda, and Novartis, and has

received research funding from BMS, AstraZeneca, Merck, Takeda, and Genentech,

Inc.

DMK and DI have declared no conflicts of interest.

Key words: HER2 amplification, HER2 overexpression, non-small cell lung cancer

(NSCLC), trastuzumab emtansine (T-DM1), human epidermal growth factor receptor 2




Funding Support: This study was funded by F. Hoffmann–La Roche, Ltd.




Translational relevance There are no standard therapies targeting human epidermal growth factor receptor 2

(HER2) in non-small cell lung cancer (NSCLC); however, HER2-targeted therapies are

standard in breast and gastric cancer. Results from this phase II study indicate a signal

of activity of the HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-

DM1) in patients with immunohistochemistry 3+ HER2–positive NSCLC. T-DM1 was

tolerable in NSCLC and safety was similar to findings from prior trials. An exploratory

biomarker analysis showed that, of the four responding patients, three had HER2

amplified tumors and two had HER2 mutations. Additional investigation into HER2

oncogenic modifications, including HER2 overexpression, amplification or mutation may

help refine a patient population likely to benefit from treatment with T-DM1. Of

importance, HER2 IHC as a single parameter was an insufficient predictive biomarker to

select patients with most benefit from T-DM1. Further trials should refine the target

population for HER-2 targeted therapies in NSCLC.




ABSTRACT

Background

HER2-targeted therapy is not standard of care for human epidermal growth factor

receptor 2 (HER2)–positive non-small cell lung cancer (NSCLC). This phase II study

investigated efficacy and safety of the HER2-targeted antibody-drug conjugate

trastuzumab emtansine (T-DM1) in patients with previously treated advanced HER2-

overexpressing NSCLC.

Methods

Eligible patients had HER2-overexpressing NSCLC (centrally-tested

immunohistochemistry [IHC]), and received previous platinum-based chemotherapy and

targeted therapy in the case of EGFR mutation or ALK gene rearrangement. Patients

were divided into cohorts based on HER2 IHC (2+, 3+). All patients received T-DM1 3.6

mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity.

The primary endpoint was investigator-determined overall response rate (ORR) using

Response Evaluation Criteria in Solid Tumors v1.1.

Results

Forty-nine patients received T-DM1 (29 IHC 2+, 20 IHC 3+). No treatment responses

were observed in the IHC 2+ cohort. Four partial responses were observed in the IHC

3+ cohort (ORR 20%; 95% confidence interval 5.7–43.7%). Clinical benefit rates were

7% and 30% in the IHC 2+ and 3+ cohorts, respectively. Response duration for the

responders was 2.9, 7.3, 8.3, and 10.8 months. Median progression-free and overall




survival were similar between cohorts. Three of four responders had HER2 gene

amplification. No new safety signals were observed.

Discussion

T-DM1 showed a signal of activity in patients with HER2-overexpressing (IHC 3+)

advanced NSCLC. Additional investigation into HER2 pathway alterations is needed to

refine the target population for T-DM1 in NSCLC; however, HER2 IHC as a single

parameter was an insufficient predictive biomarker.




Introduction

The development of targeted therapy for non-small cell lung cancer (NSCLC) with

specific molecular alterations such as anaplastic lymphoma kinase (ALK)

rearrangements or epidermal growth factor receptor (EGFR) mutations represents a

tremendous advance (1,2). Current research is focused on the identification and

development of targeted therapy for additional molecular subtypes. Human epidermal

growth factor receptor 2 (HER2) is overexpressed on the surface of multiple tumor cell

types, including NSCLC (35). Survival data meta-analyses show HER2 overexpression

is associated with poor prognosis in lung cancer (3,6). There are currently no standard

therapies targeting the HER2 pathway in NSCLC, whereas HER2-targeted therapies

are standard for breast and gastric cancer. In breast and gastric cancer, HER2

overexpression generally occurs in the context of gene amplification while discordance

between immunohistochemistry (IHC) overexpression and gene amplification is

observed in NSCLC (710). Instead, increased HER2 expression in NSCLC may result

from upregulated transcriptional/post-transcriptional mechanisms (7,9).

The reported prevalence of “HER2-positive” NSCLC varies since previous studies have

used different definitions and testing methods (in situ hybridization [ISH] and IHC), with

HER2 positivity defined by IHC 2+/3+ staining reported in 13–20%, IHC 3+ staining in

2–6%, and HER2 gene amplification by ISH in 2–4% (8). HER2 gene mutation, another

HER2 alteration in NSCLC, has a frequency of 1%–4% (8). HER2 gene mutations and

amplifications show limited co-occurrence in NSCLC (8,10). The absence of correlation

between HER2 overexpression, amplification, or mutation suggests three biologically




distinct NSCLC subtypes, leaving the question of which subtypes will be most effectively

treated with HER2-targeted therapy.

Despite observation of these three alterations in NSCLC, the role of these abnormalities

as therapeutic biomarkers remains undefined. Few data sets report on the use of

HER2-targeted therapies in patients with HER2-positive (11,12) or –mutated (13–16)

NSCLC. These studies were small and some included patients treated concurrently with

chemotherapy and a HER2 targeting agent. Of note, most trials do not assess presence

of all three types of HER2 alterations, and tend to use significantly divergent definitions,

which impairs the interpretation of the predictive value of specific HER2 alterations in

NSCLC.

Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate composed of

trastuzumab joined via a stable linker to DM1, a cytotoxic microtubule-inhibitory agent

(17). T-DM1 targets the delivery of DM1 to HER2-positive cancer cells, maximizing the

therapeutic index of DM1 and minimizing off-target effects. T-DM1 has been approved

for the treatment of previously-treated HER2-positive metastatic breast cancer. In

preclinical studies, T-DM1 demonstrated potent in vitro growth inhibition of HER2 IHC

3+ (Calu-3, H2170) and IHC 1+ (H1781) NSCLC cells (18). T-DM1 also showed robust

antitumor activity in Calu-3 HER2 IHC 3+ and H1781 HER2 IHC 1+ mouse xenograft

tumor models.

Altogether, this evidence provided rationale to conduct this first phase II study of T-DM1

in patients with HER2-overexpressing advanced NSCLC prior to considering a more

definitive trial and to investigate potential predictive biomarkers. Given the T-DM1




mechanism of action, we selected patients with moderate-to-high HER2

overexpression, defined as IHC 2+ or 3+ only. Specifically, HER2 overexpression can

occur due to increased HER2 transcription, independent of HER2 gene amplification or

mutation (710). To date, there are no clinical data suggesting T-DM1, in contrast to

trastuzumab or a HER2 tyrosine kinase inhibitor (TKI), would have a stronger effect in

HER2-mutated or HER2-amplified NSCLC. While amplification and mutations are

considered potential driver oncogenes, we hypothesize that targeting HER2

overexpression will address a potentially larger patient population that may be more

relevant taking into account the mechanism of action of T-DM1, targeting the HER2

extracellular component.

Methods

Study design and patients

In this multicenter, single-arm, clinical trial (trial registration NCT02289833), eligible

patients were aged ≥18 years with HER2-positive (IHC 2+ or 3+) locally advanced or

metastatic NSCLC previously treated with ≥1 prior platinum-based chemotherapeutic

regimen. Patients with EGFR mutated or ALK gene rearranged NSCLC were eligible if

they had also experienced disease progression following treatment with prior targeted

therapy or if they were intolerant to such treatment.

Archived tumor specimens from previously collected tissue were centrally and

prospectively tested for HER2 status (Ventana Pathway HER2 (4B5) IHC assay;

Ventana Medical Systems, Inc., Tucson, AZ, USA). HER2 overexpression was




evaluated by IHC, the gold standard for HER2 assessment in breast and gastric cancer.

If archival tissue was unavailable for HER2 testing, patients could have a newly

collected biopsy specimen tested. Based on results from central testing, patients with a

HER2 status of IHC 2+ (defined as weak-to-moderate complete, basolateral, or lateral

membranous reactivity in ≥10% of tumor cells) or IHC 3+ (defined as strong complete,

basolateral, or lateral membranous reactivity in ≥10% of tumor cells) were eligible.

A retrospective exploratory biomarker analysis was conducted if sufficient tissue was

available following IHC testing. In this analysis, HER2 gene amplification (HER2/CEP17

gene ratio ≥2) was also assessed by ISH (similar to breast and gastric cancers). HER2

mRNA expression levels were measured by quantitative reverse transcriptase

polymerase chain reaction (Roche Molecular Diagnostics, Pleasanton, CA, USA) and

evaluated in subgroups defined using the median mRNA expression distribution values

(>median versus ≤median). Pending tissue availability, HER2 mutation status and

amplification was also assessed using next-generation sequencing (NGS; Foundation

Medicine Inc., Cambridge, MA, USA), where amplification was defined by copy number

≥5 in a diploid model.

Eligible patients also had an Eastern Cooperative Oncology Group (ECOG)

performance status of 0 or 1, measurable disease (per Response Evaluation Criteria in

Solid Tumours [RECIST] v1.1), adequate organ function, and left ventricular ejection

fraction ≥50% (echocardiogram or multiple-gated acquisition scan). Patients with

untreated or symptomatic brain metastases (baseline brain imaging required but repeat

imaging was not required), or who had received anticancer or investigational therapy

within 21 days of the start of study treatment were excluded.




Procedures

Patients were able to enroll in the screening portion of the trial and underwent IHC

testing prior to disease progression on current therapy to determine if they were

potentially eligible for the trial. Eligible patients were subdivided according to HER2 IHC

status (2+ or 3+). Over-enrollment was allowed to the IHC 2+ cohort to accommodate

patients who had initiated the screening process and met the eligibility criteria. All

patients received T-DM1 (3.6 mg/kg intravenously every 3 weeks) until investigator-

assessed disease progression, unmanageable toxicity, or study termination. Survival

status was assessed every 3 months following discontinuation due to disease

progression. Tumor assessments by radiographic evaluation were performed every 6

weeks.

The trial protocol was approved by the institutional review boards at each participating

center. The study was conducted in accordance with the Declaration of Helsinki, Good

Clinical Practice guidelines, and applicable local laws. All patients provided written

informed consent.

Outcomes

The primary efficacy endpoint was confirmed investigator-assessed objective response

rate (ORR) using RECIST v1.1, defined as a complete response (CR) or partial

response (PR) determined on two consecutive assessments ≥4 weeks apart (19).

Secondary endpoints were investigator-assessed progression-free survival (PFS),

duration of response (DoR; time from initial documented response to documented

disease progression or death from any cause), clinical benefit rate (CBR; proportion of




patients with CR or PR or stable disease [SD] determined by the investigator at 6

months), overall survival (OS), and safety. Patients were monitored continuously for

adverse events (AEs).

Statistical analysis

The primary efficacy objective was investigator-assessed ORR. Given the exploratory

nature of this study, a sample size of 20 patients per cohort was selected to estimate

two-sided 95% Clopper-Pearson confidence intervals (CIs) for ORR in each cohort and

overall. The data cutoff for the ORR analysis occurred when all enrolled patients were

expected to have completed ≥ 4.5 months of follow-up (when three post-baseline tumor

assessments were expected to be performed). Efficacy and safety were evaluated in

patients who received ≥1 dose of T-DM1. DoR and Kaplan–Meier estimates of PFS and

OS are reported for all evaluable patients and separately for the two IHC cohorts. For

PFS and DoR, data for patients without disease progression or death were censored at

the time of the last tumor assessment. For OS, data from patients without a death event

were censored on the date last known to be alive. Exploratory biomarker data were

analyzed using descriptive statistics.

Safety was assessed through summaries of AEs, deaths, and changes in laboratory

results. All AEs occurring on or after first study treatment were summarized by mapped

term, appropriate thesaurus levels, and National Cancer Institute Common Terminology

Criteria for Adverse Events (NCI CTCAE) v4.0 toxicity grade. Serious AEs were listed

separately and summarized.




Results

Study population

Of 370 screened patients, 133 had IHC 2+ or 3+ tumors (Figure S1). Of these, 49

patients from five centers in the USA and 13 European centers were eligible and

enrolled between December 15, 2014 and June 21, 2016; the remaining 84 patients did

not meet eligibility criteria or elected for alternative treatment. Of the 49 enrolled

patients, HER2 status was based on archival samples for 41 patients and freshly

obtained samples (collected within 8 weeks before start of study treatment) for 6

patients; the sample collection date was unknown for 2 patients. Median age was 61

years (range, 36–80), and the majority of patients were male, previous smokers, and

had adenocarcinoma (Table 1). All but one patient previously received platinum-based

chemotherapy (98%; 48/49); information on prior and follow-up treatments is shown in

Table S1. The IHC 2+ cohort was over-enrolled and included 29 patients and the IHC

3+ cohort included 20 patients.

At the cutoff date (May 29, 2017), 15/49 (31%) patients remained on study for survival

follow-up and one in the IHC 3+ cohort remained on treatment; three were lost to follow-

up, 30 died (29 due to disease progression; one died of an unknown cause as reported

in death registry records), and one discontinued the study due to clinical progression.

Efficacy

Median follow-up was 23.1 months (range, 0.9–26.7) and 18.4 months (1.0–25.1) in the

IHC 2+ and 3+ cohorts, respectively. In the IHC 2+ cohort, there were no treatment

responses; 8/29 (28%) patients had SD, 16/29 (55%) had progressive disease (PD),




and response was not evaluable for 5/29 (17%) (Figure 1A and 1B). In the IHC 3+

cohort, ORR was 20% (95% CI 5.7–43.7%); 4/20 (20%) patients had a PR, 4/20 (20%)

had SD, 11/20 (55%) had PD, and one (5%) died prior to first scheduled tumor

assessment (response missing) (Figure 1C). CBR was 7% (2/29, 95% CI 1–23%) and

30% (6/20; 95% CI 12–54%) in the IHC 2+ and 3+ cohorts, respectively. DoR for the

four IHC 3+ responders was 2.9, 7.3, 8.3, and 10.8 months (censored for one patient

still on treatment; Figure 1D).

In the IHC 2+ and 3+ cohorts, median PFS was 2.6 months (95% CI 1.4–2.8) and 2.7

months (95% CI 1.4–8.3), respectively; median OS was 12.2 months (95% CI 3.8–23.3)

and 15.3 months (95% CI 4.1–NE), respectively (Figure 2).

Safety

Median duration of T-DM1 treatment was 3.6 months (range, 0–24.8 months) (Figure

S2). AEs, regardless of causality or attribution, are reported (Table 2). Forty-five

patients (92%) reported an AE (any grade). Ten patients reported Grade 3 AEs

(regardless of relationship to treatment), and fatigue (n=2) was the only Grade 3 AE

reported in more than one patient. One Grade 4 seizure was reported in a patient with

prior history of brain metastases receiving concurrent treatment for seizures. There

were no deaths due to AEs. Two patients withdrew from study treatment due to AEs

(Grade 2 infusion-related reaction and Grade 3 influenza). Of AEs of particular interest

in T-DM1-treated patients, one event each of Grade 3 thrombocytopenia and infusion-

related reaction/hypersensitivity occurred.

Exploratory biomarker analysis




All responding patients were in the IHC 3+ cohort (Table 3). A higher proportion of IHC

3+ patients had HER2-amplified tumors, higher HER2 gene copy number, and HER2

mRNA expression >median compared with the IHC 2+ cohort.

Biomarker characteristics of the responders and those with SD >6 months are shown in

Table 4. Of four responding patients, three had HER2 amplified tumors (ISH,

HER2/CEP17 gene ratio ≥2). Three responders had central NGS data; two of these

patients had HER2 amplification (NGS, copy number ≥5; Tables 3 and 4). The other

responder had locally-determined NGS results (same platform used for central

assessment) showing an equivocal test result for HER2 amplification. Two responders

had HER2 mutations including one HER2 gene rearrangement (unknown functional

status).

A heatmap of the top 20 genetic alterations found across all patients was prepared for

those with central NGS results (n=24, Figure S3). Of these 24 patients, HER2 mutations

were detected in four patients (no responders) and HER2 amplification was detected in

five patients (2 responders).

Discussion

In NSCLC, activation of HER2 occurs through various mechanisms including protein

overexpression, gene amplification, or mutation, and is considered an oncogenic driver.

In our study of T-DM1 in patients with HER2-overexpressing advanced NSCLC,

objective responses were observed in patients with IHC 3+ tumors. No responses were

observed in the IHC 2+ cohort, regardless of HER2 amplification status. However, four




additional patients achieved SD >6 months, resulting in CBRs of 7% and 30% in the

IHC 2+ and 3+ cohorts, respectively.

Several small studies have also investigated the use of HER2-targeted therapies in lung

cancer (Table S2). A phase II trial investigated treatment with T-DM1 in NSCLC

characterized by overexpressed, amplified or mutated HER2 and was stopped early due

to limited efficacy (20). Among 15 patients with HER2-positive NSCLC treated with T-

DM1 (five IHC 3+, three IHC 2+/FISH positive, seven with HER2 mutations), there was

only one partial response in a patient with HER2 mutation (ORR 6.7%; 90% CI 0.2–

32.0%). The small number of patients enrolled in the trial, and in the various molecular

subsets limits the interpretation of these results. Analyses from the NCT02675829

basket trial further support the potential role of TDM-1 in advanced NSCLC

characterized by HER2 oncogenic alterations. This trial investigates efficacy of T-DM1

in various HER2-amplified solid tumors and HER2 mutant lung cancers (21,22). In the

cohort of patients with advanced HER2-mutant lung adenocarcinoma, ORR was 44%

(8/18; 95% CI 22–69%), median PFS was 5 months (95% CI 3 to 9 months), and

median DoR was 4 months (95% CI 2 to 9 months). In the cohort of patients with HER2-

amplified advanced lung cancer ORR was 50% (3/6) (22).

Other limited datasets have reported activity of HER2-targeted therapy in NSCLC. In a

retrospective analysis of patients with a HER2-mutation who received 22 individual anti-

HER2 treatments, there were 11 partial responses, leading to an ORR of 50% (11/22)

(13). The MyPathway basket trial (NCT02091141) is evaluating dual inhibition of the

HER2 pathway with pertuzumab plus trastuzumab in patients with HER2-

overexpressing, -amplified, or -mutated tumors, including lung cancer (23). Based on




interim data for NSCLC, ORR was 13% (2/16; 95% CI 2–38%) in the HER2-amplified

cohort and 21% (3/14; 95% CI 5–51%) in the HER2-mutated cohort.

In a phase II study, patients with HER2-mutant or HER2-amplified lung cancer received

treatment with dacomitinib, a pan-HER TKI, and the ORR was 12% (3/26; 95% CI, 2–

30%) for HER2-mutant disease and 0% (0/4; 95% CI, 0–60%) for HER2-amplified

disease (14). Neratinib, another pan-HER TKI, has been investigated in HER2 mutated

lung cancer. In a cohort of 26 lung cancer patients with HER2 or HER3 mutations from

the phase II SUMMIT basket trial, only 1 patient with a HER2 exon 20 mutation (L755S)

achieved a response (ORR 3.8% at 8 weeks)(24). Median progression-free survival was

5.5 months. A phase I study of neratinib plus temsirolimus, a mammalian target of

rapamycin inhibitor, observed responses in 2 of 7 patients with HER2 mutated NSCLC;

however, this was at the cost of significant treatment-related toxicity (25). Pyrotinib, a

TKI targeting HER1 and HER2 receptors, has also been studied, and preliminary results

from a phase II study found on ORR of 55% (6/11) among patients with previously-

treated HER2 mutant advanced NSCLC (26). Studies of afatinib, an ErbB family

blocker, have showed varied results. In a phase II study of patients with heavily

pretreated lung adenocarcinoma, a cohort of 7 patients with HER2 mutation received

afatinib monotherapy and none experienced an objective response (27). Another phase

II study of afatinib demonstrated an ORR of 7.7% (1/13) among pretreated patients with

NSCLC harboring HER2 exon 20 mutations (28). Finally, a retrospective review of

patients with metastatic HER2-mutant lung cancer treated with afatinib from 7

institutions found an ORR of 11% (3/27) (29). Of note, a study investigating response to




immune checkpoint blockade (ICB) in HER2 mutated advanced lung cancer found an

ORR of 12% (3/26) and a median PFS of 1.9 months (95% CI 1.5-4.0) (30).

Whereas data suggest a potential role for HER2-targeted therapy in NSCLC, further

investigation of HER2 as a biological target in NSCLC is needed. The relationship

between the distinct, and probably independent, features of HER2 activation, related

biomarkers, and response to treatment needs further elucidation. For example, in our

study, all responders had IHC 3+ tumors, three had HER2 amplification (by ISH and

NGS), and two had HER2 gene mutations. By contrast, none of the eight responders to

T-DM1 in the HER2-mutant cohort of the NCT02675829 basket trial had HER2 levels

beyond IHC 2+, but one patient had HER2 amplification (21). Activity of T-DM1 in the

context of HER2 mutations remains to be biologically elucidated (21) and, given co-

occurring HER2 amplification and mutation in the majority of responders and the small

number of responders in our trial, we do not have sufficient sample size to assess for a

potential interaction between the molecular alterations. We used IHC to identify patients

with intermediate to high HER2 protein levels, as IHC is the standard assay used in

indications where HER2 targeted therapy is established. HER2 mRNA levels were

assessed as part of the exploratory biomarker evaluation, however, this did not identify

a cutoff to identify patients who responded to T-DM1. Of the 4 responders, only 1

patient had HER2 mRNA levels above the median HER2 mRNA level (Table 3). . HER2

IHC alone is insufficient as a predictive biomarker and identification of additional

biomarkers is required.

Our study has a few limitations. We did not test a predetermined response rate since

this was an exploratory study to obtain preliminary efficacy data and investigate




potential biomarkers for further rationale for development in this rare subset of NSCLC.

Higher patient numbers might be needed to provide clarity on potential relationships

between different HER2 biomarkers and response. Additionally, only 49 of 133

prescreened patients with IHC 2+ or 3+ tumors were enrolled and started treatment with

T-DM. Prescreening was allowed while patients were still on other therapy, and, at the

time of disease progression, patients may have no longer met all eligibility criteria or

may have elected for alternative treatment. As some sites screened patients for HER2

status prior to the central laboratory assessment, the prevalence of IHC 2+ and IHC 3+

NSCLC is likely higher than an actual population-based prevalence of HER2 IHC

overexpression. In our study, most tissue came from the archival specimen (41/49;

84%). The absence of mandatory re-biopsy at study entry is a weakness – adopted for

practical reasons – given that HER2 status at diagnosis and study entry may

theoretically vary under selective pressure of treatments and tumor evolution, while the

majority of patient tumor samples came from primary tumors. HER2 amplification has

been hypothesized as a resistance mechanism with EGFR TKIs (31,32), indicating

potential changes in HER2 status following treatment with EGFR TKIs. While data from

NSCLC showing loss of HER2 overexpression are not available, this cannot be

excluded. Sufficient tissue was available for evaluation of all mandatory biomarkers,

however, our biomarker analyses were limited by sample availability. Where possible,

we collected data on EGFR and ALK based on local testing; while broader NGS testing

for other molecular alterations is not routinely performed and was available for selected

patients (Figure S3). Finally, further dedicated studies would be strengthened by

independent radiologic review.




In summary, our study indicates activity of T-DM1 in selected patients with IHC 3+

HER2-positive metastatic NSCLC. The safety profile of T-DM1 was similar to findings

from prior T-DM1 clinical trials and showed that T-DM1 was also tolerable in NSCLC.

Additional investigation into HER2 signaling pathway oncogenic modifications, including

HER2 overexpression, amplification or mutation, may help to refine a patient population

more likely to benefit from treatment with T-DM1. Of importance, HER2 IHC – used as a

single parameter – was an insufficient predictive biomarker for T-DM1 activity. Further

trials are needed to refine the target population for T-DM1 as well as for other HER2

directed therapies in NSCLC.

Acknowledgements

The authors would like to thank all the patients who participated in the trial and their

families, as well as the participating study sites.

The authors are grateful for the assistance of Sven Stanzel of F. Hoffmann-La Roche,

Ltd., Yvonne G. Lin, Alan Sandler, and David Chen of Genentech, Inc.

This study was funded by F. Hoffmann La-Roche, Ltd., Basel, Switzerland. Support for

third-party writing assistance was provided by Meredith Kalish, MD, of CodonMedical,

an Ashfield Company, part of UDG Healthcare plc, and was funded by F. Hoffmann-La

Roche.




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Tables

Table 1. Patient baseline and exploratory biomarker characteristics

IHC 2+

(n=29)

IHC 3+

(n=20)

All patients

(N=49)

Baseline characteristics

Median age, years (range) 61 (36–80) 61 (40–75) 61 (36–80)

Sex, n

Male

Female

16

13

13

7

29

20

Smoking status, n

Current

Previous

Never

6

16

7

4

13

3

10

29

10

ECOG performance status, n

0

1

7

22

5

15

12

37

Stage of disease, n

Metastatic disease

Locally advanced

29

0

19

1

48

1

Histology, n

Squamous 2 1 3




Adenocarcinomaa 20 17 37

Undifferentiated/poorly

differentiated

3 2 5

Unknown 4 0 4

Prior lines of therapy, n

Any

1

2

≥3

Neoadjuvant/adjuvant

29

7

10

11

1

20

6

7

6

1

49

13

17

17

2

CNS metastases at baseline, n

Yes 3 1 4

No 26 19 45

ALK rearrangement, nb

Present

Not present/not done/not

evaluable

0

29

1

19

1

48

EGFR status, nb

Exon 19 deletion

Exon 20 T790M mutation

Exon 20 insertion

Other (including wild type/not

done/not evaluable)

0

1

3

25

1

0

1

18

1

1

4

43




HER2 mutation status, nb

A775_G776insYVMA

G776_V777>VCV

Not done/not evaluable/not

reported

2

0

27

0

1

19

2

1

46

Exploratory biomarker

characteristics

ISH HER2 amplification status, n

Non-amplified, gene ratio <2c

Amplified, gene ratio ≥2c

Missingd

17

5

7

9

11

0

26

16

7

HER2 gene copy number, n

<4

4 to <6

≥6

Missingd

12

8

2

7

6

5

9

0

18

13

11

7

HER2 mRNA expression, ne

≤Median

>Median

Missingd

14

9

6

8

12

0

22

21

6

ECOG, Eastern Cooperative Oncology Group; HER, human epidermal growth factors

receptor; IHC, immunohistochemistry.

aIncludes one patient from the IHC 2+ group with lepidic predominant adenocarcinoma.




bEGFR, ALK, and HER2 mutations are derived from local assessment.

cHER2 gene ratio represents the HER2 gene/centromere 17 ratio. HER2 amplification

(ISH) defined as HER2/CEP17 gene ratio ≥2.

dMissing values due to lack of sufficient sample, sample quality, and/or assay failure.

eMedian HER mRNA level was 7.26.




Table 2. Safety summary

Summary of adverse

events

na

Any grade adverse event 45

Grade 3b 10

Grade 4c 1

Grade 5 0

Adverse events leading to

withdrawald

2

Selected adverse events

in patients with at least

one adverse evente

Grade 1–2, na Grade 3–5, na

Hemorrhage 7 0

Infusion-related reaction/

hypersensitivity

6 1

Peripheral neuropathy 7 0

Thrombocytopenia 4 1

Hepatotoxicity 5 0

Cardiac dysfunction 2 0

Pulmonary toxicity 0 0

an represents the number of patients with an adverse event, patients may have

experienced more than one adverse event.




bThe only Grade 3 adverse events occurring in more than one patient was fatigue (n=2).

The other Grade 3 adverse events observed were: abdominal pain, anemia, bronchitis,

confusional state, decreased appetite, diarrhea, dyspnea, hyperglycemia, hypertension,

infusion-related reaction, lung infection, nausea, platelet count decreased, pneumonia,

pulmonary embolism, tumor pain (each Grade 3 adverse events reported in one

patient).

cGrade 4 adverse event was a seizure.

dWithdrawal due to adverse events was due to a Grade 2 infusion-related reaction and

Grade 3 influenza.

eEvents for selected adverse events are consistent with the United States Prescribing

Information for trastuzumab emtansine. Adverse events classified by National Cancer

Institute Common Terminology Criteria for Adverse Events grade for safety-evaluable

patients (all patients who received ≥1 dose of T-DM1). Multiple occurrences of the same

adverse event in one individual are counted once at the highest grade for this patient.




Table 3. Responders categorized by HER2 ISH, NGS, and HER2 mRNA results

IHC 2+

responder/total

(n/N)

IHC 3+

responder/total

(n/N)

All patients

responder/total

(n/N)

Responders 0/29 4/20 4/49

ISH result, na 0/22 4/20 4/42

HER2 not amplified 0/17 1/9 1/26

HER2 amplified 0/5 3/11 3/16

Missingb 7 0 7

NGS resultc

HER2 not amplified

HER2 amplified

Missing

0/12

0/12

0/0

17

3/12

1/7

2/5

8

3/24

1/19

2/5

25

HER2 mRNAd

≤Median

>Median

Missing

0/23

0/14

0/9

6

4/20

3/8

1/12

0

4/43

3/22

1/21

6

IHC, immunohistochemistry; ISH, in situ hybridization; NGS, next generation

sequencing (Foundation Medicine).

aHER2 gene amplification was defined as HER2/CEP17 gene ratio ≥2.

bMissing data due to lack of sufficient sample, sample quality, and/or unreadable assay.




cOnly 24 samples available for Foundation Medicine analysis due to insufficient sample

and/or sample quality. HER2 amplification was defined by copy number ≥5 in a diploid

model.

dHER2 mRNA values are missing for six patients, due to insufficient sample or assay

failure. HER2 mRNA expression levels were evaluated in subgroups defined using the

median distribution values for mRNA expression (>median versus ≤median). Median

HER2 mRNA level was 7.26.




Table 4. Exploratory biomarker characteristics for patients with a clinical benefit: Clinical response (CR or PR) or

prolonged SD (>6 months)

Patients with clinical response (CR or PR) Patients with SD >6 months

Demography 67 years, male,

white, 87 kg,

ECOG 1

56 years, female,

white, 79.5 kg,

ECOG 1

66 years, female,

white, 60 kg,

ECOG 0

60 years, male,

white, 71 kg,

ECOG 0

74 years, female,

white, 65 kg,

ECOG 0

36 years, male,

Black or African

American, 122 kg,

ECOG 1

52 years, male,

white, 99 kg,

ECOG 1

56 years, female,

white, 65 kg,

ECOG 1

NSCLC

histology

Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma Adenocarcinoma

Sample

source

Archival Fresha Archival Archival Archival Archival Archival Archival

Biomarkers

HER2

IHC 3+

(15% staining)

3+

(75% staining)

3+

(100% staining)

3+

(60% staining)

2+

(30% staining)

2+

(40% staining)

3+

(90% staining)

3+

(35% staining)

ISH status

(ratio)b

Negative (<2) Positive (≥2 and

<4)

Positive (≥4) Positive (≥2

and <4)

Unknown Unknown Positive (≥4) Negative (<2)

ISH gene

copy number

3.55 4.45 20.0 6.53 Unknown Unknown 20.50 4.95




NGS (HER2)

HER2

amplification

by central

FMIc (copy

number)

Nonamplified ND Amplified (145) Amplified (8) ND

ND Amplified (59)

ND

HER2

mutation by

central FMI

None ND HER2 gene

rearrangement

(unknown

functional

status)

None ND

ND None ND

HER2

mutation by

local NGS

ND G776_V777>VC ND ND ND A775_G776insYVMA ND ND

ALK No RA No RA No RA No RA No RA No RA No RA ND

EGFR ND Negative ND Exon 19 deletion ND Negative Negative Exon 20 insertion

DoR

(months)

2.9 7.3 10.8+ 8.3 NA NA NA NA

PFS

(months)

8.3 8.5 12.2+ 9.6 27.5 9.5 11.2 18.7

OS (months) 18.4+ 20.2+ 12.9+ 21.6+ 27.5+ 18.4 17.1+ 25.1+




Date of

confirmed

response

C11 C5 C5 C5 N/A N/A N/A N/A

Prior cancer

treatments

Carboplatin +

pemetrexed +

vinorelbine

Cisplatin +

pemetrexed

Bevacizumab

+ carboplatin

+ paclitaxel

Bevacizumab

Afatinib

Carboplatin +

vinorelbine

Carboplatin

Erlotinibd Cisplatin/

vinorelbine

Bevacizumab +

carboplatin +

onartuzumab/

placebo

(blinded) +

paclitaxel

Bevacizumab +

onartuzumab/

placebo

(blinded)

Docetaxel +

selumetinib/

placebo

(blinded)

Erlotinib

Bevacizumab +

carboplatin +

pemetrexed

Docetaxel

Paclitaxel

Carboplatin +

pemetrexed

AMP-514 +

durvalumab

Carboplatin +

vinorelbine

Docetaxel

Follow-up

treatments

Nivolumab Nivolumab Still on treatment

(finished C19 in

May 2017)

Unknown Unknown Afatinib,

ipilimumab,

nivolumab,

vinorelbine

Cyclophosphamide,

fludarabine,

investigational

CAR-T cell therapy

Cisplatin +

vinorelbine

C, treatment cycle; CR, complete response; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group;

FMI, Foundation Medicine, Inc; NGS, next generation sequencing (Foundation Medicine): NSCLC, non-small cell lung




cancer; OS, overall survival; PFS, progression-free survival; PR, partial response; RA, rearrangement; N/A, not

applicable; ND, not done; SD, stable disease.

+ denoted a censored observation.

aSample was considered fresh if obtained within 8 weeks before start of study treatment.

bHER2 gene amplification was defined as positive based on HER2/CEP17 gene ratio ≥2.

cHER2 amplification defined as positive based on a copy number ≥5 in a diploid model by NGS.

dPatient was not treated with prior platinum therapy (protocol violation).




Figure Legends

Figure 1. Investigator-assessed treatment response and change from baseline

tumor size over time

Best treatment response and change from baseline in tumor size for the IHC 2+ cohort

(A, B); best treatment response and change from baseline in tumor size for the IHC 3+

cohort (C, D).

CI, confidence interval; IHC, immunohistochemistry; NE, not evaluable/missing; ORR,

objective response rate; PD, progressive disease; PR, partial response; SD, stable

disease; U, unknown HER2 amplification.

*Indicates positive HER2 amplification. The ISH status of all other patients is negative.

Figure 2. Kaplan–Meier analysis of investigator-assessed PFS (A) and OS (B)

(A) Final descriptive Kaplan–Meier estimates of progression-free survival (PFS) in all

patients as well as stratified by IHC 2+ and IHC 3+. All patients were treated with

trastuzumab emtansine (T-DM1). PFS was defined as the time from first study

treatment to first documented disease progression or death from any cause. PFS data

for patients without disease progression or death was censored at the time of last tumor

assessment.

(B) Descriptive Kaplan–Meier estimates of overall survival (OS) by all patients as well

as categorized by IHC 2+ and IHC 3+. OS was defined as the time from first study




treatment to death from any cause. Patients without a death event were censored on

the date the patient was last known to be alive.

IHC, immunohistochemistry; NE, not estimable.




D.150

100

50

0

Chan

ge fr

om b

asel

ine

tum

or s

ize

(%)

–50

–1000 3 96 12 15

Study month of tumor measurement 18

IHC 3+

PRSDPDNE

100

75

50

25

0

Chan

ge in

dia

met

er fr

om b

asel

ine

(%)

–25

–50

–75

–100

Patient

IHC 3+ORR=20% (95% CI 5.7–43.7)

1 2 3

*

4 5

*

6 7 8

*

9

*

10

*

11

*

12

*

13

*

14 15 16

*

17

*

18*

19

C.

B.150

100

50

0

Chan

ge fr

om b

asel

ine

tum

or s

ize

(%)

–50

–1000 3 6 9 12

Study month of tumor measurement 15 18 21 24 27

IHC 2+

* U

PRSDPDNE

100

75

50

25

0

Chan

ge in

dia

met

er fr

om b

asel

ine

(%)

–25

–50

–75

–100

*

PRSDPDNE

PRSDPDNE

* U U U * U

Patient

IHC 2+ORR=0% (95% CI 0.0–11.9)

A.

Figure 1

* * UU

1 3 5 7 9 11 13 15 17 19 21 23 23 27 29




100

IHC 2+ (n=29)IHC 3+ (n=20)All patients (N=49)Censored

Median time to Patients with OS event, IHC status OS event, n (%) months (95% CI)IHC 2+ 20 (69) 12.2 (3.8–23.3)IHC 3+ 10 (50) 15.3 (4.1–NE)All patients 30 (61) 12.2 (4.7–23.6)

80

60

40

Ove

rall

surv

ival

(%)

20

00 3 6 9 12 15 18 21 24

Time (months)27

292049

IHC 2+IHC 3+All patients

No. patients at risk211637

281947

251742

161430

191534

171431

151227

161430

151328

141024

151126

141024

128

20

128

20

128

20

106

16

127

19

117

18

639

84

12

84

12

325

628

628

1

1

112

1

1

100

IHC 2+ (n=29)IHC 3+ (n=20)All patients (N=49)Censored

Median time to Patients with PFS event, IHC status PFS event, n (%) months (95% CI)IHC 2+ 29 (100) 2.6 (1.4–2.8)IHC 3+ 19 (95) 2.7 (1.4–8.3)All patients 48 (98) 2.6 (1.4–2.8)

80

60

40

Prog

ress

ion-

free

sur

viva

l (%

)

20

00 3 6 9 12 15 18 21 24

Time (months)27

292049

IHC 2+IHC 3+All patients

No. patients at risk68

14

271946

161228

46

10

68

14

68

14

246

369

268

123

134

134

112

112

112

112

112

112

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

1

A.Figure 2

B.




Published OnlineFirst September 11, 2018.Clin Cancer Res Solange Peters, Rolf A. Stahel, Lukas Bubendorf, et al. Cancer: Efficacy, Safety and BiomarkersTreated HER2-Overexpressing Metastatic Non-Small Cell Lung Trastuzumab Emtansine (T-DM1) in Patients with Previously

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