← Product Code [PLS](/productcode/PLS) · P150013S009

# PD-L1 IHC 22C3 pharmDx (P150013S009)

_Agilent Technologies, Inc. · PLS · Jun 12, 2018 · Pathology · APPR_

**Canonical URL:** https://fda-staging.innolitics.com/device/P150013S009

## Device Facts

- **Applicant:** Agilent Technologies, Inc.
- **Product Code:** [PLS](/productcode/PLS.md)
- **Decision Date:** Jun 12, 2018
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Pathology

## Indications for Use

PD-L1 IHC 22C3 pharmDx is a qualitative immunohistochemical assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3 intended for use in the detection of PD-L1 protein in formalin fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC), gastric or gastroesophageal junction (GEJ) adenocarcinoma and cervical cancer tissues using EnVision FLEX visualization system on Autostainer Link 48. PD-L1 protein expression in NSCLC is determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The specimen should be considered to have PD-L1 expression if TPS ≥ 1% and high PD-L1 expression if TPS ≥ 50%. PD-L1 IHC 22C3 pharmDx is indicated as an aid in identifying NSCLC patients for treatment with KEYTRUDA® (pembrolizumab). See the KEYTRUDA® product label for expression cut-off values guiding therapy in specific clinical circumstances. PD-L1 protein expression in gastric or GEJ adenocarcinoma is determined by using Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. The specimen should be considered to have PD-L1 expression if CPS ≥ 1. PD-L1 IHC 22C3 pharmDx is indicated as an aid in identifying gastric or GEJ adenocarcinoma patients for treatment with KEYTRUDA® (pembrolizumab). PD-L1 protein expression in cervical cancer is determined by using Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. The specimen should be considered to have PD-L1 expression if CPS ≥ 1. PD-L1 IHC 22C3 pharmDx is indicated as an aid in identifying cervical cancer patients for treatment with KEYTRUDA® (pembrolizumab).

## Device Story

In vitro diagnostic immunohistochemistry (IHC) assay; detects PD-L1 protein in FFPE tissue sections. Uses Monoclonal Mouse Anti-PD-L1 (Clone 22C3) antibody; EnVision FLEX visualization system; Autostainer Link 48 instrument. Workflow: deparaffinization, rehydration, target retrieval (PT Link); incubation with primary antibody, linker, and HRP-labeled visualization reagent; DAB+ chromogen precipitation; hematoxylin counterstain. Pathologist evaluates stained slides via light microscopy (20x magnification). Calculates Tumor Proportion Score (TPS) for NSCLC or Combined Positive Score (CPS) for gastric/GEJ/cervical cancers. Output: qualitative PD-L1 expression status (positive/negative). Used in clinical laboratories to select patients for KEYTRUDA® (pembrolizumab) therapy. Benefits: identifies patients likely to respond to immunotherapy; avoids unnecessary treatment in non-responders.

## Clinical Evidence

Clinical performance evaluated in KEYNOTE-158 (Phase 2, multicenter, open-label, nonrandomized study). Cohort E included 98 patients with advanced cervical cancer. 77 evaluable patients with PD-L1 expression (CPS ≥ 1) received pembrolizumab. Primary endpoint: Objective Response Rate (ORR) per RECIST 1.1 by independent central review. Results: ORR 14.3% (95% CI: 7.4, 24.1); 2.6% complete response, 11.7% partial response. No responses observed in PD-L1 negative (CPS < 1) patients. Median duration of response not reached (range 4.1-18.6+ months).

## Technological Characteristics

IHC assay; Monoclonal Mouse Anti-PD-L1 (Clone 22C3). Components: Peroxidase-Blocking Reagent, Linker (Anti-Mouse), Visualization Reagent-HRP, DAB+ Chromogen/Substrate, Target Retrieval Solution (pH 6.1). Automated staining on Dako Autostainer Link 48. FFPE tissue sections (4-5 μm). Connectivity: DakoLink software 4.2. Storage: 2-8°C.

## Regulatory Identification

The programmed death-ligand 1 (PD-L1) antibody is a qualitative immunohistochemical antibody intended to identify PD-L1 protein expression in human clinical tissue specimens.  The PD-L1 antibody is indicated as an aid in identifying patients eligible for treatment with specific FDA approved therapeutic drugs or to assess PD-L1 expression level in patients who may respond particularly well to specific FDA approved therapeutic drugs.

## Submission Summary (Full Text)

> This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com.
>
> Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/).

{0}

# SUMMARY OF SAFETY AND EFFECTIVENESS DATA
(SSED)

## I. GENERAL INFORMATION

Device Generic Name: In vitro diagnostic immunohistochemistry (IHC) test for detection of PD-L1 in formalin-fixed, paraffin-embedded (FFPE) human tissue sections

Device Trade Name: PD-L1 IHC 22C3 pharmDx

Device Procode: PLS

Applicant's Name and Address: Dako North America, Inc.
6392 Via Real
Carpinteria, CA 93013

Date(s) of Panel Recommendation: None

Premarket Approval Application (PMA) Number: P150013/S009

Date of FDA Notice of Approval: June 12, 2018

The PD-L1 IHC 22C3 pharmDx (P150013) was approved on October 2, 2015 for the qualitative detection of PD-L1 protein in formalin-fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC) tissue using EnVision FLEX visualization system on the Autostainer Link 48. PD-L1 protein expression is determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining. The indication for use of the device as approved in P150013 is to aid in identifying patients with NSCLC whose tumors are considered PD-L1 positive if TPS ≥ 50% and for whom safety and efficacy of KEYTRUDA® (pembrolizumab) have been established. The SSED to support the indication is available on the CDRH website and is incorporated by reference here.

The current supplement was submitted to expand the indication for the PD-L1 IHC 22C3 pharmDx to include cervical cancer for treatment with KEYTRUDA® (pembrolizumab). PD-L1 protein expression is determined by using Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. The specimen should be considered to have PD-L1 expression if CPS ≥ 1.

## II. INDICATIONS FOR USE

For in vitro diagnostic use.

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 1

{1}

PD-L1 IHC 22C3 pharmDx is a qualitative immunohistochemical assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3 intended for use in the detection of PD-L1 protein in formalin fixed, paraffin-embedded (FFPE) non-small cell lung cancer (NSCLC), gastric or gastroesophageal junction (GEJ) adenocarcinoma and cervical cancer tissues using EnVision FLEX visualization system on Autostainer Link 48.

### Non-Small Cell Lung Cancer (NSCLC)

PD-L1 protein expression in NSCLC is determined by using Tumor Proportion Score (TPS), which is the percentage of viable tumor cells showing partial or complete membrane staining at any intensity. The specimen should be considered to have PD-L1 expression if TPS ≥ 1% and high PD-L1 expression if TPS ≥ 50%.

PD-L1 IHC 22C3 pharmDx is indicated as an aid in identifying NSCLC patients for treatment with KEYTRUDA® (pembrolizumab). See the KEYTRUDA® product label for expression cut-off values guiding therapy in specific clinical circumstances.

### Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

PD-L1 protein expression in gastric or GEJ adenocarcinoma is determined by using Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. The specimen should be considered to have PD-L1 expression if CPS ≥ 1.

PD-L1 IHC 22C3 pharmDx is indicated as an aid in identifying gastric or GEJ adenocarcinoma patients for treatment with KEYTRUDA® (pembrolizumab).

### Cervical Cancer

PD-L1 protein expression in cervical cancer is determined by using Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. The specimen should be considered to have PD-L1 expression if CPS ≥ 1.

PD-L1 IHC 22C3 pharmDx is indicated as an aid in identifying cervical cancer patients for treatment with KEYTRUDA® (pembrolizumab).

### III. CONTRAINDICATIONS

There are no known contraindications.

### IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the PD-L1 IHC 22C3 pharmDx labeling.

### V. DEVICE DESCRIPTION

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 2

{2}

# Device Kit Components

PD-L1 IHC 22C3 pharmDx contains optimized reagents required to complete an immunohistochemical (IHC) staining procedure for formalin-fixed and paraffin-embedded (FFPE) specimens using the EnVision FLEX visualization system and the Dako Autostainer Link 48 with DakoLink software 4.2. Wash buffer and hematoxylin are required, but not included in the kit. Deparaffinization is performed using the PT Link. Coverslipping can be manual or automated. The kit contains the reagents necessary to perform 50 tests in up to 15 individual runs. An overview of the kit components is shown in the table below.

Table 1: Overview of PD-L1 IHC 22C3 pharmDx Components

|  Reagent | Description | Qty x Vol  |
| --- | --- | --- |
|  Peroxidase-Blocking Reagent | Buffered solution containing hydrogen peroxide, detergent and 0.015 mol/L sodium azide. | 1 x 34.5 mL  |
|  Monoclonal Mouse anti-PD-L1, Clone 22C3 | Monoclonal mouse anti-PD-L1 antibody in a buffered solution, containing stabilizing protein(3 μg/mL protein concentration), and 0.015 mol/L sodium azide. | 1 x 19.5 mL  |
|  Negative Control Reagent | Monoclonal mouse control IgG antibody in a buffered solution, containing stabilizing protein, and 0.015 mol/L sodium azide. | 1 x 15 mL  |
|  Linker, Anti-Mouse | Rabbit secondary antibody against mouse immunoglobulins in a buffered solution containing stabilizing protein and 0.015 mol/L sodium azide. | 1x 34.5 mL  |
|  Visualization Reagent-HRP | Dextran coupled with peroxidase molecules and goat secondary antibody molecules against rabbit and mouse immunoglobulins in a buffered solution containing stabilizing protein and an antimicrobial agent. | 1 x 34.5 mL  |
|  DAB+ Buffered Substrate | Buffered solution, containing hydrogen peroxide and an antimicrobial agent. | 15 x 7.2 mL  |
|  DAB+ Chromogen | 3,3'-diaminobenzidine tetrahydrochloride in an organic solvent. | 1 x 5 mL  |
|  DAB Enhancer | Cupric sulfate in water. | 1 x 34.5 mL  |
|  Target Retrieval Solution Low pH (50X) | Buffered solution, pH 6.1, containing detergent and an antimicrobial agent. | 6 x 30 mL  |
|  Cell Line Control Slides | Each slide contains sections of two pelleted, formalin-fixed paraffin-embedded cell lines: NCI-H226 with moderate PD-L1 protein expression (positive control), and MCF-7 with negative PD-L1 protein expression (negative control). | 3 x 5 slides  |

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 3

{3}

PD-L1 IHC 22C3 pharmDx comes with individually labeled reagent components that are recognized together. The kit components can only be used on the specified instrument with the PD-L1 IHC 22C3 pharmDx protocol. The DakoLink software has been designed to recognize and group PD-L1 IHC 22C3 pharmDx reagents, mandating that the reagents are run together.

## Device Instrument and Software

PD-L1 IHC 22C3 pharmDx assay is performed on the Dako Autostainer Link 48 automated staining system using the DakoLink software 4.2. The Autostainer system is designed to mimic the staining steps performed manually by a lab technician. The PD-L1 IHC 22C3 pharmDx protocol is assay specific. The DakoLink software has been designed to recognize and group PD-L1 IHC 22C3 pharmDx reagents, requiring that all system reagents are used together. Deparaffinization, rehydration and target retrieval (3-in-1) procedures are performed in the PT Link Pre-treatment module (PT100/200 modules).

## Specimen Preparation

Cervical cancer specimens must be handled appropriately to preserve the tissue for IHC staining. Standard methods of tissue processing should be used for all specimens. Only formalin-fixed, paraffin-embedded (FFPE) tissues are suitable for use. Tissue specimens should be cut into sections of 4-5 μm and mounted on charged microscope slides. Cut sections should be stored at 2-8 °C until staining, which should be performed within 5 months of sectioning or if stored at room temperature (25°C) should be stained within 1 month of sectioning.

## Test Controls and Calibrators

Run controls are included in each staining run to establish the validity of the test results. The following controls should be run with the assay:

1) Control cell line slides provided as part of the kit should be used to verify the staining procedure. One Control Slide should be stained with the primary antibody to PD-L1 in each staining run. The evaluation of the Control Slide cell lines supplied in the kit indicates the validity of the staining run. The Control Slides should not be used as an aid in interpretation of patient results.
2) Run controls are to be provided by the end-user laboratory. Positive and negative run controls should be fresh biopsy/surgical specimens of the same tumor indication as the patient specimen, fixed, processed and embedded as soon as possible in the same manner as the patient sample(s). The positive control tissue should include weak staining for PD-L1 to detect subtle changes in assay sensitivity. Negative control tissue is required to detect unintended antibody cross reactivity to tissue and is expected to be negative for PD-L1 expression.
3) The Kit includes a Negative Control Reagent that is used in parallel with the PD-L1 Clone 22C3 primary antibody on patient tissue. The matched negative control aids the reader in differentiating a true signal from tissue-specific background staining that

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 4

{4}

occurs from reaction with detection chemistry and not the anti PD-L1 primary antibody.

Additional information about positive and negative controls are available in the product labeling.

## Principles of Procedure

PD-L1 IHC 22C3 pharmDx contains optimized reagents required to complete an IHC staining procedure on FFPE specimens using the Autostainer Link 48. Following deparaffinization of the tissue sections, rehydration and target retrieval, the slides are incubated with the primary monoclonal antibody to PD-L1 (Clone 22C3) or the Negative Control Reagent. Specimens are then incubated with a linker antibody specific to the host species of the primary antibody, and then are incubated with the ready-to-use Visualization Reagent consisting of secondary antibody molecules and horseradish peroxidase (HRP) molecules coupled to a dextran polymer backbone. The enzymatic conversion of the subsequently added DAB+ Chromogen results in precipitation of a visible reaction product at the site(s) of antigen. The color of the chromogenic reaction is modified by a chromogen enhancement reagent, DAB Enhancer. The specimen may then be counterstained with hematoxylin and coverslipped.

## Staining protocol

The PD-L1 IHC 22C3 pharmDx is designed to be run on the Autostainer Link 48 with DakoLink software according to the following staining protocol:

Peroxidase-Blocking Reagent (2 drop zones x 150μL): 5 minutes (± 1 minute);

Rinse in buffer;

Monoclonal Mouse anti-PD-L1 (or Negative Control Reagent) (2 drop zones x 150 μL): 30 minutes (± 1 minute);

Rinse in buffer;

Linker, anti-Mouse Ig (2 drop zones x 150μL): 30 minutes (± 1 minute);

Rinse in buffer;

Visualization Reagent (2 drop zones x 150μL): 30 minutes (± 1 minute);

Rinse in buffer: 5 minutes;

DAB+ solution (2 drop zones x 150μL): 2 x 5 minutes (± 1 minute);

Rinse in buffer;

DAB+ Enhancer (2 drop zones x 150μL): 5 minutes (± 1 minute);

Rinse in buffer;

Hematoxylin (2 x 150μL): 5 minutes (± 1 minute);

Rinse in deionized water;

Rinse in buffer: 5 minutes;

Rinse in deionized water;

Remove slides from autostainer and place in bath of reagent water.

Additional information about the staining protocol is available in the product labeling.

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 5

{5}

## Interpretation of PD-L1 Staining

Interpretation of stained slides should be performed by a pathologist using a light microscope with an objective of 20x magnification. All viable tumor cells on the entire slide must be evaluated and included in the PD-L1 scoring assessment together with tumor associated PD-L1 positive lymphocytes and macrophages. A minimum of 100 viable tumor cells must be present in the PD-L1 stained slide for the specimen to be considered adequate for evaluation. For specimens with less than 100 viable tumor cells, tissue from a deeper level of the block or potentially another block, could present sufficient tumor cells for PD-L1 evaluation.

PD-L1 expression in cervical cancer is defined as follows: Tumor cells with convincing partial or complete linear membrane staining (at any intensity) that is perceived distinct from cytoplasmic staining. Lymphocytes and macrophages (mononuclear inflammatory cells, MICs) within the tumor nests and/or adjacent supporting stroma with convincing membrane and/or cytoplasmic staining (at any intensity). MICs must be directly associated with the response against the tumor.

PD-L1 expression in cervical cancer is determined by Combined Positive Score (CPS), which is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. Distinction of viable tumor cells, lymphocytes, and macrophages is essential for accurate denominator estimation. Although the result of the calculation can exceed 100, the maximum score is defined as CPS 100. CPS is defined as follows:

$$CPS = \frac{\# \text{ PD-L1 staining cells (tumor cells, lymphocytes, macrophages)}}{\text{Total \# of viable tumor cells}} \times 100$$

Specimens are considered to have PD-L1 expression if CPS ≥ 1. Specimens with CPS < 1 are considered to have no PD-L1 expression.

Table 2: CPS Numerator Inclusion/Exclusion Criteria

|  Tissue Elements | Included in the Numerator | Excluded from the Numerator  |
| --- | --- | --- |
|  **Tumor Cells** | Convincing partial or complete linear membrane staining (at any intensity) of viable invasive cervical tumor cells. | - Non-staining tumor cells - Tumor cells with only cytoplasmic staining - Normal squamous or glandular mucosa, cervical polyp  |

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 6

{6}

|  **Immune Cells** | Membrane and/or cytoplasmic* staining (at any intensity) of mononuclear inflammatory cells (MICs) within tumor nests and adjacent supporting stroma**: • Lymphocytes (including lymphocyte aggregates) • Macrophages*** | • Non-staining MICs • MICs associated with normal squamous or glandular mucosa, cervical polyp, microglandular hyperplasia, dysplasia, and carcinoma in situ • MICs (including lymphoid aggregates) associated with ulcers, and other processes not associated with the tumor such as cervicitis • MICs associated with normal  |
| --- | --- | --- |
|  **Other Cells** | Not included | • Normal cells (including ganglion cells) • Stromal cells (including fibroblasts) • Necrotic cells and/or cellular debris  |

*In MICs membrane and cytoplasmic staining are often indistinguishable due to high nuclear to cytoplasmic ratio. Therefore, membrane and/or cytoplasmic staining of MICs is included in the CPS numerator.

**Adjacent MICs are defined as being within the same 20x field as the tumor. However, MICs that are NOT directly associated with the response to the tumor should be excluded.

***Macrophages and histiocytes are considered the same cells.

## VI. ALTERNATIVE PRACTICES AND PROCEDURES

There is no other FDA-cleared or -approved alternative class III immunohistochemistry assays available for detection of PD-L1 in formalin-fixed, paraffin embedded (FFPE) cervical carcinoma tissues for the selection of patients to be treated with KEYTRUDA® (pembrolizumab).

## VII. MARKETING HISTORY

PD-L1 IHC 22C3 pharmDx was approved under P150013 on October 2, 2015 for selection of non small cell carcinoma (NSCLC) patients eligible for treatment with KEYTRUDA® (pembrolizumab) and under P150013/S006 on September 22, 2017 for selection of gastric or GEJ adenocarcinoma patients for treatment with KEYTRUDA® (pembrolizumab). The device is currently marketed in the United States, as well as Austria, Belgium, Canada, Denmark, Finland, France, Germany, Hong Kong, Hungary, Iceland, Ireland, Israel, Italy, Japan, Korea, Kuwait, Lebanon, Malaysia, Netherlands, New Zealand, Norway, Philippines, Poland, Singapore, Slovakia, South Africa, Spain, Sweden, Switzerland, Turkey, and United Arab Emirates.

## VIII. PROBABLE ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Failure of the device to perform as expected or failure to correctly interpret test results may lead to incorrect PD-L1 test results, and subsequently improper patient management decisions in cervical cancer treatment.

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 7

{7}

For the specific adverse events that occurred in the clinical studies, please see Section X below.

# IX. SUMMARY OF NONCLINICAL STUDIES

# A. Laboratory Studies

Since approval of the original PMA (P150013), there have been no changes to the device design including reagent formulation or kit configuration. Preclinical studies were performed using the PD-L1 IHC 22C3 pharmDx kit to support the analytical performance of device at the 1% cut-off (CPS ≥1%) for the cervical cancer indication. These studies were performed using squamous cell (SQ) cancer specimens from the cervix, supplemented with SQ cancer specimens from vulva, anus and salivary gland (SQ subgroup). Studies were conducted to characterize the assay, demonstrate the impact of pre-analytical variables on assay performance, verify precision and robustness of the assay, and establish assay stability.

# 1. Analytical Sensitivity

Analytical sensitivity of PD-L1 IHC 22C3 pharmDx was tested on 370 unique cases of FFPE cervical SQ cancer tissue using one lot of the device. Assessment of PD-L1 expression demonstrated staining across a range of positive tumor cells and immune cells. The rate of PD-L1 positivity in cervical cancer at the CPS ≥ 1 cut-off was 85.14%.

# 2. Analytical Specificity

# a. Western Blot

See Summary of Safety and Effectiveness Data for P150013.

# b. Immunoreactivity in Human Tissues

See Summary of Safety and Effectiveness Data for P150013.

# 3. Robustness

Robustness of PD-L1 IHC 22C3 pharmDx was tested using two lots of the device and 13 specimens from the SQ histology group (cervical SQ - 5, anal SQ - 3, salivary gland SQ - 2 and vulva SQ - 3) were used in each of the robustness testing conditions listed below. The distribution of positive and negative PD-L1 specimens in this study were approximately equal and approximately 20% of the specimens were around the cut-off. Three replicate sections from each study specimens were stained with PD-L1 IHC 22C3 pharmDx.

The robustness conditions tested were the following:

Tissue Thickness: 3μm, 4μm – standard and 5μm; Target Retrieval Solution Incubation Time: 18 minutes, 20 minutes – standard, 22 minutes; Target Retrieval Solution Temperature: 95°C, 97°C – standard, 99°C; Target Retrieval Solution pH: pH 5.9, pH 6.1- standard, pH 6.3

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 8

{8}

As compared to the standard condition, no significant difference in results was observed for the experimental conditions listed above.

#### 4. Precision

The objective of the precision study was to demonstrate the PD-L1 IHC 22C3 pharmDx assay produces consistent, repeatable and reproducible results. Summaries and results of the repeatability studies are presented Table 3 (cervical cancer) and Table 4 (combined cervical cancer and SQ subgroup). Negative percent agreement (NPA), positive percent agreement (PPA) and overall agreement (OA) were determined for the CPS≥ 1 cut-off. Additional performance data will be collected on a comprehensive set of samples in a post approval study (PAS).

Table 3: Repeatability of PD-L1 IHC 22C3 pharmDx Tested at One Site (CPS ≥ 1) in Cervical Cancer

|   | Study Design | % Agreement (95% CI)  |
| --- | --- | --- |
|  Cervical Cancer: Combined Precision (inter-instrument, inter-operator, inter-lot, inter-day) | 6 Cervical Cancer specimens (3 PD-L1 negative and 3 PD-L1-positive) with a range of PD-L1 expression were tested using three Autostainer Link 48 instruments, four operators, three kit lots, over three non-consecutive days. | NPA 100.0% (81.6-100%) PPA 100.0% (82.4-100%) OA 100.0 (90.1-100%)  |
|  Cervical Cancer: Intra-run precision (Repeatability) | 2 Cervical Cancer specimens (0 PD-L1-negative and 2 PD-L1-positive) with a range of PD-L1 IHC expression were tested with five replicates within a run on the Autostainer Link 48 instrument. | NPA N/A PPA 100.0% (72.2-100%) OA 100.0% (72.2-100.0%)  |
|  Cervical Cancer: Inter-observer precision | 21 Cervical Cancer specimens [8 PD-L1 positive/13 PD-L1 negative, 2 near the cut-off (CPS >0-10)] with a range of PD-L1 IHC expression, were stained with PD-L1 IHC 22C3 pharmDx and then scored by three pathologists over three non-consecutive days. | NPA 100% (94.9-100%) PPA 99.1% (95.3-99.8%) OA 99.5% (97.1-99.9%)  |
|  Cervical Cancer: Intra-observer precision | 21 Cervical Cancer specimens (8 PD-L1 positive/13 PD-L1 negative, 2 near the cut-off (CPS >0-10)] with a range of PD-L1 IHC expression, were stained with PD-L1 IHC 22C3 pharmDx and then scored by three pathologists over three non-consecutive days. | NPA 100% (94.9-100%) PPA 99.1% (95.3-99.8%) OA 99.5% (97.1-99.9%)  |

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 9

{9}

**Table 4: Repeatability of PD-L1 IHC 22C3 pharmDx Tested at One Site (CPS ≥ 1) in Combined Cervical Cancer and SQ Subgroup**

|   | Study Design | % Agreement (95% CI)  |
| --- | --- | --- |
|  Combined Precision (inter-instrument, inter-operator, inter-lot, inter-day) | Each of 18 human cancer specimens of the squamous subgroup [7 PD-L1 negative and 11 PD-L1-positive, (7 around the cut-off); 6 cervical cancer (3 PD-L1 positive/3 PD-L1 negative)] with a range of PD-L1 expression were tested using three Autostainer Link 48 instruments, four operators, three kit lots, over three non-consecutive days. | NPA 100% (91.4-100%) PPA 100% (94.5-100%) OA 100% (96.5-100%)  |
|  Intra-run precision (Repeatability) | Each of 8 human cancer specimens [0 PD-L1-negative and 8 PD-L1-positive, (2 around the cut-off); 2 cervical cancer (2 PD-L1 positive)] with a range of PD-L1 IHC expression was tested with five replicates within a run on the Autostainer Link 48 instrument. | NPA N/A PPA 97.5% (87.1-99.6%) OA 97.5% (87.1-99.6%)  |
|  Inter-observer precision | 52 human cancer specimens of the squamous subgroup [(22 PD-L1 positive/30 PD-L1 negative) (10 around the cut-off) (21 cervical cancer, 14 PD-L1 positive/7 PD-L1 negative)] with a range of PD-L1 IHC expression, were stained with PD-L1 IHC 22C3 pharmDx and then scored by three pathologists over three non-consecutive days. | NPA 98.4% (95.5-99.5%) PPA 98.9% (96.8-99.6%) OA 98.7% (97.2-99.4%)  |
|  Intra-observer precision | 52 human cancer specimens of the squamous subgroup [(22 PD-L1 positive/30 PD-L1 negative) (10 around the cut-off) (21 cervical cancer, 14 PD-L1 positive/7 PD-L1 negative)] with a range of PD-L1 IHC expression, were stained with PD-L1 IHC 22C3 pharmDx and then scored by three pathologists over three non-consecutive days. | NPA 97.9% (94.8-99.2%) PPA 99.6% (97.9-99.9%) OA 98.9% (97.5-99.5%)  |

##### 5. External Reproducibility

The objective of this study was to evaluate PD-L1 IHC 22C3 pharmDx with respect to Inter-Day, Inter-Laboratory, Inter- and Intra-Observer reproducibility on FFPE human SQ cancer histology sub-type specimens including cervical SQ specimens when using the device at the cut-off of CPS ≥1. The study was a blinded and randomized reproducibility study performed at three external sites covering 5 non-consecutive days. The study included specimens that were pre-qualified at Dako to represent full PD-L1 expression range and a minimum of 25% of the specimens were around cut-off. The study was divided into Part A (Inter-Day and Inter-Laboratory endpoints) and Part B (Inter- and Intra-Observer endpoints). Each study part had a minimum of a 2 week washout period to minimize recall bias along with requiring different observers from each participating laboratory for Part A and Part B. The results are summarized in the Table 5 and 6 below. Additional performance data will be collected on a comprehensive set of samples in a PAS.

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 10

{10}

**Table 5: Reproducibility of PD-L1 IHC 22C3 pharmDx at Three External Sites (CPS ≥ 1) in Cervical Cancer**

|   | Study Design | % Agreement (95% CI)  |
| --- | --- | --- |
|  Inter-site | 6 Cervical Cancer specimens (2 PD-L1 negative and 4 PD-L1 positive) with a range of PD-L1 IHC expression was tested on five non-consecutive days. Inter-site analysis was performed between three sites. | NPA 100% (88.6-100%) PPA 95.0% (86.3-98.3%) OA 96.7% (90.7-98.9%)  |
|  Intra-site | 6 Cervical Cancer specimens (2 PD-L1 negative and 4 PD-L1 positive) with a range of PD-L1 IHC expression was tested on five non-consecutive days. Inter-site analysis was performed between three sites. | NPA 100% (88.6-100%) PPA 95.0% (86.3-98.3%) OA 96.7% (90.7-98.9%)  |
|  Inter-observer | 6 Cervical Cancer specimens (2 PD-L1 negative and 4 PD-L1 positive) with a range of PD-L1 IHC expression, stained with PD-L1 IHC 22C3 pharmDx, was performed by three pathologists, one at each of three study sites, on three non-consecutive days. Inter-observer analysis was performed between three sites.. | NPA 100% (82.4-100%) PPA 100% (90.4-100%) OA 100% (93.4-100%)  |
|  Intra-observer | 6 Cervical Cancer specimens (2 PD-L1 negative and 4 PD-L1 positive) with a range of PD-L1 IHC expression, stained with PD-L1 IHC 22C3 pharmDx, was performed by three pathologists, one at each of three study sites, on three non-consecutive days. Intra-observer analysis was performed for three sites. | NPA 100% (82.4-100%) PPA 100% (90.4-100%) OA 100% (93.4-100%)  |

**Table 6: Reproducibility of PD-L1 IHC 22C3 pharmDx at Three External Sites (CPS ≥ 1) in combined Cervical Cancer and SQ Cancer Subgroup**

|   | Study Design | % Agreement (95% CI)  |
| --- | --- | --- |
|  Inter-site | Each of 22 human cancer specimens of the SQ cancer subgroup (9 PD-L1 negative and 13 PD-L1 positive; including 6 cervical cancer) with a range of PD-L1 IHC expression was tested on five non-consecutive days. | NPA 94.8% (89.7-97.5%) PPA 97.4% (94.1- 98.9%) OA 96.4% (93.7 - 97.9%)  |

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 11

{11}

|  Intra-site | Each of 22 human cancer specimens of the SQ cancer subgroup (9 PD-L1 negative and 13 PD-L1 positive; including 6 cervical cancer) with a range of PD-L1 IHC expression was tested on five non-consecutive days. | NPA 98.5% (94.6-99.6%) PPA 97.5% (94.3-98.9%) OA 97.9% (95.7-99.0%)  |
| --- | --- | --- |
|  Inter-observer | Each of 22 human cancer specimens of the SQ cancer subgroup (9 PD-L1 negative and 13 PD-L1 positive; including 6 cervical cancer) with a range of PD-L1 IHC expression, stained with PD-L1 IHC 22C3 pharmDx, was performed by three pathologists, one at each of three study sites, on three non-consecutive days. | NPA 95.1% (88.0-98.1%) PPA 99.1% (95.2-99.8%) OA 97.4% (94.1-98.9%)  |
|  Intra-observer | Each of 22 human cancer specimens of the SQ cancer subgroup (9 PD-L1 negative and 13 PD-L1 positive; including 6 cervical cancer) with a range of PD-L1 IHC expression, stained with PD-L1 IHC 22C3 pharmDx, was performed by three pathologists, one at each of three study sites, on three non-consecutive days. | NPA 97.4% (91.1-99.3%) PPA 98.3% (93.9-99.5%) OA 97.9% (94.8-99.2%)  |

## 6. Stability Studies

### a. Cut Section Stability

Based on real time results, cervical cancer tissue sections should be stained within 5 months of sectioning if stored at 2-8°C or stained within 1 month of sectioning if stored at 25°C.

### b. Block Stability

See SSED for P150013.

### c. PD-L1 IHC 22C3 pharmDx Stability

Based on a real time stability study with three lots of PD-L1 IHC 22C3 pharmDx components, the following results were supported for transport simulation, working stability and in-use/on-board stability:

Total Shelf Life (Includes Margin of Safety):

11 months at 2-8 °C

Finished Good Shelf Life:

9 months at 2-8 °C

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 12

{12}

In-Use/On-Board Stability Testing

Eighteen cycles to room temperature

Working/Reconstituted Stability Testing

DAB Substrate-Chromogen Solution: 5 Days at 2-8 °C, protected from light.

Target Retrieval Solution: 5 days at room temperature in a PT-Link with up to 3 uses for 3-in-1 pretreatment.

# **B. Animal Studies**

None

# **C. Additional Studies**

1. Impact on Ischemia/Fixation

See SSED for P150013.

2. Intra-Case Heretogeneity/Intra-Block Heretogeneity

See SSED for P150013/S006.

3. Control Cell Line Validation

See SSED for P150013.

# **X. SUMMARY OF PRIMARY CLINICAL STUDY**

The clinical performance of PD-L1 IHC 22C3 pharmDx for CPS ≥ 1 was based on a Phase 2 multicenter, open-label, nonrandomized world-wide clinical study conducted to assess the safety and efficacy of KEYTRUDA® (pembrolizumab) in patients with multiple types of advanced (unresectable or metastatic) rare solid tumors. KEYNOTE-158 or KN158). KN158 - Group E included patients with advanced (unresectable and/or metastatic) cervical cancer. The major efficacy outcome measures were ORR (according to RECIST 1.1 as assessed by blinded independent central review). The efficacy evaluation was performed in patients with positive PD-L1 expression at CPS ≥ 1 and who had progression of disease following systemic chemotherapy in the metastatic setting. This clinical trial was used to support approval of KEYTRUDA® (pembrolizumab) under sBLA125514/S034 and to support the performance of PD-L1 IHC 22C3 pharmDx in selecting PD-L1 positive (CPS≥ 1) cervical cancer patients for treatment with KEYTRUDA® (pembrolizumab).

# **A. Study Design**

KEYNOTE-158 is a nonrandomized, multisite, open-label trial of pembrolizumab designed to evaluate predictive biomarkers in subjects with multiple types of advanced (unresectable or metastatic) rare solid tumors.

The primary objective of this study is to evaluate the objective response rate (ORR) to treatment with pembrolizumab based on Response Evaluation Criteria in Solid

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 13

{13}

Tumors Version 1.1 (RECIST 1.1) as assessed by Independent central radiologic review (ICR) in both biomarker-unselected and biomarker-selected subjects with any one of multiple types of advanced solid tumors. After independent central radiologic confirmation of measurable disease, all subjects were treated with pembrolizumab 200 mg intravenous (IV) Q3W, with evaluation of clinical response by RECIST 1.1, as assessed by ICR. Subjects were evaluated with radiographic imaging to assess response to treatment; the first imaging assessment was obtained at 9 weeks and subsequent imaging occurred every 9 weeks for the first year, and then every 12 weeks thereafter.

# 1. Clinical Inclusion and Exclusion Criteria

Enrollment in the study was limited to patients who met the following inclusion criteria:

1. Be willing and able to provide written informed consent/assent for the trial.
2. Be ≥18 years of age on day of signing informed consent.
3. Have a histologically or cytologically-documented, advanced (metastatic and/or unresectable) solid tumor that is incurable and for which prior standard first-line treatment has failed. Patients must have progressed on or be intolerant to therapies that are known to provide clinical benefit. There is no limit to the number of prior treatment regimens.
4. Have one of the following advanced (unresectable and/or metastatic) tumor types:

(A) Anal Squamous Cell Carcinoma,
(B) Biliary Adenocarcinoma (gallbladder or biliary tree (intrahepatic or Extrahepatic cholangiocarcinoma) except Ampulla of Vater Cancers,
(C) Neuroendocrine Tumors (well- and moderately-differentiated), of the lung, appendix, small intestine, colon, rectum, or pancreas,
(D) Endometrial Carcinoma (sarcomas and mesenchymal tumors are excluded),
(E) Cervical Squamous Cell Carcinoma,
(F) Vulvar Squamous Cell Carcinoma,
(G) Small Cell Lung Carcinoma,
(H) Mesothelioma (Malignant Pleural Mesothelioma),
(I) Thyroid Carcinoma (Papillary or Follicular Subtypes),
(J) Salivary Gland Carcinoma (sarcomas and mesenchymal tumors are excluded), OR
(K) Any advanced solid tumor (except CRC), which is MSI-H.

5. Have submitted an evaluable tissue sample for biomarker analysis from a tumor lesion not previously irradiated. The tumor tissue submitted for analysis must be from a single tumor tissue specimen and of sufficient quantity and quality to allow assessment of ALL required primary biomarkers.
6. Have radiologically measurable disease based on RECIST 1.1. Independent central radiologic review must confirm the presence of radiologically measureable disease based on RECIST 1.1 for the subject to be eligible to

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 14

{14}

participate in the trial. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

7. Have a performance status of 0 or 1 on the ECOG Performance Scale. This performance status must be confirmed within 3 days prior to the first dose of pembrolizumab or the subject must be excluded.

Exclusion Criterion:

Patients with active autoimmune disease, a medical condition that required immunosuppression, or ECOG PS ≥2 were ineligible.

2. Follow-up Schedule

Tumor assessments were performed at baseline and every 9 weeks thereafter.

3. Clinical Endpoints

A primary objective of the study was to evaluate the anti-tumor activity of KEYTRUDA® (pembrolizumab) in patients with advanced cervical cancer who had at least one prior systemic therapy and whose tumors were positive for PD-L1 expression CPS≥1. The primary efficacy endpoints was ORR defined as the proportion of subjects in the analysis population who had a response (complete response [CR] or partial response [PR]) per RECIST 1.1 as determined by ICR at any time during the trial.

The secondary objectives were Duration of Response (DOR): The time from the first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurred first; Progression-free survival (PFS): Defined as the time from the date of allocation to the first documented progressive disease or death due to any cause, whichever occurred first; Overall Survival (OS): Defined as the time from the date of allocation to the date of death due to any cause. The all subjects as treated (ASaT) population consisted of all allocated subjects who received at least 1 dose of pembrolizumab and was used for efficacy and safety analyses.

With regard to safety, information about adverse events was collected from time of signed informed consent throughout the treatment period and least 30 days after their last dose of study drug or until initiation of a new anti-cancer treatment, whichever occurred first. The safety analysis was performed in all patients who had received at least 1 dose of study treatment.

With regard to effectiveness, the intention-to-treat (ITT) population were patients who had tumors that expressed PD-L1 with a CPS ≥ 1 and received at least one line of chemotherapy in the metastatic setting and served as the primary populations for the efficacy analyses in this trial.

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 15

{15}

## B. Accountability of PMA Cohort

The PMA cohort consisted of a total of 98 patients with recurrent or metastatic cervical cancer enrolled in a single cohort (Cohort E) in Study KEYNOTE-158. All 98 patients in this cohort had their tumor tissue tested with the PD-L1 IHC 22C3 pharmDx test. Additional details are in the Table below.

Table 7: Accountability of PMA Cohort

|   | Number of Study subjects  |
| --- | --- |
|  Enrolled | 98  |
|  Tumor sample collected at baseline | 98  |
|  Specimens with insufficient tissue | 1  |
|  Total evaluable PD-L1 expression | 97  |
|  PD-L1 positive CPS ≥ 1 | 82  |
|  PD-L1 negative CPS <1 | 15  |
|  Site of Tumor: (N=98) |   |
|  Primary Site | 62  |
|  Metastatic Site | 36  |
|  Specimen type (N= 98) |   |
|  Newly Obtained* | 21  |
|  Archival | 77  |
|  Sample Procedure (N= 98) |   |
|  Biopsy | 53  |
|  Resection | 45  |

*tumor specimen collected since the completion of the most recent cancer therapy

## C. Study Population Demographics and Baseline Parameters

Study enrollment occurred at 98 geographic regions, 11 of which were in the US. The baseline characteristics for Cohort E are shown in the table below.

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 16

{16}

**Table 8: Subject Characteristics by PD-L1 Status, (Cohort E: Cervical Carcinoma) (MK3475 200mg Q3W) (ASaT Population)**

|   | Positive |   | Negative  |   |
| --- | --- | --- | --- | --- |
|   |  n | (%) | n | (%)  |
|  Subjects in population | 82 |  | 15 |   |
|  **Gender**  |   |   |   |   |
|  Female | 82 | (100.0) | 15 | (100.0)  |
|  **Age (Years)**  |   |   |   |   |
|  < 65 | 77 | (93.9) | 13 | (86.7)  |
|  >= 65 | 5 | (6.1) | 2 | (13.3)  |
|  Mean | 47.0 |  | 50.3 |   |
|  SD | 11.0 |  | 8.9 |   |
|  Median | 45.0 |  | 47.0 |   |
|  Range | 24 to 75 |  | 41 to 69 |   |
|  **Race**  |   |   |   |   |
|  American Indian Or Alaska Native | 1 | (1.2) | 0 | (0.0)  |
|  Asian | 12 | (14.6) | 2 | (13.3)  |
|  Black Or African American | 2 | (2.4) | 0 | (0.0)  |
|  Multiple | 1 | (1.2) | 0 | (0.0)  |
|  Native Hawaiian Or Other Pacific Islander | 1 | (1.2) | 0 | (0.0)  |
|  White | 64 | (78.0) | 13 | (86.7)  |
|  Missing | 1 | (1.2) | 0 | (0.0)  |
|  **Ethnicity**  |   |   |   |   |
|  Hispanic Or Latino | 2 | (2.4) | 1 | (6.7)  |
|  Not Hispanic Or Latino | 73 | (89.0) | 12 | (80.0)  |
|  Not Reported | 3 | (3.7) | 0 | (0.0)  |
|  Unknown | 4 | (4.9) | 2 | (13.3)  |
|  **Geographic Region**  |   |   |   |   |
|  US | 11 | (13.4) | 0 | (0.0)  |
|  Ex-US | 71 | (86.6) | 15 | (100.0)  |
|  **ECOG**  |   |   |   |   |
|  [0] Normal Activity | 28 | (34.1) | 6 | (40.0)  |
|  [1] Symptoms, but ambulatory | 54 | (65.9) | 9 | (60.0)  |

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 17

{17}

|  **Metastatic Staging**  |   |   |   |   |
| --- | --- | --- | --- | --- |
|  M0 | 5 | (6.1) | 1 | (6.7)  |
|  M1 | 77 | (93.9) | 14 | (93.3)  |
|  **Brain Metastases Present**  |   |   |   |   |
|  Yes | 1 | (1.2) | 0 | (0.0)  |
|  No | 81 | (98.8) | 15 | (100.0)  |
|  **Treatment Naïve (Y/N)**  |   |   |   |   |
|  No | 82 | (100.0) | 15 | (100.0)  |
|  **Prior Adjuvant/Neoadjuvant Therapy**  |   |   |   |   |
|  Yes | 16 | (19.5) | 5 | (33.3)  |
|  No | 66 | (80.5) | 10 | (66.7)  |
|  **Number of Prior Lines of Therapy for Recurrent/Metastatic Disease**  |   |   |   |   |
|  Adjuvant/Neoadjuvant | 3 | (3.7) | 1 | (6.7)  |
|  1 | 29 | (35.4) | 1 | (6.7)  |
|  2 | 26 | (31.7) | 7 | (46.7)  |
|  3 | 12 | (14.6) | 4 | (26.7)  |
|  4 | 8 | (9.8) | 2 | (13.3)  |
|  5 or more | 4 | (4.9) | 0 | (0.0)  |
|  **Sum of Target Lesions Measureable at Baseline (mm) Per IRC**  |   |   |   |   |
|  Subjects with data | 82 |  | 15 |   |
|  Mean | 81.3 |  | 73.9 |   |
|  SD | 69.9 |  | 54.8 |   |
|  Median | 54.4 |  | 64.9 |   |
|  Range | 10.2 to 305. |  | 11.2 to 208.7 |   |
|  **Histology of Current Diagnosis**  |   |   |   |   |
|  Adenocarcinoma | 5 | (6.1) | 0 | (0.0)  |
|  Adenosquamous | 1 | (1.2) | 0 | (0.0)  |
|  Squamous Cell Carcinoma | 76 | (92.7) | 15 | (100.0)  |
|  **Prior Radiation Therapy**  |   |   |   |   |
|  Yes | 70 | (85.4) | 14 | (93.3)  |
|  No | 12 | (14.6) | 1 | (6.7)  |

#### **D. Safety and Effectiveness Results**

##### **1. Safety Results**

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 18

{18}

In the trial, there were no device related adverse events. KEYTRUDA was discontinued due to adverse reactions in 8% of patients. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA. The most frequent serious adverse reactions reported included anemia (7%), fistula (4.1%), hemorrhage (4.1%), and infections [except UTIs] (4.1%). Safety of the drug was also addressed in the previous drug approvals.

# 2. Effectiveness Results

The analysis of effectiveness was based on the 77 evaluable patients who had positive PD-L1 expression (CPS ≥1) and had at least one line of chemotherapy in the metastatic setting. Key effectiveness outcomes are presented in Tables 9 to 11.

Table 9: Efficacy Results in Cohort E of KEYNOTE-158 (CPS ≥1) (at least One Prior Line of Chemotherapy in Metastatic Setting)

|  Endpoint | n=77*  |
| --- | --- |
|  Objective response rate |   |
|  ORR (95% CI) | 14.3% (7.4, 24.1)  |
|  Complete response rate | 2.6%  |
|  Partial response rate | 11.7%  |
|  Response duration |   |
|  Median in months (range) | NR (4.1, 18.6+)†  |
|  % with duration ≥ 6 months | 91%  |

* Median follow-up time of 11.7 months (range 0.6 to 22.7 months)

† Based on patients (n=11) with a response by independent review

+ Denotes ongoing

NR = not reached

No responses were observed in patients whose tumors did not have PD-L1 expression (CPS <1).

# 3. Subgroup Analyses

There was no subgroup analyses performed in this trial.

# 4. Pediatric Extrapolation

In this premarket application, existing clinical data was not leveraged to support approval of a pediatric patient population.

# E. Financial Disclosure

The Financial Disclosure by Clinical Investigators regulation (21 CFR 54) requires applicants who submit a marketing application to include certain information concerning the compensation to, and financial interests and arrangement of, any clinical investigator conducting clinical studies covered by the regulation. The pivotal clinical study included 4 investigators. None of the clinical investigators had disclosable financial interests/arrangements as defined in sections 54.2(a), (b), (c),

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 19

{19}

and (f). The information provided does not raise any questions about the reliability of the data.

## XI. SUMMARY OF SUPPLEMENTAL CLINICAL INFORMATION

Not applicable

## XII. PANEL MEETING RECOMMENDATION AND FDA'S POST-PANEL ACTION

In accordance with the provisions of section 515(c)(3) of the act as amended by the Safe Medical Devices Act of 1990, this PMA was not referred to the Hematology and Pathology Devices Panel, an FDA advisory committee, for review and recommendation because the information in the PMA substantially duplicates information previously reviewed by this panel.

## XIII. CONCLUSIONS DRAWN FROM PRECLINICAL AND CLINICAL STUDIES

### A. Effectiveness Conclusions

Effectiveness of the of PD-L1 IHC 22C3 pharmDx is based on the clinical performance and benefit to patients with advanced cervical cancer as assessed in the KN-158 study which was conducted to evaluate the safety and the efficacy of single agent KEYTRUDA (pembrolizumab) in these patients who had at least one line of chemotherapy in the metastatic setting. In this single-arm study, the PD-L1 IHC 22C3 pharmDx was used to determine patient PD-L1 status. KEYTRUDA® (pembrolizumab) demonstrated a significant improvement in ORR for cervical cancer patients who had tumors that expressed PD-L1 with a CPS ≥ 1 (ORR: 14.3% (7.4, 24.1)) and received at least one line of chemotherapy in the metastatic setting compared to no responses in cervical cancer patients whose tumors did not express PD-L1(CPS < 1). The data supports the performance of this device in identifying cervical cancer patients who will benefit from the therapeutic when used in accordance with the instructions for use.

The performance of the PD-L1 IHC 22C3 pharmDx was also supported by the analytical validation studies.

### B. Safety Conclusions

The risks of the device are based on nonclinical laboratory studies as well as data collected in a clinical study conducted to support PMA approval as described above.

The PD-L1 IHC 22C3 pharmDx is an in vitro diagnostic device, which involves tumor specimens collected from patients with cervical cancer. The risks of the device are based on data collected in the clinical study conducted to support PMA approval as described above. Risks of the PD-L1 IHC 22C3 pharmDx are associated with failure of the device to perform as expected or failure to correctly interpret test results. As PD-L1 IHC 22C3 pharmDx is intended for use to identify patients for KEYTRUDA® (pembrolizumab)

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 20

{20}

therapy, if incorrect, or false, results are reported, then cervical cancer patients may not receive the proper treatment. Patients with false positive results may undergo treatment with KEYTRUDA® (pembrolizumab) without much clinical benefit, and may experience adverse reactions associated with KEYTRUDA® (pembrolizumab) therapy. Patients with false negative results may not be considered for treatment with KEYTRUDA® (pembrolizumab), and therefore, may receive other treatment options. There is also a risk of delayed results, which may lead to a delay in treatment with KEYTRUDA® (pembrolizumab).

### C. Benefit-Risk Determination

The probable benefits of the device are based on data collected in the clinical study, which were used to support panel track PMA supplement approval as described above.

The probable risks of the device are also based on data collected in the clinical study, which were used to support panel track PMA supplement approval as described above.

The clinical benefit of PD-L1 IHC 22C3 pharmDx was investigated in a multicenter, open-label, randomized clinical study conducted to assess the safety and efficacy of KEYTRUDA® (pembrolizumab) in patients with advanced cervical cancer. Clinical study samples were tested at a US based reference laboratory with PD-L1 IHC 22C3 pharmDx. KEYTRUDA® (pembrolizumab) demonstrated a robust overall response rate with a clinically meaningful duration of response in cervical cancer patients with positive PD-L1 expression (CPS ≥ 1) as determined by the PD-L1 IHC 22C3 pharmDx. The response rate in patients with positive PD-L1 expressing cervical cancer is better than what would be expected of available therapy and represents an improvement that is reasonably likely to predict clinical benefit.

Additional factors to be considered in determining probable risks and benefits for the PD-L1 IHC 22C3 pharmDx included: analytical performance of the device, and the availability of alternative tests. The primary risks associated with the PD-L1 IHC 22C3 pharmDx are the possibility of inaccurate, or false, results that may lead to mismanagement of patient treatment. The performance of the device is supported by analytical validation studies. The PD-L1 IHC 22C3 pharmDx is currently FDA-approved for the selection of previously treated NSCLC patients with PD-L1 expression (TPS ≥ 1%) and gastric cancer patients (CPS ≥ 1) for treatment with KEYTRUDA. Thus, the probable benefits are based on evaluation that the test performs consistently and provides clinically relevant results for evaluating PD-L1 status (CPS ≥ 1) in advanced cervical cancer patients who are being considered for KEYTRUDA.

### 1. Patient Perspectives

This submission did not include specific information on patient perspectives for this device.

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 21

{21}

In conclusion, given the available information above, the data support that for the use of this device in selecting patients with advanced cervical cancer for treatment with KEYTRUDA®, the probable benefits outweigh the probable risks.

# D. Overall Conclusions

The data in this application support the reasonable assurance of safety and effectiveness of this device when used in accordance with the indications for use. Data from the open-label, randomized clinical study support the use of the PD-L1 IHC 22C3 pharmDx as an aid in selecting patients with previously treated advanced cervical cancer with PD-L1 CPS ≥ 1 who may be eligible for treatment with KEYTRUDA® (pembrolizumab). These patients showed a significant improvement in ORR when treated with KEYTRUDA® (pembrolizumab).

# XIV. CDRH DECISION

CDRH issued an approval order on June 12, 2018. The final conditions of approval cited in the approval order are described below.

In the precision studies, limited numbers of samples from the intended use specimen type were evaluated using PD-L1 IHC 22C3 pharmDx. Additional testing of samples and analyses should be conducted for a comprehensive characterization of the performance of your device. The results from these studies will be included in the labeling.

The applicant's manufacturing facilities have been inspected and found to be in compliance with the device Quality System (QS) regulation (21 CFR 820).

# XV. APPROVAL SPECIFICATIONS

Directions for use: See device labeling.

Hazards to Health from Use of the Device: See Indications, Contraindications, Warnings, Precautions, and Adverse Events in the device labeling.

Post-approval Requirements and Restrictions: See approval order.

PMA P150013/S009: FDA SUMMARY OF SAFETY AND EFFECTIVENESS DATA

page 22

---

**Source:** [https://fda-staging.innolitics.com/device/P150013S009](https://fda-staging.innolitics.com/device/P150013S009)

**Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. If you're preparing [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/), [get in touch](https://innolitics.com/contact).

**Cite:** Innolitics at https://innolitics.com