On December 12, 2019 Applied DNA Sciences, Inc. (NASDAQ: APDN) ("Applied DNA" or the "Company"), a leader in Polymerase Chain Reaction (PCR)-based DNA manufacturing for product authenticity, traceability solutions and nucleic acid-based biotherapeutic development reported consolidated financial results for the full fiscal year and quarter ended September 30, 2019 (Press release, Applied DNA Sciences, DEC 12, 2019, View Source [SID1234552309]).

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"In fiscal 2019 total revenues increased 38%, and total operating expenses decreased by 5% as we sharpened our focus on our ability to produce linear DNA at scale for our tagging, diagnostics and preclinical biotherapeutic businesses," said Dr. James A. Hayward, chairman, president and CEO of Applied DNA.

Added Dr. Hayward, "Over the past year we focused on elevating the Company’s profile for preclinical biotherapeutics and diagnostic applications. With the Company’s unique ability – approximately 130 patents and patents pending – to produce large quantities of ultra-pure linear DNA, the Company’s linear DNA manufacturing platform is a potential industry disrupter that offers therapeutic developers a replacement to plasmid DNA that we believe is cheaper, faster and easily scalable. Over the past 15 months, we developed a robust pipeline of more than 15 contract research opportunities with top cancer, gene therapy, vaccine and RNA partners, which is already generating initial revenue."

"The recent acquisition of the assets and IP of Vitatex, Inc. gives us a second compelling branch to the linear DNA story that we believe lends itself to the diagnostics, prognostics and therapeutics of invasive circulating tumor cells (iCTC). Within just three months of acquisition, we signed an agreement with Tyme Technologies, Inc. for the supply of our Vita-AssayTM iCTC capture assay and associated services for iCTC detection in their pivotal stage pancreatic cancer clinical trial. In addition, our protocols for obtaining and studying iCTCs in colorectal cancer have recently been approved by an Institutional Review Board."

Continued Dr. Hayward, "Within our product authenticity and traceability solutions segment, our textile business, led by an experienced sales team, broadened awareness and adoption of our CertainT platform. Expanding beyond our relationship with Himatsingka for cotton home textiles, we established a technology partnership that gives us entrée into the cotton apparel market. We continued the global implementation of our tagging platform by completing commercial scale pilots at approximately 20 textile manufacturing sites using varied materials throughout China, Southeast Asia and India. In synthetic textiles, brands and retailers are increasingly relying on materials that offer high performance, sustainability and transparency and the promise of circular manufacturing. Our efforts have yielded strategic alliances that position us alongside key participants along multiple points in the global textile value chain to more broadly drive adoption of our authentication technology platform. We have begun to integrate our CertainT platform to provide end-to-end material traceability to multiple related categories, including leather, wool, down and feather, specialty coatings and additives, recycled PET, viscose, and other synthetics. We believe we are well positioned for uptake by brands and retailers."

Concluded Dr. Hayward, "Looking ahead, we have set our sights on generating top-line growth from our linear DNA manufacturing platform, that should be driven by textiles and cannabis, as well as biotherapeutic and diagnostics, as we begin to convert our business-building activities in fiscal 2019 into pre-commercial and commercial revenues in fiscal 2020. Having recently completed an equity raise, re-established our compliance with the Nasdaq listing requirements, and eliminated our Going Concern opinion, we have our strongest balance sheet in years and the financial resources to support a sustainable growth trajectory."

2019 Full Fiscal Year Financial Highlights

Revenues for fiscal 2019 totaled $5.4 million, an increase of 38% from $3.9 million from the prior fiscal year. The increase in revenues was due to an increase in service revenues of $1.2 million, or 57%, and an increase in product revenues of $308 thousand, or 17%. The increase in revenue was primarily attributable to an increase of $1 million from our now terminated cannabis licensing agreement, as well as an $889 thousand increase in textiles relating to shipments of DNA concentrate to protect the cotton supply chain. These increases in revenue were offset by a decrease in consumer asset marking sales.
·Effective October 1, 2018, the Company was required to adopt Accounting Standards Update (ASU; the "Update") No. 2014-09, Revenue from Contracts with Customers (Topic 606), utilizing the modified retrospective method. Had the Company not adopted the Update, the Company would have recognized additional revenue of approximately $915 thousand during fiscal 2019. This amount was primarily comprised of the recognition of $766 thousand during the twelve-month period ended September 30, 2019, under a $1.15 million cotton order shipped in June 2018, with extended payment terms. The total cumulative impact of the Update that was recorded to opening retained earnings in fiscal 2019 was approximately $493 thousand. See Cumulative Effect Adjustment and the Impact on Current Period Financial Statements of Adopting Topic 606 attached.
·Operating expenses for the fiscal year ended September 30, 2019 decreased by $707 thousand or 5% as compared to the prior fiscal year. The decrease is primarily attributable to approximately an $890 thousand decrease in payroll, due to a realignment of the sales force and reductions in overall headcount. This decrease in payroll was offset by an increase in legal fees.
·Net loss for the twelve months ended September 30, 2019 was $8.6 million or $9.69 per share, compared with a net loss of $11.7 million or $15.86 per share for the twelve months ended September 30, 2018, an improvement of 26%.
·Excluding non-cash expenses and interest, Adjusted EBITDA for the fiscal year ended September 30, 2019 was a negative $7.6 million as compared to a negative $9.8 million for the prior fiscal year, an improvement of 22%. See below for information regarding non-GAAP measures.

Fiscal Fourth Quarter 2019 Financial Results:

·Revenues increased 40% for the fourth quarter of fiscal 2019 to $1.7 million, compared with $1.2 million reported in the same period of the prior fiscal year and decreased 19% from $2.1 million for the third quarter of fiscal 2019. The increase in revenues year over year was due primarily to an increase in product revenues from shipments of DNA concentrate to protect the cotton supply chain. The decrease in revenue quarter over quarter was due to the recognition of $1 million in revenue from a licensing agreement in the cannabis industry during the third fiscal quarter of fiscal 2019.
·Total operating expenses decreased to $3.2 million for the fourth fiscal quarter of 2019, compared with $4.4 million in the prior fiscal year’s fourth quarter. This decrease is primarily attributable to an approximate $231 thousand decrease in payroll, due to a realignment of the sales force and reductions in overall headcount as well as a decrease of $954 thousand in stock-based compensation expense.
·Net loss for the quarter ended September 30, 2019 was $1.2 million, or $1.44 per share, compared with a net loss of $3.5 million, or $4.62 per share, for the quarter ended September 30, 2018, an improvement of 69%, and a net loss of $1.5 million, or $1.60 per share, for the quarter ended June 30, 2019.
·Excluding non-cash expenses, Adjusted EBITDA was negative $1.6 million and a negative $2.2 million for the quarters ended September 30, 2019 and 2018, respectively. See below for information regarding non-GAAP measures.

Select Recent Operational Highlights:

·On November 26, Applied DNA’s majority-owned subsidiary focused on next-generation biotherapeutics and diagnostics, LineaRx, signed a definitive agreement with Tyme Technologies, Inc. to supply the Company’s Vita-AssayTM invasive Circulating Tumor Cell (iCTC) capture assay and associated services for use in the pivotal stage of the TYME-88-PANC clinical trial for patients with third-line pancreatic cancer. The potential value of the Agreement is the largest contract to-date for LineaRx, and we believe the largest in the development history of the iCTC assay;
·On November 12, the Company announced the successful DNA tagging of leather at one of the world’s largest tanneries based in Asia. The work follows a successful research project undertaken within the UK that demonstrated SigNature DNA could be successfully used to trace the hide of an animal from a farm to the product in a store;
·On October 16, Applied DNA announced that it had entered into a partnership with Molecular Isotope Technologies, LLC ("MIT LLC"), a pioneer and leader in the application of natural-abundance stable-isotopic analysis provided under the trademarks Nature’s Fingerprint and IsoPedigree. MIT LLC’s technology utilizes stable isotopic "fingerprints" as a method for verification of product origin and supply chain processing to support product claims. MIT LLC’s technology will be offered by Applied DNA as an additional component of its CertainT platform to tag, test and track raw materials and finished goods. MIT LLC will support and promote the CertainT platform as a service complementary to its own;
·On October 1, LineaRx announced that its invasive Circulating Tumor Cells (iCTCs) platform demonstrated superior correlation over Prostate Specific Antigen (PSA) in an ongoing Phase II trial in recurrent prostate cancer. The Company believes that the study shows that iCTCs may be used to accurately follow therapy success in prostate cancer while also providing new tools for cell and gene therapy design and production;
·On September 24, the Company announced that it received a $1 million order to supply SigNature T taggant for cotton in the upcoming 2019 – 2020 ginning season that began in October. The Company’s SigNature T technology, paired with its genotyping and digital systems, will be used to tag, test and track the Pima cotton variety grown in the San Joaquin Valley, California that is sold under the PimaCott brand nationwide and online by the largest home goods retailer in the U.S. Since 2014, and including the cotton tagged with this order, over 250 million pounds of cotton will have been tagged as the key to a total end-to-end traceability solution that is substantiated by forensic test data;
·On September 19, LineaRx announced that its collaborators Takis/Evvivax have completed pre-clinical animal studies of two vaccine candidates produced with linear DNA. Tests of both vaccines in mouse models demonstrated their ability to eliminate tumors in vivo, and to potentially prevent initial occurrence. Clinical data accumulated from linear DNA vaccines for companion animals can be used to accelerate translation to human therapies by Evvivax and Takis;
·On September 5, Applied DNA announced a sales and marketing partnership with Navarpluma that extends the Company’s Textiles business to include the global down and feather supply chain. Navarpluma S.L., one of the world’s premier suppliers of down and feathers to the textile industry, will be the first to offer this new system to its customer base that counts some of the world’s most prestigious brands as clients.

Fiscal Fourth Quarter 2019 Conference Call Information

The Company will hold a conference call and webcast to discuss its fiscal fourth quarter-end 2019 results on Thursday, December 12, 2019 at 4:30 PM ET. To participate on the conference call, please follow the instructions below. While every attempt will be made to answer investors’ questions on the Q&A portion of the call, due to the large number of expected participants, not all questions may be answered.

To Participate:

·Participant Toll Free:1-844-887-9402
·Participant Toll: 1-412-317-6798
Please ask to be joined to the Applied DNA Sciences call

Live webcast: View Source

Replay (available 1 hour following the conclusion of the live call through December 19, 2019):

·Participant Toll Free: 1-877-344-7529
·Participant Toll: 1-412-317-0088
·Participant Passcode: 10136194
·Webcast replay: View Source

For those investors unable to attend the live call, a copy of management’s PowerPoint presentation will be available for review under the ‘Events and Presentations’ section of the company’s Investor Relations web site: View Source

Information about Non-GAAP Financial Measures

As used herein, "GAAP" refers to accounting principles generally accepted in the United States of America. To supplement our condensed consolidated financial statements prepared and presented in accordance with GAAP, this earnings release includes Adjusted EBITDA, which is a non-GAAP financial measure as defined in Rule 101 of Regulation G promulgated by the Securities and Exchange Commission. Generally, a non-GAAP financial measure is a numerical measure of a company’s historical or future performance, financial position, or cash flows that either excludes or includes amounts that are not normally excluded or included in the most directly comparable measure calculated and presented in accordance with GAAP. The presentation of this non-GAAP financial information is not intended to be considered in isolation or as a substitute for, or superior to, the financial information presented in accordance with GAAP. We use this non-GAAP financial measure for internal financial and operational decision making purposes and as a means to evaluate period-to-period comparisons of the performance and results of operations of our core business. Our management believes that these non-GAAP financial measures provide meaningful supplemental information regarding the performance of our business by excluding non-cash expenses that may not be indicative of our recurring operating results. We believe this non-GAAP financial measure is useful to investors as they allow for greater transparency with respect to key metrics used by management in its financial and operational decision making.

"EBITDA"- is defined as earnings (loss) before interest expense, income tax expense and depreciation and amortization expense.

"Adjusted EBITDA"- is defined as EBITDA adjusted to exclude (i) stock-based compensation and (ii) other non-cash expenses.

On December 12, 2019, Amgen reported that it entered into a second amended and restated revolving credit agreement with Citibank, N.A., as administrative agent ("Citibank"), JPMorgan Chase Bank, N.A., as syndication agent, and the other banks party thereto, for a total commitment of $2.5 billion (Filing, 8-K, Amgen, DEC 12, 2019, View Source [SID1234552308]). Financing under the revolving credit agreement is available for general corporate purposes, including as a liquidity backstop to our commercial paper program. The commitments under the revolving credit agreement may be increased by up to $750 million in the aggregate upon our request at the discretion of the banks and subject to certain customary requirements. The commitments of each bank under the revolving credit agreement have an initial term of five years and may be extended for up to two additional one year periods upon our request at the discretion of the respective bank, subject to certain customary requirements. The revolving credit agreement amends and restates our existing revolving credit agreement dated as of July 30, 2014.

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Advances under the revolving credit agreement will bear interest at an annual rate of, at our option, either (i) the applicable LIBOR rate (or EURIBOR rate for certain advances denominated in Euros) plus between 0.700% and 1.125%, depending on the rating of our senior long-term unsecured debt or (ii) the highest of (A) Citibank’s base commercial lending rate, (B) the overnight federal funds rate plus 0.50% and (C) one month LIBOR plus 1.00%, plus between 0.000% and 0.125%, depending on the rating of our senior long-term unsecured debt. The revolving credit agreement contains provisions relating to the determination of successor rates to address the possible phase-out or unavailability of designated reference rates under the revolving credit agreement. We have also agreed to pay a fee for committed funds under the revolving credit agreement, whether used or unused, of between 0.05% and 0.125% per annum depending on the rating of our senior long-term unsecured debt. The revolving credit agreement includes a $300 million sub-limit for issuances of letters of credit.

The revolving credit agreement contains customary affirmative and negative covenants, including limitations on mergers, consolidations and sales of assets; limitations on liens and sales and leasebacks; limitations on transactions with affiliates and limitations on subsidiary indebtedness. In addition, the revolving credit agreement requires maintenance of a minimum consolidated interest coverage ratio of EBITDA to total interest expense, each on a consolidated basis.

The description of the revolving credit agreement above does not purport to be complete and is qualified in its entirety by reference to the revolving credit agreement, which is filed as Exhibit 10.1 to this report.

On December 12, 2019 Veru Inc. (NASDAQ: VERU), The Prostate Cancer Company, an oncology and urology biopharmaceutical company developing novel medicines for the management of prostate cancer, reported that its fiscal 2019 full-year net revenues doubled to $31.8 million and gross profit increased 147% to $21.7 million (Press release, Veru, DEC 12, 2019, View Source [SID1234552306]).

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"For both the fiscal 2019 fourth quarter and full year, we continue to generate impressive increases to net revenues and gross profit compared with the prior year," said Mitchell Steiner, M.D., Chairman, President and Chief Executive Officer of Veru. "The robust ramp up of prescription as well as global public sector sales of FC2 and increased consumer demand for our PREBOOST/Roman Swipes product drove the significantly improved financial performance."

"I would like to highlight on the clinical development front, VERU-111 — our proprietary, oral, next generation, first-in-class, selective antitubulin – as it continues to show antitumor activity and no dose related toxicity in men with metastatic castration resistant prostate cancer. VERU-111 appears to be well tolerated with no evidence of neutropenia, neurotoxicity or allergic (hypersensitivity) reactions that typically occur with IV taxane chemotherapy. To date, our Phase 1b/2 clinical study has enrolled and dosed 33 patients from 4.5 mg per day up to 81 mg per day. The study will continue to enroll patients using increasing doses of VERU-111 until maximum tolerated dose is observed.

"Although this study was designed for determination of safety, we do see evidence of significant antitumor activity. Historical controls from the literature report that the time to imaging based tumor progression in men like those enrolled in our study averages about 2-3 months. In our Phase 1b/2, we have 20 men in the study that had the potential to be treated for 4.5 months. Even without having an optimal dose or dose schedule yet determined, there are 4 men who are still ongoing in the trial with no progression at 9.75, 8.4, 8.4 and 5.6 months. All of these men have prostate-specific antigen (PSA) reductions. We have another 6 men that progressed at 4.2 months. The patient who has reached 9.75 months had a PSA reduction of -63% and has had 2 of his cancerous lymph nodes shrink as measured by CT scan. Another patient in the study with stable disease stopped losing weight, reported that his fatigue resolved, and had a PSA reduction."

"Based on reports in the scientific literature, it appears that just like cabazitaxel, VERU-111 is a very active compound in metastatic castration resistant prostate cancer, and it seems to perform better than adding another androgen blocking agent in a similar patient population. VERU-111 appears to be well tolerated with a wide safety margin. Wide safety margin means that we are seeing anticancer activity at doses where we are not seeing drug toxicity. We plan to present full clinical results for this ongoing Phase 1b/2 at a future major scientific meeting.

Dr. Steiner added: "Since VERU-111 has signs of antitumor activity and an acceptable safety profile, we plan to expand and initiate in early 2020 three additional Phase 2 studies where we had demonstrated significant preclinical anticancer activity: metastatic pancreatic cancer, metastatic breast cancer and postchemotherapy (taxane) metastatic castration resistant prostate cancer. This clearly positions Veru as an oncology company with a novel oral agent that selectively targets alpha and beta subunits of tubulin."

"We also plan to submit the Investigation New Drug (IND) application for VERU-100 – our long-acting 3-month subcutaneous depot gonadotropin-releasing hormone (GnRH) antagonist for the treatment of hormone sensitive advanced prostate cancer – in early 2020. Regarding our Phase 2 clinical trial of zuclomiphene citrate, our proprietary drug to treat hot flashes caused by androgen deprivation therapy in men with advanced prostate cancer, we expect top line clinical data by no later than next month."

"Growing strong revenues from our base business will continue to support not only the current Phase 1b/2 VERU-111 oral selective antitubulin clinical trial and other VERU-111 Phase 2 clinical trials for different tumor types, but also the completion of the Phase 2 zuclomiphene citrate trial, and the planned Phase 2 VERU-100 3-month depot GnRH antagonist clinical trial in 2020. We are very pleased with the significant clinical progress we are making in advancing our entire product development program."

Full-Year Financial Highlights: Fiscal 2019 vs Fiscal 2018

Net revenues rose 100% to $31.8 million from $15.9 million;

Gross profit climbed 147% to $21.7 million, or 68% of net revenues, from $8.8 million, or 55% of net revenues;

FC2 US prescription revenue increased more than five-fold to $14.1 million from $2.4 million;

FC2 public sector net revenues were $16.8 million, a 25% increase from $13.5 million;

Operating loss significantly narrowed to $6.4 million from $20.9 million;

Net loss was $12.0 million, or $0.19 per share, compared with $23.9 million, or $0.44 per share; and,

At September 30, 2019, cash and accounts receivable were $11.3 million, an increase of $3.6 million from $7.7 million at the end of the prior year.

Fourth-Quarter Financial Highlights: Fiscal 2019 vs Fiscal 2018

Net revenues increased 68% to $8.7 million from $5.2 million;

Gross profit increased to $5.8 million, or 67% of net revenues, from $3.2 million, or 61% of net revenues;

FC2 US prescription net revenues increased nearly three-fold to $4.7 million from $1.6 million;

Operating loss significantly narrowed to $1.5 million from $3.8 million; and

Net loss was $3.1 million, or $0.05 per share, compared with $7.9 million, or $0.14 per share.

Based on our resources on hand and the anticipated performance of our commercial businesses together with already existing sources of capital, the Company believes that it has sufficient resources to execute our clinical drug trial programs through year end 2021.

Pharmaceutical Products Development Program Highlights

VERU-111. VERU-111 is an oral, next generation, first-in-class, selective small molecule that targets and binds to the alpha and beta antitubulin subunits of microtubules in cells. VERU-111 is being evaluated in a Phase 1b/2 clinical trial in men who have metastatic prostate cancer and whose disease is resistant to both castration and novel androgen blocking agents (abiraterone or enzalutamide). The objective of this clinical trial is to determine the dose limiting toxicity of VERU-111. At this point, 33 men in total have received doses of VERU-111, with each separate cohort receiving a higher dose. In clinical observations, VERU-111 has been well-tolerated with a favorable safety profile, and no dose limiting toxicity has been observed. There has been no neutropenia, neurotoxicity, or allergic (hypersensitivity) reactions which typically occur with IV taxane chemotherapy. In some of the men whose PSA blood levels were rapidly rising, a marker of cancer progression, as well as bone scans and/or CT scans showing cancer lesions progression at enrollment, treatment with VERU-111 resulted in PSA stabilizations and reductions consistent with early promising signals of anticancer efficacy. Furthermore, some patients have also demonstrated arrested progression of CT and/or bone scan cancer lesions beyond 8 and 9 months. Once a dose limiting toxicity level has been reached, a dose will be selected for evaluation in the Phase 2 clinical study. There are no drugs that are FDA approved to treat men who have both castration and novel androgen blocking agent resistant prostate cancer and which are also prechemotherapy (chemotherapy naïve), representing an estimated global market of $4.5 billion annually. As VERU-111 has signs of antitumor activity and an acceptable safety profile, the Company plans to expand and initiate in early 2020 three additional Phase 2 studies where we had demonstrated significant preclinical anticancer activity: metastatic pancreatic cancer, metastatic breast cancer and postchemotherapy (taxane) metastatic castration resistant prostate cancer.

VERU-100. VERU-100 is a long-acting 3-month subcutaneous depot GnRH antagonist for the treatment of hormone sensitive advanced prostate cancer. Currently, there are no GnRH antagonists commercially approved beyond 1 month, which would make VERU-100, if approved, the only commercially available GnRH antagonist 3-month depot. Based on regulatory clarity obtained in the pre-IND meeting with the FDA in May 2019, the Company plans to submit the IND application for VERU-100 in early 2020. Androgen deprivation therapy for advanced prostate cancer is an established multi-billion-dollar global market.

Zuclomiphene Citrate. Zuclomiphene citrate is a novel, proprietary, oral, nonsteroidal, estrogen receptor agonist being evaluated as a treatment for hot flashes caused by androgen deprivation therapy for men with advanced prostate cancer. Hot flashes, also known as vasomotor symptoms, are one of the main reasons why men want to stop androgen deprivation therapy. There have been no reports of gynecomastia, breast pain, or venothromboembolic events (blood clots in legs or lungs, or stroke) in the Intent to Treat safety database in the Phase 2 clinical study which are side effects commonly seen with off label use of steroidal estrogens and progestins for hot flashes in these patients. Top line clinical data results are expected by no later than next month. An independent market analysis sponsored by the Company estimates potential U.S. sales for zuclomiphene citrate to be between $600-800 million annually.

TADFIN (Tadalafil and Finasteride Combination Capsule). TADFIN is being developed for benign prostatic hyperplasia (BPH) and would be the first combination of a PDE5 inhibitor and 5 alpha reductase inhibitor. The Company had a successful preNDA meeting with the FDA in May 2019. After the Company has 12-month stability data on manufacturing batches, the Company will submit an NDA for TADFIN which is expected in the second half of 2020. BPH is an established multi-billion-dollar market.

Conference Call Event Details

Veru Inc. will host a conference call today at 8 a.m. ET to review the Company’s performance. Interested investors may access the call by dialing 800-341-1602 from the U.S. or 412-902-6706 from outside the U.S. and asking to be joined into the Veru Inc. call. In addition, investors may access a replay of the conference call the same day beginning at approximately noon Eastern Time by dialing 877-344-7529 for U.S. callers, or 412-317-0088 from outside the U.S., passcode 10136891. The replay will be available for one week, after which, the recording will be available via the Company’s website at View Source

On December 12, 2019 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported that KEYTRUDA, Merck’s anti-PD-1 therapy, showed improvements in overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) as monotherapy for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC) whose tumors expressed PD-L1 (tumor proportion score [TPS] ≥1%), regardless of KRAS mutational status (Press release, Merck & Co, DEC 12, 2019, View Source [SID1234552304]). These findings, which are based on an exploratory analysis of the pivotal Phase 3 KEYNOTE-042 trial, were presented today in a proffered paper presentation (Abstract #LBA4) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno-Oncology Congress 2019 in Geneva, Switzerland.

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"KRAS mutations occur in approximately 20% of people with non-small cell lung cancer, and some previous studies have suggested that these mutations are associated with a poorer response to treatment," said Dr. Jonathan Cheng, vice president, oncology clinical research, Merck Research Laboratories. "It was therefore encouraging to see in this exploratory analysis that KEYTRUDA monotherapy was associated with a survival benefit in certain patients with metastatic nonsquamous non-small cell lung cancer, regardless of KRAS mutational status."

The objective of the exploratory analysis was to assess the prevalence of KRAS mutations and their association with efficacy in the KEYNOTE-042 trial. Of the 1,274 untreated patients with metastatic nonsquamous NSCLC whose tumors expressed PD-L1 (TPS ≥1%) enrolled in KEYNOTE-042, 301 patients had KRAS evaluable data (n=232 without any KRAS mutation; n=69 with any KRAS mutation, including n=29 with the KRAS G12C mutation). Tissue tumor mutational burden (tTMB) and KRAS mutational status were determined by whole-exome sequencing (WES) of tumor tissue and matched normal DNA (blood). Patients were randomized 1:1 to receive KEYTRUDA 200 mg intravenously every three weeks (Q3W) (n=637) or investigator’s choice of chemotherapy (pemetrexed or paclitaxel) (n=637). Treatment continued until progression of disease or unacceptable toxicity. The primary endpoint was OS with a TPS of ≥50%, ≥20% and ≥1%, which were assessed sequentially. The secondary endpoints were PFS and ORR.

Findings from this exploratory analysis showed that KEYTRUDA monotherapy was associated with improved clinical outcomes, regardless of KRAS mutational status, in patients with metastatic nonsquamous NSCLC versus chemotherapy. In this analysis, KEYTRUDA reduced the risk of death by 58% (HR=0.42 [95% CI, 0.22-0.81]) in patients with any KRAS mutation and by 72% (HR=0.28 [95% CI, 0.09-0.86]) in patients with the KRAS G12C mutation compared to chemotherapy. The safety profile of KEYTRUDA was consistent with what has been seen in previously reported studies among patients with metastatic NSCLC.

Additional efficacy results from this exploratory analysis showed:

With Any KRAS
Mutation

With KRAS G12C
Mutation

Without Any KRAS
Mutation

KEYTRUDA Mono-therapy

(N = 30)

Chemo-therapy

(N = 39)

KEYTRUDA Mono-therapy
(N = 12)

Chemo-therapy
(N = 17)

KEYTRUDA Mono-therapy

(N = 127)

Chemo-therapy
(N = 105)

OS, median, mo
(95% CI)

28 (23-NR)

11 (7-25)

NR (23-NR)

8 (5-NR)

15 (12-24)

12 (11-18)

OS, HR
(95% CI)

0.42 (0.22-0.81)

0.28 (0.09-0.86)

0.86 (0.63-1.18)

ORR, %
(95% CI)

56.7

18.0

66.7

23.5

29.1

21.0

PFS, median, mo
(95% CI)

12 (8-NR)

6 (4-9)

15 (10-NR)

6 (4-8)

6 (4-7)

6 (6-8)

PFS, HR
(95% CI)

0.51 (0.29-0.87)

0.27 (0.10-0.71)

1.00 (0.75-1.34)

Data from an exploratory analysis of KEYNOTE-189 (Abstract #LBA5), which evaluated KRAS mutations and their association with efficacy outcomes for KEYTRUDA in combination with pemetrexed and platinum chemotherapy, were also presented in a mini-oral session today at the ESMO (Free ESMO Whitepaper) Immuno-Oncology Congress 2019. KEYNOTE-189 was conducted in collaboration with Eli Lilly and Company, the makers of pemetrexed (ALIMTA).

About Lung Cancer

Lung cancer, which forms in the tissues of the lungs, usually within cells lining the air passages, is the leading cause of cancer death worldwide. Each year, more people die of lung cancer than die of colon and breast cancers combined. The two main types of lung cancer are non-small cell and small cell. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for about 85% of all cases. Small cell lung cancer (SCLC) accounts for about 10 to 15% of all lung cancers. Lung cancer can also be characterized by the presence of different biomarkers, including PD-L1, KRAS, ALK, EGFR and ROS1. KRAS mutations occur in about 20% of NSCLC cases. Between 2008 and 2014, the five-year survival rate for patients diagnosed in the U.S. with advanced NSCLC was only 5%.

About KEYTRUDA (pembrolizumab) Injection, 100mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,000 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Small Cell Lung Cancer

KEYTRUDA is indicated for the treatment of patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) ≥1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma (cHL), or who have relapsed after 3 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. KEYTRUDA is not recommended for the treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [CPS ≥10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Microsatellite Instability-High (MSI-H) Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or
colorectal cancer that has progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Gastric Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors express PD-L1 (CPS ≥10) as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Cervical Cancer

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS ≥1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Selected Important Safety Information for KEYTRUDA

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis, including fatal cases. Pneumonitis occurred in 3.4% (94/2799) of patients with various cancers receiving KEYTRUDA, including Grade 1 (0.8%), 2 (1.3%), 3 (0.9%), 4 (0.3%), and 5 (0.1%). Pneumonitis occurred in 8.2% (65/790) of NSCLC patients receiving KEYTRUDA as a single agent, including Grades 3-4 in 3.2% of patients, and occurred more frequently in patients with a history of prior thoracic radiation (17%) compared to those without (7.7%). Pneumonitis occurred in 6% (18/300) of HNSCC patients receiving KEYTRUDA as a single agent, including Grades 3-5 in 1.6% of patients, and occurred in 5.4% (15/276) of patients receiving KEYTRUDA in combination with platinum and FU as first-line therapy for advanced disease, including Grade 3-5 in 1.5% of patients.

Monitor patients for signs and symptoms of pneumonitis. Evaluate suspected pneumonitis with radiographic imaging. Administer corticosteroids for Grade 2 or greater pneumonitis. Withhold KEYTRUDA for Grade 2; permanently discontinue KEYTRUDA for Grade 3 or 4 or recurrent Grade 2 pneumonitis.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis. Colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 2 (0.4%), 3 (1.1%), and 4 (<0.1%). Monitor patients for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater colitis. Withhold KEYTRUDA for Grade 2 or 3; permanently discontinue KEYTRUDA for Grade 4 colitis.

Immune-Mediated Hepatitis (KEYTRUDA) and Hepatotoxicity (KEYTRUDA in Combination With Axitinib)

Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.4%), and 4 (<0.1%). Monitor patients for changes in liver function. Administer corticosteroids for Grade 2 or greater hepatitis and, based on severity of liver enzyme elevations, withhold or discontinue KEYTRUDA.

Hepatotoxicity in Combination With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity with higher than expected frequencies of Grades 3 and 4 ALT and AST elevations compared to KEYTRUDA alone. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed.

Immune-Mediated Endocrinopathies

KEYTRUDA can cause hypophysitis, thyroid disorders, and type 1 diabetes mellitus. Hypophysitis occurred in 0.6% (17/2799) of patients, including Grade 2 (0.2%), 3 (0.3%), and 4 (<0.1%). Hypothyroidism occurred in 8.5% (237/2799) of patients, including Grade 2 (6.2%) and 3 (0.1%). The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC (16%) receiving KEYTRUDA, as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. Hyperthyroidism occurred in 3.4% (96/2799) of patients, including Grade 2 (0.8%) and 3 (0.1%), and thyroiditis occurred in 0.6% (16/2799) of patients, including Grade 2 (0.3%). Type 1 diabetes mellitus, including diabetic ketoacidosis, occurred in 0.2% (6/2799) of patients.

Monitor patients for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency), thyroid function (prior to and periodically during treatment), and hyperglycemia. For hypophysitis, administer corticosteroids and hormone replacement as clinically indicated. Withhold KEYTRUDA for Grade 2 and withhold or discontinue for Grade 3 or 4 hypophysitis. Administer hormone replacement for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Withhold or discontinue KEYTRUDA for Grade 3 or 4 hyperthyroidism. Administer insulin for type 1 diabetes, and withhold KEYTRUDA and administer antihyperglycemics in patients with severe hyperglycemia.

Immune-Mediated Nephritis and Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 2 (0.1%), 3 (0.1%), and 4 (<0.1%) nephritis. Nephritis occurred in 1.7% (7/405) of patients receiving KEYTRUDA in combination with pemetrexed and platinum chemotherapy. Monitor patients for changes in renal function. Administer corticosteroids for Grade 2 or greater nephritis. Withhold KEYTRUDA for Grade 2; permanently discontinue for Grade 3 or 4 nephritis.

Immune-Mediated Skin Reactions

Immune-mediated rashes, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (some cases with fatal outcome), exfoliative dermatitis, and bullous pemphigoid, can occur. Monitor patients for suspected severe skin reactions and based on the severity of the adverse reaction, withhold or permanently discontinue KEYTRUDA and administer corticosteroids. For signs or symptoms of SJS or TEN, withhold KEYTRUDA and refer the patient for specialized care for assessment and treatment. If SJS or TEN is confirmed, permanently discontinue KEYTRUDA.

Other Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue in patients receiving KEYTRUDA and may also occur after discontinuation of treatment. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of the adverse reaction, withhold KEYTRUDA and administer corticosteroids. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Resume KEYTRUDA when the adverse reaction remains at Grade 1 or less following corticosteroid taper. Permanently discontinue KEYTRUDA for any Grade 3 immune-mediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction.

The following clinically significant immune-mediated adverse reactions occurred in less than 1% (unless otherwise indicated) of 2799 patients: arthritis (1.5%), uveitis, myositis, Guillain-Barré syndrome, myasthenia gravis, vasculitis, pancreatitis, hemolytic anemia, sarcoidosis, and encephalitis. In addition, myelitis and myocarditis were reported in other clinical trials, including cHL, and postmarketing use.

Treatment with KEYTRUDA may increase the risk of rejection in solid organ transplant recipients. Consider the benefit of treatment vs the risk of possible organ rejection in these patients.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% (6/2799) of patients. Monitor patients for signs and symptoms of infusion-related reactions. For Grade 3 or 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Immune-mediated complications, including fatal events, occurred in patients who underwent allogeneic HSCT after treatment with KEYTRUDA. Of 23 patients with cHL who proceeded to allogeneic HSCT after KEYTRUDA, 6 (26%) developed graft-versus-host disease (GVHD) (1 fatal case) and 2 (9%) developed severe hepatic veno-occlusive disease (VOD) after reduced-intensity conditioning (1 fatal case). Cases of fatal hyperacute GVHD after allogeneic HSCT have also been reported in patients with lymphoma who received a PD-1 receptor–blocking antibody before transplantation. Follow patients closely for early evidence of transplant-related complications such as hyperacute graft-versus-host disease (GVHD), Grade 3 to 4 acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease (VOD), and other immune-mediated adverse reactions.

In patients with a history of allogeneic HSCT, acute GVHD (including fatal GVHD) has been reported after treatment with KEYTRUDA. Patients who experienced GVHD after their transplant procedure may be at increased risk for GVHD after KEYTRUDA. Consider the benefit of KEYTRUDA vs the risk of GVHD in these patients.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with a PD-1 or PD-L1 blocking antibody in this combination is not recommended outside of controlled trials.

Embryofetal Toxicity

Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. Advise women of this potential risk. In females of reproductive potential, verify pregnancy status prior to initiating KEYTRUDA and advise them to use effective contraception during treatment and for 4 months after the last dose.

Adverse Reactions

In KEYNOTE-006, KEYTRUDA was discontinued due to adverse reactions in 9% of 555 patients with advanced melanoma; adverse reactions leading to permanent discontinuation in more than one patient were colitis (1.4%), autoimmune hepatitis (0.7%), allergic reaction (0.4%), polyneuropathy (0.4%), and cardiac failure (0.4%). The most common adverse reactions (≥20%) with KEYTRUDA were fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).

In KEYNOTE-054, KEYTRUDA was permanently discontinued due to adverse reactions in 14% of 509 patients; the most common (≥1%) were pneumonitis (1.4%), colitis (1.2%), and diarrhea (1%). Serious adverse reactions occurred in 25% of patients receiving KEYTRUDA. The most common adverse reaction (≥20%) with KEYTRUDA was diarrhea (28%).

In KEYNOTE-189, when KEYTRUDA was administered with pemetrexed and platinum chemotherapy in metastatic nonsquamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 20% of 405 patients. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonitis (3%) and acute kidney injury (2%). The most common adverse reactions (≥20%) with KEYTRUDA were nausea (56%), fatigue (56%), constipation (35%), diarrhea (31%), decreased appetite (28%), rash (25%), vomiting (24%), cough (21%), dyspnea (21%), and pyrexia (20%).

In KEYNOTE-407, when KEYTRUDA was administered with carboplatin and either paclitaxel or paclitaxel protein-bound in metastatic squamous NSCLC, KEYTRUDA was discontinued due to adverse reactions in 15% of 101 patients. The most frequent serious adverse reactions reported in at least 2% of patients were febrile neutropenia, pneumonia, and urinary tract infection. Adverse reactions observed in KEYNOTE-407 were similar to those observed in KEYNOTE-189 with the exception that increased incidences of alopecia (47% vs 36%) and peripheral neuropathy (31% vs 25%) were observed in the KEYTRUDA and chemotherapy arm compared to the placebo and chemotherapy arm in KEYNOTE-407.

In KEYNOTE-042, KEYTRUDA was discontinued due to adverse reactions in 19% of 636 patients; the most common were pneumonitis (3%), death due to unknown cause (1.6%), and pneumonia (1.4%). The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia (7%), pneumonitis (3.9%), pulmonary embolism (2.4%), and pleural effusion (2.2%). The most common adverse reaction (≥20%) was fatigue (25%).

In KEYNOTE-010, KEYTRUDA monotherapy was discontinued due to adverse reactions in 8% of 682 patients with metastatic NSCLC; the most common was pneumonitis (1.8%). The most common adverse reactions (≥20%) were decreased appetite (25%), fatigue (25%), dyspnea (23%), and nausea (20%).

Adverse reactions occurring in patients with SCLC were similar to those occurring in patients with other solid tumors who received KEYTRUDA as a single agent.

In KEYNOTE-048, KEYTRUDA monotherapy was discontinued due to adverse events in 12% of 300 patients with HNSCC; the most common adverse reactions leading to permanent discontinuation were sepsis (1.7%) and pneumonia (1.3%). The most common adverse reactions (≥20%) were fatigue (33%), constipation (20%), and rash (20%).

In KEYNOTE-048, when KEYTRUDA was administered in combination with platinum (cisplatin or carboplatin) and FU chemotherapy, KEYTRUDA was discontinued due to adverse reactions in 16% of 276 patients with HNSCC. The most common adverse reactions resulting in permanent discontinuation of KEYTRUDA were pneumonia (2.5%), pneumonitis (1.8%), and septic shock (1.4%). The most common adverse reactions (≥20%) were nausea (51%), fatigue (49%), constipation (37%), vomiting (32%), mucosal inflammation (31%), diarrhea (29%), decreased appetite (29%), stomatitis (26%), and cough (22%).

In KEYNOTE-012, KEYTRUDA was discontinued due to adverse reactions in 17% of 192 patients with HNSCC. Serious adverse reactions occurred in 45% of patients. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The most common adverse reactions (≥20%) were fatigue, decreased appetite, and dyspnea. Adverse reactions occurring in patients with HNSCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of facial edema and new or worsening hypothyroidism.

In KEYNOTE-087, KEYTRUDA was discontinued due to adverse reactions in 5% of 210 patients with cHL. Serious adverse reactions occurred in 16% of patients; those ≥1% included pneumonia, pneumonitis, pyrexia, dyspnea, GVHD, and herpes zoster. Two patients died from causes other than disease progression; 1 from GVHD after subsequent allogeneic HSCT and 1 from septic shock. The most common adverse reactions (≥20%) were fatigue (26%), pyrexia (24%), cough (24%), musculoskeletal pain (21%), diarrhea (20%), and rash (20%).

In KEYNOTE-170, KEYTRUDA was discontinued due to adverse reactions in 8% of 53 patients with PMBCL. Serious adverse reactions occurred in 26% of patients and included arrhythmia (4%), cardiac tamponade (2%), myocardial infarction (2%), pericardial effusion (2%), and pericarditis (2%). Six (11%) patients died within 30 days of start of treatment. The most common adverse reactions (≥20%) were musculoskeletal pain (30%), upper respiratory tract infection and pyrexia (28% each), cough (26%), fatigue (23%), and dyspnea (21%).

In KEYNOTE-052, KEYTRUDA was discontinued due to adverse reactions in 11% of 370 patients with locally advanced or metastatic urothelial carcinoma. Serious adverse reactions occurred in 42% of patients; those ≥2% were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. The most common adverse reactions (≥20%) were fatigue (38%), musculoskeletal pain (24%), decreased appetite (22%), constipation (21%), rash (21%), and diarrhea (20%).

In KEYNOTE-045, KEYTRUDA was discontinued due to adverse reactions in 8% of 266 patients with locally advanced or metastatic urothelial carcinoma. The most common adverse reaction resulting in permanent discontinuation of KEYTRUDA was pneumonitis (1.9%). Serious adverse reactions occurred in 39% of KEYTRUDA-treated patients; those ≥2% were urinary tract infection, pneumonia, anemia, and pneumonitis. The most common adverse reactions (≥20%) in patients who received KEYTRUDA were fatigue (38%), musculoskeletal pain (32%), pruritus (23%), decreased appetite (21%), nausea (21%), and rash (20%).

Adverse reactions occurring in patients with gastric cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

Adverse reactions occurring in patients with esophageal cancer were similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy.

In KEYNOTE-158, KEYTRUDA was discontinued due to adverse reactions in 8% of 98 patients with recurrent or metastatic cervical cancer. Serious adverse reactions occurred in 39% of patients receiving KEYTRUDA; the most frequent included anemia (7%), fistula, hemorrhage, and infections [except urinary tract infections] (4.1% each). The most common adverse reactions (≥20%) were fatigue (43%), musculoskeletal pain (27%), diarrhea (23%), pain and abdominal pain (22% each), and decreased appetite (21%).

Adverse reactions occurring in patients with HCC were generally similar to those in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy, with the exception of increased incidences of ascites (8% Grades 3–4) and immune-mediated hepatitis (2.9%). Laboratory abnormalities (Grades 3–4) that occurred at a higher incidence were elevated AST (20%), ALT (9%), and hyperbilirubinemia (10%).

Among the 50 patients with MCC enrolled in study KEYNOTE-017, adverse reactions occurring in patients with MCC were generally similar to those occurring in patients with melanoma or NSCLC who received KEYTRUDA as a monotherapy. Laboratory abnormalities (Grades 3–4) that occurred at a higher incidence were elevated AST (11%) and hyperglycemia (19%).

In KEYNOTE-426, when KEYTRUDA was administered in combination with axitinib, fatal adverse reactions occurred in 3.3% of 429 patients. Serious adverse reactions occurred in 40% of patients, the most frequent of which (≥1%) included hepatotoxicity (7%), diarrhea (4.2%), acute kidney injury (2.3%), dehydration (1%), and pneumonitis (1%). Permanent discontinuation due to an adverse reaction occurred in 31% of patients; KEYTRUDA only (13%), axitinib only (13%), and the combination (8%). The most common adverse reactions (>1%) resulting in permanent discontinuation of KEYTRUDA, axitinib or the combination were hepatotoxicity (13%), diarrhea/colitis (1.9%), acute kidney injury (1.6%), and cerebrovascular accident (1.2%). When KEYTRUDA was used in combination with axitinib, the most common adverse reactions (≥20%) were diarrhea (56%), fatigue/asthenia (52%), hypertension (48%), hepatotoxicity (39%), hypothyroidism (35%), decreased appetite (30%), palmar-plantar erythrodysesthesia (28%), nausea (28%), stomatitis/mucosal inflammation (27%), dysphonia (25%), rash (25%), cough (21%), and constipation (21%).

Lactation

Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 4 months after the final dose.

Pediatric Use

There is limited experience in pediatric patients. In a trial, 40 pediatric patients (16 children aged 2 years to younger than 12 years and 24 adolescents aged 12 years to 18 years) with various cancers, including unapproved usages, were administered KEYTRUDA 2 mg/kg every 3 weeks. Patients received KEYTRUDA for a median of 3 doses (range 1–17 doses), with 34 patients (85%) receiving 2 doses or more. The safety profile in these pediatric patients was similar to that seen in adults; adverse reactions that occurred at a higher rate (≥15% difference) in these patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), increased transaminases (28%), and hyponatremia (18%).

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On December 12, 2019 Exact Sciences Corp. (NASDAQ: EXAS) reported new outcomes data from two large population-based studies1,2 presented at the 2019 San Antonio Breast Cancer Symposium (SABCS) (Press release, Exact Sciences, DEC 12, 2019, View Source [SID1234552300]). The real-world evidence suggests that use of the Oncotype DX Breast Recurrence Score test in clinical practice is consistent with previous clinical validation studies including TAILORx, the largest ever breast cancer treatment trial. This landmark study was featured in the William L. McGuire Memorial Lecture Award, which recognized Joseph A. Sparano, M.D., TAILORx study chair, for his leadership, collaboration and practice-changing achievements in breast cancer research.

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"Last year, TAILORx established the highest level of evidence and unprecedented precision supporting the use of the Oncotype DX Breast Recurrence Score test to guide adjuvant chemotherapy treatment for women with early-stage breast cancer," said Dr. Sparano, associate director for clinical research at the Albert Einstein Cancer Center and Montefiore Health System in New York, and vice chair of the ECOG-ACRIN Cancer Research Group. "I am honored to receive this prestigious award and pleased that the TAILORx results have been incorporated in major clinical practice guidelines and used to guide patient care around the world."

Outcomes Data in Patients Age 50 or Younger Reinforce Ability of Oncotype DX to Identify Those Who Can Be Treated with Hormone Therapy Alone

An analysis from the U.S. National Cancer Database in over 4,700 women age 40 or younger with node-negative disease showed a distribution of Recurrence Score results consistent with existing clinical evidence, with as many as 80% of patients having low Recurrence Score results (0-25). Higher Recurrence Score results were associated with worse five-year overall survival.

Another analysis from the Surveillance, Epidemiology, and End Results (SEER) registry program of the National Cancer Institute (NCI) provides real-world evidence of the value of the Oncotype DX test in patients age 50 or younger with node-positive disease (up to three positive nodes). Results from more than 2,500 patients indicated a significant association between Recurrence Score results and breast cancer-specific mortality (BCSM), with five-year BCSM of less than 2% in young patients with Recurrence Score results 0-25 and no or unknown use of chemotherapy reported.

New Publication of Long-term Data from Real-world Clinical Practice Confirms Major Finding of TAILORx Study

Separately, the first reported 10-year outcomes data, including distant recurrence risk, from a large cohort of patients using the Recurrence Score results to guide treatment decisions in clinical practice were recently published.3 This analysis from investigators working with Clalit Health Services, the largest health services organization in Israel, examined medical records of more than 1,300 patients with node-negative breast cancer and applied the Recurrence Score cut points established by the landmark TAILORx study.4

The findings showed that use of chemotherapy was aligned with Recurrence Score results, and that patients with Recurrence Score results up to 25, the vast majority of whom were treated with hormonal therapy alone, had excellent outcomes at 10 years, with low rates of distant recurrence. For the group of patients with Recurrence Score results 11-25, there were no statistically significant differences in 10-year distant recurrence rates between patients who received chemotherapy and those treated with hormonal therapy alone. These results are consistent with the primary findings of the large TAILORx randomized clinical trial.

"The additional insight from the new analyses in young patients is consistent with, and further supports, the value of the Recurrence Score result in younger women," said Steven Shak, M.D., chief medical officer, Exact Sciences. "We are pleased to see the publication of new real-world evidence that reinforces the paradigm established by the TAILORx study, which has influenced positive treatment guidelines updates over the past 18 months and is having an important impact on global reimbursement and standard use of the Oncotype DX test."

Additional Oncotype DX Presentations at 2019 SABCS Reinforce Value of the Test in Multiple Patient Populations Throughout Disease Continuum

A prospective multicenter study5 from Ireland in more than 120 patients with node-positive disease highlights the significant impact on treatment decisions and reduction in chemotherapy recommendations based on the Recurrence Score result.
The largest clinical utility study6 to date with the Oncotype DX DCIS Score assessed the impact of the test on radiotherapy (RT) recommendations in more than 200 patients. Results showed that the test combined with clinicopathological features identified more women with an estimated low (<10%) 10-year risk of local recurrence after breast-conserving surgery, leading to a significant change in RT recommendations and significantly more women not receiving RT.
About Oncotype DX
The Oncotype DX portfolio of breast, colon and prostate cancer tests applies advanced genomic science to reveal the unique biology of a tumor in order to optimize cancer treatment decisions. In breast cancer, the Oncotype DX Breast Recurrence Score test is the only test that has been shown to predict the likelihood of chemotherapy benefit as well as recurrence in invasive breast cancer. Additionally, the Oncotype DX Breast DCIS Score test predicts the likelihood of recurrence in a pre-invasive form of breast cancer called DCIS. In prostate cancer, the Oncotype DX Genomic Prostate Score test predicts disease aggressiveness and further clarifies the current and future risk of the cancer prior to treatment intervention, and the Oncotype DX AR-V7 Nucleus Detect test helps determine which patients with metastatic castration-resistant prostate cancer (mCRPC) are resistant to androgen receptor (AR)-targeted therapies. The Oncotype DX AR-V7 Nucleus Detect test is performed by Epic Sciences at its centralized, CLIA-certified laboratory in San Diego and offered exclusively by Exact Sciences. With more than 1 million patients tested in more than 90 countries, the Oncotype DX tests have redefined personalized medicine by making genomics a critical part of cancer diagnosis and treatment. To learn more about Oncotype DX tests, visit www.OncotypeIQ.com, www.MyBreastCancerTreatment.org or www.MyProstateCancerTreatment.org.