On October 23, 2021 Turning Point Therapeutics, Inc. (NASDAQ: TPTX), a precision oncology company developing next-generation therapies that target genetic drivers of cancer, reported the presentation of early clinical data from the ongoing Phase 1/2 CARE study in pediatric and young adult patients with advanced solid tumors harboring ALK, ROS1 or NTRK alterations (Press release, Turning Point Therapeutics, OCT 23, 2021, View Source [SID1234591834]). These data are being presented today at the virtual 53rd Congress of the International Society of Paediatric Oncology (SIOP) being held October 21-24.

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"These early data for repotrectinib demonstrate encouraging clinical activity in this pediatric patient population," said Mohammad Hirmand, M.D., chief medical officer. "Patient enrollment is continuing in the Phase 1/2 CARE study, and we look forward to further advancing the development of repotrectinib in this patient population."

Early Data from Phase 1/2 CARE Study
The primary objective of the Phase 1 dose escalation portion of the study is to evaluate the safety and tolerability and determine the recommended Phase 2 dose (RP2D) of repotrectinib in pediatric patients less than 12 years old. The primary objective of the Phase 2 portion of the study is to determine the anti-tumor activity of repotrectinib in pediatric and young adult patients less than 25 years old. Repotrectinib is administrated in capsule or suspension formulation using weight-based dosing for patients less than 12 years old. Patients 12 to 25 years old can enroll directly into the Phase 2 portion of the study with a repotrectinib dose of 160 mg QD for the first 14 days and may increase to 160 mg BID thereafter.

The early Phase 1/2 CARE dataset utilizes an August 2, 2021 data cutoff date. Ten patients were treated across two dose levels. The safety analysis includes the ten treated patients, and the preliminary efficacy analysis includes eight evaluable patients. Patients included in the efficacy analysis had baseline measurable disease and at least one post-baseline evaluable scan. Response evaluation was by physician assessment and per RECIST v1.1 or RANO for CNS tumors. Responses were confirmed with a subsequent scan at least 28 days later.

The findings were reported in a pre-recorded presentation by Steven G. Dubois, M.D., associate professor of Pediatrics, Harvard Medical School available on October 23 at 9:12 a.m. ET on the meeting website.

Preliminary Safety Analysis (n=10) and Pharmacokinetic Analysis

Repotrectinib was generally well tolerated.

The most frequently reported treatment-emergent adverse events (TEAEs) were anemia (n=5) and fatigue (n=5). Among patients with anemia, three had baseline history of anemia.

Dizziness events (n=4) were grade 1 or 2 and none led to treatment discontinuation.

No patients discontinued treatment due to reasons other than disease progression and no patients had TEAEs that led to dose reduction.

No dose-limiting toxicities were reported.

Preliminary pharmacokinetics data indicated that the exposure of repotrectinib in different age groups was comparable to the adult exposure at steady-state.
Preliminary Efficacy Analysis (n=8)

Eight patients were evaluable for efficacy, including four TKI-naïve and four TKI-pretreated patients. TKI-naive patients included those with NTRK amplified anaplastic ependymoma (n=1), NTRK fusion glioblastoma multiforme (GBM)/high grade glioma (n=1), NTRK fusion sarcoma (n=1), and ROS1 fusion inflammatory myofibroblastic tumor (IMT) (n=1). TKI-pretreated patients included those with NTRK fusion GBM/high grade glioma (n=2), NTRK fusion mesoblastic nephroma (n=1), and NTRK fusion sarcoma (n=1).

Three TKI-naïve patients (2 NTRK fusion solid tumors; 1 ROS1 fusion IMT) achieved confirmed responses. One of the three responding patients had a NTRK fusion GBM/high grade glioma, was previously treated with tumor resection, whole brain radiotherapy, and multi-agent chemotherapy, and achieved a complete response (CR) and remained in a response for 3.8+ months as of the data cutoff date. The other two confirmed responders remained in response with duration of response of 7.3+ and 12.1+ months, respectively.

Of the four TKI-pretreated patients, one patient with NTRK fusion sarcoma had a best response of stable disease.
The Phase 1 dose finding portion of the study is ongoing in pediatric patients less than 12 years old to confirm the pediatric RP2D. The Phase 2 portion of the study is ongoing for patients 12 to 25 years old.

Turning Point also announced the publication of preclinical data of repotrectinib in neuroblastoma, the most common pediatric extracranial solid tumor, in the American Association of Cancer Research’s peer reviewed journal, Molecular Cancer Therapeutics. Preclinical studies described in the publication titled "Translational Strategies for Repotrectinib in Neuroblastoma" show that repotrectinib inhibits tumor growth and prolongs survival in patient-derived neuroblastoma xenograft models. In addition, the studies indicated that combining repotrectinib with chemotherapy may be a promising treatment paradigm for neuroblastoma patients.

On October 23, 2021 NANOBIOTIX (Euronext: NANO – NASDAQ: NBTX – the ‘‘Company’’), a late-stage clinical biotechnology company pioneering physics-based approaches to expand treatment possibilities for patients with cancer, reported first ever survival data from its priority head and neck cancer development program at the 2021 Annual Meeting of the American Society for Radiation Oncology (ASTRO) (Press release, Nanobiotix, OCT 23, 2021, View Source [SID1234591835]).

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As specified by the ASTRO Annual Meeting embargo policy, "information beyond what is included in the abstract, such as updated or additional results, is embargoed until the date and time of scientific presentation or presentation at an ASTRO news briefing, whichever occurs first." However, Nanobiotix has become aware that ASTRO made a late decision to release the posters at the same time as the abstracts and did not sufficiently update the embargo policy. As a result, the Company is releasing this data in advance of its intended embargo date.

New Data from Locally Advanced Head and Neck Squamous Cell Carcinoma (LA-HNSCC) Program

Data show a median Overall Survival (mOS) of 18.1 months and a median Progression Free survival of (mPFS) of 10.6 months in the evaluable population (n=41) from the dose expansion part of its phase I, multicenter, open-label, non-randomized dose escalation and dose expansion study evaluating NBTXR3 as a single-agent activated by radiotherapy in tough-to-treat elderly and frail LA-HNSCC patients ineligible for cisplatin and intolerant to cetuximab (Study 102 Expansion). In the full population (all evaluable and non-evaluable patients treated; n=54), data showed a 14.1-month mOS and a 9.4-month mPFS. The data suggest that lower mOS and mPFS observed in the full population versus the evaluable population in the study could be related to early death associated with high burden of comorbidity in the non-evaluable population.

Evaluability in Study 102 Expansion was determined based on the patient receiving at least 80% of the intended intratumoral dose of NBTXR3, at least 60 Gy of radiotherapy, and the required imaging to assess the target lesion at baseline and at least once post treatment.

Response rates remained consistent with previously reported results from the dose escalation and dose expansion study, showing a best observed target lesion objective response rate (ORR) of 85.4% and a best observed target lesion complete response rate (CRR) of 63.4%2.

"I have held the belief that NBTXR3 could have a real impact for patients with solid tumors since reviewing the proof-of-concept data from the phase II/III in soft tissue sarcoma and throughout my participation in Study 102 Expansion," said study principal investigator Professor Christophe Le Tourneau, senior medical oncologist and head of the Department of Drug Development and Innovation (D3i) at Institut Curie. "This first look at survival data has added to my confidence that NBTXR3 could provide a promising new therapeutic option for the practice. I look forward to leading the upcoming phase III global registration study, and to have the opportunity to evaluate the promise of this innovation in a larger patient population."

Of the 21 evaluable patients with a best observed overall response of complete response (CR) with a mean follow-up of 16.1 months, 6 patients died for non-oncologic reasons and only one died from disease progression.

NBTXR3 administration was feasible and well-tolerated overall. A total of 8 Grade 3-4 NBTXR3-related adverse events (AEs) were observed in 8 patients, representing 1.3% of all observed AEs. Of these AEs related to NBTXR3, 5 serious adverse events (SAEs) were observed including dysphagia, sepsis, soft tissue necrosis, stomatitis, and tumor hemorrhage. Of the SAEs, one death from sepsis assessed by the investigator as possibly related to NBTXR3, radiotherapy, and cancer was observed.

While the incidence of LA-HNSCC has continued to rise, patients in the elderly and frail LA-HNSCC population have significant unmet needs. Many are not eligible to receive concurrent chemoradiation due to frailty associated with comorbidities. The modified Charlson Comorbidity Index (mCCI) is a measure of comorbidity burden on a patient-by-patient basis, and high mCCI (i.e., mCCI ≥ 4) is correlated with higher risk of death relative to the broader population. In this study, 63% of all patients treated had high mCCI, which is two to three times the prevalence of comorbidity in the overall LA-HNSCC population3.

Despite the prevalence of high mCCI in Study 102 Expansion, these preliminary data support further evaluation of NBTXR3 activated by radiotherapy as a therapeutic option that may translate to a survival benefit for elderly and frail LA-HNSCC patients. The data also suggest that the potential benefits of the therapy could improve in a population with a lower burden of comorbidity.

"Bringing innovation to the patients that need it most has always been the backbone of our development strategy for NBTXR3," said Laurent Levy, co-founder and chief executive officer of Nanobiotix. "We started with soft tissue sarcoma—a disease indication notoriously resistant to radiotherapy. After proving we could provide a therapeutic benefit versus radiotherapy alone for patients with locally advanced disease and achieving European market approval, we pivoted to patients with locally advanced head and neck cancer that have substantially limited treatment options. The new survival data we are seeing from Study 102 Expansion bolster our confidence in the promise of NBTXR3 as we near the launch of our pivotal phase III study in head and neck cancer. We have designed this study with the benefit of our learnings from the phase I and look forward to the opportunity to prove that our product candidate can expand treatment possibilities for patients with cancer around the world."

About NBTXR3

NBTXR3 is a novel, potentially first-in-class oncology product composed of functionalized hafnium oxide nanoparticles that is administered via one-time intratumoral injection and activated by radiotherapy. The product candidate’s physical mechanism of action (MoA) is designed to induce significant tumor cell death in the injected tumor when activated by radiotherapy, subsequently triggering adaptive immune response and long-term anti-cancer memory. Given the physical MoA, Nanobiotix believes that NBTXR3 could be scalable across any solid tumor that can be treated with radiotherapy and across any therapeutic combination, particularly immune checkpoint inhibitors.

NBTXR3 is being evaluated in locally advanced head and neck squamous cell carcinoma (HNSCC) as the primary development pathway. The company-sponsored phase I dose escalation and dose expansion study has produced favorable safety data and early signs of efficacy; and the launch of a phase III global registrational study is planned. In February 2020, the United States Food and Drug Administration granted regulatory Fast Track designation for the investigation of NBTXR3 activated by radiation therapy, with or without cetuximab, for the treatment of patients with locally advanced HNSCC who are not eligible for platinum-based chemotherapy—the same population being evaluated in the planned phase III study.

Nanobiotix has also prioritized an Immuno-Oncology development program—beginning with a Company sponsored phase I clinical study evaluating NBTXR3 activated by radiotherapy in combination with anti-PD-1 checkpoint inhibitors for patients with locoregional recurrent or recurrent/metastatic HNSCC and lung or liver metastases from any primary cancer eligible for anti-PD-1 therapy.

Given the Company’s focus areas, and balanced against the scalable potential of NBTXR3 , Nanobiotix has engaged in a strategic collaboration strategy with world class partners to expand development of the product candidate in parallel with its priority development pathways. Pursuant to this strategy, in 2019 Nanobiotix entered into a broad, comprehensive clinical research collaboration with The University of Texas MD Anderson Cancer Center to sponsor several phase I and phase II studies to evaluate NBTXR3 across tumor types and therapeutic combinations.

On October 23, 2021 Orion Biotechnology reported that The Bio-Europe Conference will be held virtually again this year, and Orion Biotechnology will be providing a pre-recorded presentation describing our exciting drug discovery technology for unlocking the therapeutic potential of G Protein-Coupled Receptors (GPCRs), a very large and important group of drug targets in the human body (Press release, Orion Biotechnology, OCT 23, 2021, View Source [SID1234591885]).

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On October 22, 2021 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported U.S. Food and Drug Administration (FDA) approval of the VENTANA PD-L1 (SP263) Assay in non- small cell lung cancer (NSCLC) as a companion diagnostic test for Tecentriq, advancing the company’s commitment to guide clinical decision making through innovative, high quality assays that improve patient access to personalized healthcare (Press release, Hoffmann-La Roche, OCT 22, 2021, View Source [SID1234591765]).

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The current standard of care for patients with early stage lung cancer is surgery to remove the tumor, which may be followed by chemotherapy. Unfortunately, about half of these patients will have their cancer return following surgery.2 Tecentriq received FDA approval on 15 October 2021 as adjuvant treatment following surgery and platinum-based chemotherapy for adults whose Stage II-IIIA NSCLC tumors have PD-L1 expression on ≥1% of tumor cells. The VENTANA PD-L1 (SP263) Assay identifies NSCLC patients who may be eligible for Tecentriq (atezolizumab) monotherapy in this indication.

"Early detection of lung cancer can change the treatment pathway for patients and give them more treatment options," said Thomas Schinecker, CEO Roche Diagnostics. "We are proud to offer a companion diagnostic PD-L1 test that identifies lung cancer patients who may qualify for Tecentriq therapy. With the FDA approval of this companion diagnostic test, clinicians now have an effective tool for offering better patient care through targeted immunotherapy treatment."

The VENTANA PD-L1 (SP263) Assay was used as part of the IMpower010 study sponsored by Genentech, a member of the Roche Group, to identify patients whose tumors expressed the PD-L1 protein. The IMpower010 clinical study began in 2015 with the goal of understanding how patients would respond to treatment with Tecentriq following traditional surgery and chemotherapy. In 2021, Genentech reported a 34% reduction in the risk of disease recurrence or death amongst Tecentriq patients whose tumors were shown to express PD-L1 protein. For details of the study go to www.roche.com.

About the VENTANA PD-L1 (SP263) Assay
VENTANA PD-L1 (SP263) Assay is used to detect programmed death ligand-1 (PD-L1) protein in non-small cell lung carcinoma (NSCLC) patients. PD-L1 expression on tumor cells and immune cells has been shown in clinical studies to help predict the likelihood a patient may benefit from PD-L1/PD-1 immunotherapy drugs.3-6

VENTANA PD-L1 (SP263) Assay testing is performed on a BenchMark ULTRA instrument and is visualized using the OptiView DAB IHC Detection Kit.

Roche has developed a leading, comprehensive and differentiated lung cancer immunohistochemical portfolio, with biomarkers that support multiple guidelines for the diagnosis and stratification of lung cancers.7-9

On October 22, 2021 Thermo Fisher Scientific Inc. (the "Company") reported that issued $1,000,000,000 aggregate principal amount of 18-Month Floating Rate Senior Notes due 2023 (the "18-Month Floating Rate Notes"), $500,000,000 aggregate principal amount of Floating Rate Senior Notes due 2023 (the "2023 Floating Rate Notes"), $500,000,000 aggregate principal amount of Floating Rate Senior Notes due 2024 (the "2024 Floating Rate Notes" and, together with the 18-Month Floating Rate Notes and the 2023 Floating Rate Notes, the "Floating Rate Notes"), $1,350,000,000 aggregate principal amount of 0.797% Senior Notes due 2023 (the "2023 Notes") and $2,500,000,000 aggregate principal amount of 1.215% Senior Notes due 2024 (the "2024 Notes" and, together with the 2023 Notes, the "Fixed Rate Notes", and together with the Floating Rate Notes, the "Notes") in a public offering (the "Offering") pursuant to a registration statement on Form S-3 (File No. 333-229951) and a preliminary prospectus supplement and prospectus supplement related to the offering of the Notes, each as previously filed with the Securities and Exchange Commission (the "SEC") (Filing, 8-K, Thermo Fisher Scientific, OCT 22, 2021, View Source [SID1234591781]).

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The Notes were issued under an indenture, dated as of November 20, 2009 (the "Base Indenture"), and the Twenty-Third Supplemental Indenture, dated as of October 22, 2021 (the "Supplemental Indenture" and, together with the Base Indenture, the "Indenture"), between the Company, as issuer, and The Bank of New York Mellon Trust Company, N.A., as trustee.

The Floating Rate Notes are subject to a Calculation Agency Agreement, dated as of October 22, 2021, between the Company and The Bank of New York Mellon Trust Company, N.A., as calculation agent.

The 18-Month Notes will mature on April 18, 2023, the 2023 Floating Rate Notes will mature on October 18, 2023, the 2024 Floating Rate Notes will mature on October 18, 2024, the 2023 Notes will mature on October 18, 2023 and the 2024 Notes will mature on October 18, 2024. Interest on the Floating Rate Notes will be paid quarterly in arrears on January 18, April 18, July 18 and October 18 of each year, commencing on January 18, 2022. Interest on the Fixed Rate Notes will be paid semi-annually in arrears on April 18 and October 18 of each year, commencing on April 18, 2022.

Prior to October 18, 2022, the Company may redeem each series of Fixed Rate Notes, in whole at any time or in part from time to time, at a redemption price equal to the greater of (1) 100% of the principal amount of the Fixed Rate Notes to be redeemed and (2) the sum of the present values of the remaining scheduled payments of principal and interest in respect of the Fixed Rate Notes being redeemed (not including any portion of the payments of interest accrued but unpaid as of the date of redemption and assuming that such Fixed Rate Notes to be redeemed matured on October 18, 2022), discounted to the date of redemption on a semi-annual basis (assuming a 360-day year of twelve 30-day months), at the Treasury Rate (as defined in the Indenture) plus, in each case, 7.5 basis points and accrued and unpaid interest on the Fixed Rate Notes being redeemed, if any, to, but excluding, the date of redemption.

In addition, on and after April 18, 2022, with respect to the 18-Month Floating Rate Notes, and October 18, 2022, with respect to the 2023 Floating Rate Notes, the 2024 Floating Rate Notes and the Fixed Rate Notes, the Company may redeem some or all of each series of Notes at a redemption price equal to 100% of the principal amount of the Notes to be redeemed, plus accrued and unpaid interest, if any, to, but excluding the date of redemption.

In the event that the Company does not consummate the previously announced acquisition of PPD, Inc. (the "PPD Acquisition") on or prior to October 15, 2022 or the merger agreement related thereto is terminated at any time prior to such date, the Company will be required to redeem all of the 2023 Floating Rate Notes, the 2024 Floating Rate Notes, the 2023 Notes and the 2024 Notes (collectively, the "SMR Notes") on a special mandatory redemption date at a redemption price equal to 101% of the aggregate principal amount of the SMR Notes, plus accrued and unpaid interest, if any, to, but excluding, the special mandatory redemption date.

Upon the occurrence of a change of control (as defined in the Indenture) of the Company and a contemporaneous downgrade of the Notes below an investment grade rating by at least two of Moody’s Investors Service, Inc., S&P Global Ratings, a division of S&P Global, Inc., and Fitch Ratings, Limited, the Company will, in certain circumstances, be required to make an offer to purchase the Notes at a price equal to 101% of the principal amount of the Notes, plus any accrued and unpaid interest to, but excluding, the date of repurchase.

The Notes are general unsecured obligations of the Company. The Notes rank equally in right of payment with existing and any future unsecured and unsubordinated indebtedness of the Company and rank senior in right of payment to any existing and future indebtedness of the Company that is subordinated to the Notes. The Notes are also effectively subordinated to any existing and future secured indebtedness of the Company to the extent of the assets securing such indebtedness, and are structurally subordinated to all existing and any future indebtedness and any other liabilities of its subsidiaries.

The Indenture contains limited affirmative and negative covenants of the Company. The negative covenants restrict the ability of the Company and its subsidiaries to incur debt secured by liens on Principal Properties (as defined in the Indenture) or on shares of stock of the Company’s Principal Subsidiaries (as defined in the Indenture) and engage in sale and lease-back transactions with respect to any Principal Property. The Indenture also limits the ability of the Company to merge or consolidate or sell all or substantially all of its assets.

Upon the occurrence of an event of default under the Indenture, which includes payment defaults, defaults in the performance of affirmative and negative covenants, bankruptcy and insolvency related defaults and failure to pay certain indebtedness, the obligations of the Company under the Notes may be accelerated, in which case the entire principal amount of the Notes would be immediately due and payable.

Wilmer Cutler Pickering Hale and Dorr LLP, counsel to the Company, has issued an opinion to the Company, dated October 22, 2021, regarding the Notes. A copy of this opinion is filed as Exhibit 5.1 hereto.

The foregoing description is qualified in its entirety by reference to the full text of the Base Indenture and the Supplemental Indenture, which are filed with this report as Exhibits 4.1 and 4.2 hereto, respectively. Each of the foregoing documents is incorporated herein by reference.