On April 13, 2022 Bayer reported that the Center of Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) approved larotrectinib, under the brand name Vitrakvi, for the treatment of adult and pediatric patients with advanced solid tumors that harbor a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion (Press release, Bayer, APR 13, 2022, View Source;ref=irrefndcd [SID1234612317]). NTRK gene fusions should be identified by a sufficiently validated test. Larotrectinib is a first-in-class, highly selective TRK inhibitor exclusively designed to treat solid tumors that have an NTRK gene fusion, also known as TRK fusion solid tumors. This precision oncology treatment has demonstrated high response rates, durable responses and a favorable safety profile in adults and children with TRK fusion solid tumors. Vitrakvi is already approved in the U.S., Japan, countries of the European Union (EU), the UK and other markets around the world.

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"These clinically meaningful high response rates and durable responses as well as the favorable safety profile seen in larotrectinib trials involving patients from China and worldwide, support its efficacy and safety in adults and children," said Prof. Xu Ruihua, MD, PhD, President of Sun Yat-sen University Cancer Center. "A high unmet need remains for new and innovative cancer treatments in China. Advancements in precision therapies, like larotrectinib, demonstrate the importance of comprehensive genomic testing to uncover actionable oncogenic drivers and identify patients most likely to benefit from a targeted treatment approach."

"The approval of larotrectinib in China represents a meaningful advancement in cancer care with a highly innovative treatment option that addresses the genomic alteration driving solid tumor growth, regardless of the location where the tumor originates," said Christine Roth, Member of the Executive Committee of Bayer’s Pharmaceuticals Division and Head of Bayer’s Oncology Strategic Business Unit. "This approval further demonstrates Bayer’s commitment to delivering next-generation precision medicines to appropriate patients and clinicians."

The approval of larotrectinib in China is based on data from the Phase I trial of adult patients, the Phase II NAVIGATE trial in adult and adolescent patients and the Phase I/II pediatric SCOUT trial. In these trials, larotrectinib was investigated across more than 20 different histologies of solid tumors including lung cancer, thyroid cancer and colorectal cancer as well as salivary gland cancer and soft tissue sarcomas including infantile fibrosarcoma and gastrointestinal stromal tumors. The compound has shown powerful efficacy with high response rates and durable responses as well as a favorable safety profile across tumor types in adults and children with TRK fusion solid tumors. The clinical activity has been shown across multiple tumor types including primary central nervous system (CNS) tumors and brain metastases.

TRK fusion cancer is rare overall. It affects both children and adults and occurs in varying frequencies across various tumor types. TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing a chimeric TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering the activation of an intercellular signaling cascade leading to tumor growth and spread.

Larotrectinib will be available in China in oral capsules for adults and children. The CDE of China’s NMPA is currently reviewing its regulatory application as a liquid formulation.

About Vitrakvi (larotrectinib)
Vitrakvi (larotrectinib), a first-in-class oral TRK inhibitor, was exclusively designed to treat tumors that have an NTRK gene fusion. The compound has demonstrated high response rates and highly durable responses of over four years in adults and children with TRK fusion cancer, including central nervous system (CNS) tumors. To date, it has the largest dataset and longest follow-up data of any TRK inhibitor. The trials are still ongoing, with the latest dataset presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 and additional updates planned to be presented at upcoming scientific meetings.

Larotrectinib is approved under the brand name Vitrakvi in more than 40 countries around the world, including the U.S., countries of the European Union (EU), and most recently in China. Filings in other regions are underway or planned. In the EU, the product is approved for the treatment of adult and pediatric patients with solid tumors that harbor a Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion, who have a disease that is locally advanced, metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory treatment options.

About TRK Fusion Cancer
TRK fusion cancer occurs when an NTRK gene fuses with another unrelated gene, producing a chimeric TRK protein. The altered protein, or TRK fusion protein, becomes constitutively active or overexpressed, triggering a signaling cascade. These TRK fusion proteins are oncogenic drivers promoting cell growth and survival, leading to TRK fusion cancer. TRK fusion cancer is not limited to certain types of tissues and can occur in any part of the body. TRK fusion cancer occurs in various adult and pediatric solid tumors with varying frequency, including lung, thyroid, gastrointestinal (GI) cancers (colon, cholangiocarcinoma, pancreatic and appendiceal), sarcoma, CNS cancers (glioma and glioblastoma), salivary gland cancers (including secretory carcinoma of the salivary gland) and pediatric cancers (infantile fibrosarcoma and other soft tissue sarcomas).

About Oncology at Bayer
Bayer is committed to delivering science for a better life by advancing a portfolio of innovative treatments. The company has the passion and determination to develop innovative medicines that help improve and extend the lives of people living with cancer. The oncology franchise at Bayer includes six marketed products across various indications and several compounds in different stages of clinical development. Bayer focuses its research activities on first-in-class innovations across the following scientific platforms: Precision Molecular Oncology, Targeted Alpha Therapies, and Immuno-Oncology. Across the areas of focus, we have several prostate cancer treatments on the market or in development, with the goal of extending survival while limiting side effects of treatment throughout the different stages of the disease. Another key focus at Bayer is on innovative precision oncology treatments, with an approved TRK inhibitor exclusively designed to treat tumors that have an NTRK gene fusion, the oncogenic driver of tumor growth and spread. The company’s approach to research prioritizes targets and pathways with the potential to impact the way that cancer is treated.

On April 13, 2022 Helix BioPharma Corp. (TSX: "HBP") ("Helix" or the "Company"), a clinical-stage biopharmaceutical company developing unique therapies in the field of immuno-oncology, based on its proprietary technological platform DOS47, reported that it has received conditional approval from the Toronto Stock Exchange (the "TSX") to extend its previously announced Early Warrant Exercise Incentive Program (the "Incentive Program") from April 28, 2022 to May 31, 2022 (Press release, Helix BioPharma, APR 13, 2022, View Source [SID1234612284]). The Incentive Program is a period during which holders of the Company’s eligible common share purchase warrants ("Eligible Warrants") may take advantage of a temporary reduction in the exercise price of the Eligible Warrants to a price of C$0.26 "Incentive Exercise Price") and is more fully detailed in the Company’s March 11, 2022 news release. The extension of the Incentive Program is subject to final approval of the TSX.

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On April 13, 2022 InxMed Co., Ltd. reported that IN0018, its focal adhesion kinase (FAK) inhibitor, had been granted with Breakthrough Therapy Designation by the China National Medical Products Administration (Press release, InxMed, APR 13, 2022, View Source [SID1234612183]). This designation is based on the results of a Phase Ib/II clinical trial of IN10018 for platinum-resistant ovarian cancer, with the proposed indication for the treatment of platinum-resistant ovarian cancer in combination with PEG-liposomal doxorubicin. InxMed plans to disclose more data on IN10018 at the Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) in June 2022 and initiate a pivotal trial in the second half of the year.

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Breakthrough Therapy Designation aims to help companies work closely with authorities to accelerate research, development, and approval of innovative therapies that can address unmet medical needs. IN10018 received fast track designation from the U.S. Food and Drug Administration for the treatment of patients with platinum-resistant ovarian cancer in August 2021. InxMed will live up to the high expectations and strive to deliver the benefits of innovative drugs to patients as quickly as possible.

FAK is a non-receptor tyrosine kinase and transmitter that plays an important role in cell adhesion, migration, and regulation. It exhibits expression upregulation in multiple tumor types. Researchers have found that inhibiting the FAK signaling pathway can effectively reverse previously failed chemotherapy and targeted therapy caused by drug resistance and enhance the response and efficacy of immunotherapy for solid tumors.

IN10018 is a potent and highly selective adenosine triphosphate competitive FAK inhibitor, and InxMed has its exclusive global development and commercial operation rights. InxMed Nanjing Translational Medicine Center has conducted extensive original exploratory research on IN10018 and FAK targets and has published research results in renowned academic journals. Early clinical data on IN10018 showed its safety and efficacy in multiple tumor types, and the latest research results and preclinical data demonstrated that IN10018 can also be effective in combination therapies. It is expected to overcome the tumor-associated fibrosis barrier and improve local immunity, and therefore has the potential to act as an important anchor molecule in synergy with different therapeutic modalities including immunotherapy, chemotherapy, and targeted therapy.

InxMed set up a global clinical development program for IN10018. Clinical trials currently underway in the US and China are designed for platinum-resistant ovarian cancer, NRAS mutant metastatic melanoma, triple-negative breast cancer, head and neck cancer, pancreatic cancer, and other solid tumors that are still lacking effective treatment.

For more information, visit View Source

On April 13, 2022 Ascentage Pharma (6855.HK), a global biopharmaceutical company engaged in developing novel therapies for cancers, chronic hepatitis B (CHB), and age-related diseases, reported that it has presented the latest results from six preclinical studies of the company’s five investigational drug candidates: the Bcl-2 inhibitor lisaftoclax (APG-2575) and the MDM2-p53 inhibitor alrizomadlin (APG-115), two key candidates in the company’s apoptosis-targeted pipeline, as well as the FAK inhibitor APG-2449, the EED inhibitor APG-5918 and the KRAS inhibitor APG-1842, at the 2022 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Ascentage Pharma, APR 13, 2022, View Source;ascentage-pharma-presents-latest-results-from-six-preclinical-studies-at-aacr-annual-meeting-2022-301525433.html [SID1234612181]).

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The AACR (Free AACR Whitepaper) Annual Meeting is one of the world’s largest and long-standing scientific gatherings in the field of cancer research. Covering cutting-edge advances in all the areas of cancer research and innovation, the annual event attracts tremendous interest from the global cancer research community.

Dr. Yifan Zhai, Chief Medical Officer of Ascentage Pharma, said: "At this year’s AACR (Free AACR Whitepaper) Annual Meeting, we presented preclinical data that support potential combination approaches between our lead candidates with drugs of different targets and mechanism of actions. These studies represent our ongoing effort in addressing important unmet medical needs in cancer treatment. It is worth pointing out that the results from three preclinical studies of the MDM2-p53 inhibitor alrizomadlin have demonstrated broad therapeutic potential and highlighted a novel mechanism of action. Meanwhile, we also reported encouraging results supporting the upcoming clinical development of the EED inhibitor APG-5918. We will actively advance these programs to bring meaningful clinical benefits to patients."

The details of these posters presented at AACR (Free AACR Whitepaper) 2022 are as follows:

Drug Candidate

Presentation Title

Abstract#

Lisaftoclax & Alrizomadlin

Co-targeting MDM2-p53 and BCL-2 apoptosis pathways overcomes resistance conferred by acquired BCL-2 gene mutations in preclinical models

3964

Alrizomadlin

Inhibition of MDM2-p53 interaction by alrizomadlin (APG-115) induces pyroptotic cell death in gasdermin E (GSDME)-expressing cancer cells

2998

MDM2 inhibitor alrizomadlin (APG-115) stabilizes p53 and synergizes with proteasome inhibitors in multiple myeloma

5439

APG-2449

FAK inhibitor APG-2449 and CDK4/6 inhibitor palbociclib synergistically suppress mesothelioma tumor growth via autophagy induction

2563

APG-5918

Preclinical development of embryonic ectoderm development (EED) inhibitor APG-5918/EEDi-5273 for cancer therapy

3939

APG-1842

Development of covalent KRASG12C inhibitor APG-1842 for the treatment of solid tumors

2664

Co-targeting MDM2-p53 and BCL-2 apoptosis pathways overcomes resistance conferred by acquired BCL-2 gene mutations in preclinical models

Abstract/Poster Number: 3964
Introduction:
The BCL-2 inhibitor venetoclax, although efficacious in patients with chronic lymphocytic leukemia, meets significant resistance in a large number of patients due to acquired BCL-2 gene mutations. Among acquired mutations, those proximal to BH3 binding motifs (e.g., G101V, D103E, and V156D) have the most significant impact on BCL-2 binding to BH3-only pro-death proteins and BH3 mimetics (e.g., venetoclax). Hence, it is important to identify novel therapeutics that address this emerging unmet need.

Conclusions:
Our study demonstrates, alrizomadlin combined with lisaftoclax synergistically inhibited the proliferation of RS4:11-BCL-2 mutant cell lines and the growth of cell-derived xenografts in vivo. Co-targeting BCL-2 and MDM2-p53 apoptosis pathways represents a new and effective strategy to overcome drug resistance conferred by clinically BCL-2 gene mutations.

Inhibition of MDM2-p53 interaction by alrizomadlin (APG-115) induces pyroptotic cell death in gasdermin E (GSDME)-expressing cancer cells

Abstract/Poster Number: 2998
Introduction:
The mouse double minute-2 (MDM2)-p53 inhibitor alrizomadlin (APG-115) is an investigational agent known to induce apoptosis of TP53-wild type cancer cells (Aguilar et al, J Med Chem 2017). Emerging evidence suggests that activation of p53 by alrizomadlin also promotes antitumor immunity in the tumor microenvironment (Fang et al, JITC 2019; Zhou et al, Nat Immunol 2021), but the links between these processes are not yet completely understood. Pyroptosis refers to inflammatory programmed cell death. Central to this process is the family of gasdermins, which can form pores in cell plasma membranes, resulting in lysis and release of immune stimulants. In cells expressing these proteins, GSDME can be cleaved by caspase-3, which converts noninflammatory apoptosis to pyroptosis (Zhang et al, Nature 2020). In this context, caspase-3/GSDME appears to represent a switch between apoptosis and pyroptosis. Given that alrizomadlin elicits its apoptogenic activity primarily by activating caspase-3, we hypothesized that the MDM2-p53 inhibitor might also induce pyroptosis in GSDME-expressing cells by cleaving caspases.

Conclusions:
Our study demonstrates that, in addition to apoptosis, MDM2-p53 inhibitor alrizomadlin induces caspase-mediated pyroptosis in GSDME-expressing cancer cells. In this study, we reveal for the first time that apoptosis-inducing, alrizomadlin induces both apoptosis and pyroptosis in GSDME-expressing cancer cells. GSDME-dependent pyroptosis is a previously unrecognized mechanism of action for alrizomadlin to exert antitumor immunity, with potentially important implications for clinical development of therapy involving MDM2-p53 inhibition.

MDM2 inhibitor alrizomadlin (APG-115) stabilizes p53 and synergizes with proteasome inhibitors in multiple myeloma

Abstract/Poster Number: 5439
Introduction:
Multiple myeloma (MM) accounts for about 2% of all cancers and 18% of all hematologic malignancies in the US. Recent therapeutic advances (e.g., immunomodulators, proteasome inhibitors, monoclonal antibodies) have improved outcomes, but MM inevitably relapses and is considered incurable. Genomic analysis shows that the TP53 gene encoding tumor suppressor protein p53 is infrequently mutated in patients with MM, of whom about 82% retain wildtype (WT) TP53. Mouse double minute 2 (MDM2) is an E3 ubiquitin ligase that inhibits p53 via proteasome degradation. Proteasome inhibitors might help to stabilize p53 and synergize with MDM2 inhibitors. Therefore, MDM2 inhibitors that activate p53 might constitute an attractive pharmacologic approach to MM. Alrizomadlin is an investigational, novel small molecule targeting the p53/MDM2 interaction and is in clinical development for solid and hematologic cancers. This study aimed to evaluate whether alrizomadlin can potentiate the antitumor effects of proteasome inhibitors in MM.

Conclusions:
The results demonstrate that the combination of MDM2 inhibitor alrizomadlin and proteasome inhibitors have synergistic antitumor effects on MM tumors harboring WT TP53 in animal models. These data warrant clinical studies to test this novel therapeutic option for patients with refractory MM.

FAK inhibitor APG-2449 and CDK4/6 inhibitor palbociclib synergistically suppress mesothelioma tumor growth via autophagy induction

Abstract/Poster Number: 2563
Introduction:
Malignant mesothelioma is a rare but highly lethal malignancy, with a 5-year survival rate of less than 10%. Among the most common genomic abnormalities are alterations of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) and neurofibromin 2 (NF2). Mesothelioma cells lacking expression of CDKN2A/B or NF2 are reported to be sensitive to CDK4/6 or focal adhesion kinase (FAK) inhibition. In this study, APG-2449 as a clinical stage FAK/ALK/ROS1 multi-kinase inhibitor combined with CDK4/6 inhibitor palbociclib demonstrated anti-tumor activity.

Conclusions:
These results demonstrate that the combination of palbociclib and APG-2449 synergistically inhibits tumor growth in mesothelioma and such effect is mediated by induced autophagy and enhanced cellular senescence. The preclinical study suggests that APG-2449 combined with CDK4/6 inhibitors may have therapeutic potential in mesothelioma and may warrant future clinical development.

Preclinical development of embryonic ectoderm development (EED) inhibitor APG-5918/EEDi-5273 for cancer therapy

Abstract/Poster Number: 3939
Introduction:
Three core components constitute the polycomb repressive complex 2 (PRC2), a multiprotein complex that catalyzes the methylation of histone H3 at lysine 27 (H3K27me3): enhancer of zeste homolog 2 (EZH2), embryonic ectoderm development (EED) and suppressor of zeste 12 protein homolog (SUZ12). Dysregulated function of PRC2 has been implicated in the development of a variety of cancer types. With the use of tazemetostat, an EZH2 inhibitor, inhibition of PRC2 functions has been proven to be a successful cancer therapeutic strategy. Nevertheless, the activity of an EZH2 inhibitor might be compensated due to acquired resistance through secondary mutations in EZH2 or its paralog EZH1. Because binding of EED with trimethylated H3K27 (H3K27me3) is the prerequisite for the activation of the methyltransferase activity of EZH2, allosterically targeting EED is emerging as a novel approach to inhibit PRC2. APG-5918/EEDi-5273 has been reported as a novel, bioactive, and potent EED inhibitor. In this study, we further characterized APG-5918 for cancer therapy in a preclinical setting.

Conclusions:
APG-5918 was thoroughly characterized in the preclinical stage, with potent biochemical binding activity to EED protein, in vitro anti-proliferatively activity, and in vivo antitumor activities. APG-5918 showed definitive in vitro and in vivo target engagement and on-target antitumor activity. APG-5918 demonstrated strong PD/PK correlation in mice bearing KARPAS-422 xenograft tumors. APG-5918 appeared to be similar or more potent than MAK683, an EED inhibitor under clinical development, in terms of biochemical, in vitro, and in vivo activities. In summary, our results suggest potential utility of APG-5918 in cancer therapy and it deserves further clinical investigation.

Development of covalent KRASG12C inhibitor APG-1842 for the treatment of solid tumors

Abstract/Poster Number: 2664
Introduction:
The KRAS gene is frequently mutated in human cancers, and the KRASG12C mutation occurs in approximately 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other solid tumors. KRASG12C small molecule inhibitors, AMG510 and MRTX849, have been investigated as treatment options for solid tumors with the KRAS G12C mutation. In this study, APG-1842 was characterized as a potent, selective, and covalent KRASG12C inhibitor with demonstrated inhibition on KRAS-dependent signaling and anti-tumor activity both in vitro and in vivo.

Conclusions:
Collectively, these results demonstrate that APG-1842 is a potent, bioavailable, and highly selective KRASG12C inhibitor. Our data provide the preclinical evidence for clinical development of APG-1842 in patients with KRASG12C-mutant solid tumors.

On April 13, 2022 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, metabolic, autoimmune and other major diseases, reported that the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) has granted Breakthrough Therapy Designation (BTD) for IBI310 in combination with sintilimab for the treatment of patients with recurrent or metastatic cervical cancer (Press release, Innovent Biologics, APR 13, 2022, View Source [SID1234612178]).

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The NMPA BTD for IBI310 was based on results from First part of a Phase 2 trial (CDE Registration No. CTR20202017). This study enrolled 205 patients in patients with advanced cervical cancer. The safety profile in this study was consistent with that observed in previously reported studies, and no additional safety signals were identified for the combination of IBI310 and sintilimab. Relevant study results will be published at an upcoming medical conference in 2022.

"We are glad to see the NMPA grant Breakthrough Therapy Designation based on the results of First part of Phase 2 data of IBI310," said Dr. Hui Zhou, Senior Vice President of Innovent. "Patients with advanced cervical cancer currently have limited treatment options. Patients treated with chemotherapy show limited clinical benefit and the overall survival is limited to a few months. The results of First part of the Phase 2 study of IBI310 in combination with sintilimab show potential for this combination as a new treatment option for patients in need. We look forward to obtaining more data from the ongoing pivotal Phase 2 trial which may support a future regulatory application in China for IBI310 in combination with sintilimab in recurrent or metastatic cervical cancer."

NMPA Breakthrough Therapy Designation is intended to facilitate and expedite the development and review of an investigational drug to treat a serious disease or condition when preliminary clinical evidence indicates that the drug has demonstrated substantial improvement over current therapies. The BTD will not only qualify a drug candidate to receive status for rapid review by the CDE, but it will also allow the sponsor to obtain timely advice and communication from the CDE to accelerate the approval and launch to address the unmet clinical need of patients at an accelerated pace. Click here for the published list of drugs which have been granted BTD by NMPA.

About Cervical Cancer

According to GLOBOCAN 2020 report，there were approximately 110,000 new cases and 60,000 death cases of cervical cancer in China in 2020, making cervical cancer one of the most common malignant tumor types in gynecology. There is an urgent clinical need for more treatment options, especially for recurrent or metastatic cervical cancer, as traditional treatments such as surgery, chemotherapy and radiotherapy are ineffective with a low overall survival rate for those patients with recurrent or metastatic cervical cancer.

About IBI310

IBI310 is a recombinant fully-human IgG1 monoclonal antibody against cytotoxic T lymphocytic associated antigen 4 (CTLA-4) developed independently by Innovent Biologics. IBI310 can bind to CTLA-4 molecules and block the inhibition of T cells induced by CTLA-4, thereby leading to T cell activation and proliferation, and enhancing the anti-tumor activity of immune system to achieve the goal of tumor treatment.

About Sintilimab

Sintilimab, marketed as TYVYT (sintilimab injection) in China, is a PD-1 immunoglobulin G4 monoclonal antibody developed by Eli Lilly and Company and Innovent. Sintilimab is a type of immunoglobulin G4 monoclonal antibody, which binds to PD-1 molecules on the surface of T-cells, blocks the PD-1 / PD-Ligand 1 (PD-L1) pathway, and reactivates T-cells to kill cancer cells. Innovent is currently conducting more than 20 clinical studies of sintilimab to evaluate its safety and efficacy in a wide variety of cancer indications, including more than 10 registrational or pivotal clinical trials.

In China, sintilimab has been approved and included in the National Reimbursement Drug List (NRDL) for four indications, including:

The treatment of relapsed or refractory classic Hodgkins lymphoma after two lines or later of systemic chemotherapy;
In combination with pemetrexed and platinum chemotherapy, for the first-line treatment of non-squamous non-small cell lung cancer lacking EGFR or ALK driver mutations;
In combination with gemcitabine and platinum chemotherapy, for the first-line treatment of squamous non-small cell lung cancer;
In combination with BYVASDA (bevacizumab biosimilar injection) for the first-line treatment of unresectable or advanced hepatocellular carcinoma.
Additionally, Innovent currently has three regulatory submissions under review in China’s NMPA for sintilimab:

In combination with cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil for the first-line treatment of esophageal squamous cell carcinoma;
In combination with chemotherapy for the first-line treatment of unresectable, locally advanced, recurrent or metastatic gastric or gastroesophageal junction adenocarcinoma;
In combination with bevacizumab biosimilar and chemotherapy for EGFR-mutated non-squamous NSCLC following EGFR-TKI treatment.
Additionally, two clinical studies of sintilimab have met their primary endpoints:

Phase 2 study as second-line treatment of esophageal squamous cell carcinoma;
Phase 3 study as second-line treatment for squamous NSCLC with disease progression following platinum-based chemotherapy.