Pharma Focus Asia

The Rapidly Evolving Landscape of Cancer Therapeutics

Rajesh Kumar, Assistant Professor of Pharmaceutical Sciences at Kerala University of Health Sciences

Seetha Harilal, Assistant Professor of Pharmacology at Kerala University of Health Sciences

The therapeutic strategies for cancer management have been rapidly evolving in the recent past, resulting in a significant improvement in the survival and quality of life of cancer patients. Advancements in therapeutic techniques resulted in cancer being considered a chronic disease rather than a fatal disease in the past. Therapeutic strategies are rapidly evolving towards shifting the status of cancer to a chronic and manageable disease with a possibility of cure.

Introduction

Cancer is considered as a common name to address a large group comprising more than 100 diseases affecting several parts of the body. All cancers show common characteristics such as the uncontrolled growth and proliferation of abnormal cells, infiltrating and spreading to different tissues and organs throughout the body, and destroying the normal cells and tissues. Cancer can begin in the epithelial tissue and is known as carcinomas, and when it begins in the connective or supportive tissue, they are called sarcomas. The blood cancers are known as leukemias, and when it begins in the plasma cells, they are known as myeloma. If the cancer begins in the lymphatic system, they are known as lymphoma, and if the cancer begins in the brain or spinal cord, they are known as cancers of the central nervous system. Cancers at the initial stages are currently considered as curable, and recurrent/metastatic cancers are considered chronic and difficult to manage, and needs multimodal therapies.

Molecular characterisation

The advancements in molecular characterisation of the disease, examining cancer at the molecular level, have resulted in the classification of a large number of cancer subtypes, and the current cancer therapies are also based on the cancer subtype, along with the stage and grade of the cancer. For example, in the case of colorectal cancer, the assessment of MMR status, KRAS,BRAF, and NRAS gene mutations, as well as the HER2/neu status to precisely identify the subtype, is considered indispensable for selecting the appropriate effective therapeutic approaches.

Multiple lines of therapy

Significant advancements have been made in cancer treatment modalities, resulting in the therapeutic continuum of care strategy with multiple lines of therapy leading to progression-free survival or cure in a large number of patients. The combinatorial strategies include surgery, chemotherapy, radiotherapy, targeted and biological therapy, as well as immunotherapy. For example, there have been limited treatment options for type II endometrial carcinoma, such as surgery, radiation, hormonal therapy, and the standard first-line chemotherapy with paclitaxel and carboplatin. The second-line chemotherapy in advanced/recurrent cancer utilised hormonal therapy, doxorubicin, and cisplatin without much benefits.

Currently, the advancements in therapeutic techniques resulted in several options in advanced/recurrent endometrial carcinoma after the treatment with surgery, adjuvant radiation or newer targeted brachytherapy, and neoadjuvant or adjuvant first-line chemotherapy with carboplatin and newer liposomal formulation of paclitaxel. The therapies include cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastasis, or cytoreductive surgery alone for advanced cancer, targeted biological therapy with antiangiogenic agents such as bevacizumab, mTOR inhibitors, and trastuzumab for HER2/neupositive cancer. The estrogen receptor and progesterone receptor (ER/PR) positive cancer can be managed with hormonal therapy such as tamoxifen. The second line chemotherapy has been almost replaced with immunotherapy utilising programmed cell death protein 1 (PD-1) inhibitor pembrolizumab or dostarlimab for mismatch repair deficient (dMMR)/ microsatellite instability-high (MSI-H) advanced cancer and pembrolizumab in combination with the multiple tyrosine kinase inhibitor lenvatinib for proficient mismatch repair (pMMR)/ microsatellite stable (MSS) advanced cancer, altogether resulting in a significant progression-free survival with a possibility of cure in several cancer patients.

Advancements in surgical techniques

Surgery is considered even now as the first line therapy in several types of cancers, but the advancements in surgical techniques, such as minimally invasive and precision surgery with the assistance of artificial intelligence, robotic techniques, and advanced molecular imaging, make it highly effective and minimises the side effects/complications after surgery. Surgical technique is also considered indispensable in the treatment of metastatic and advanced cancers, such as debulking or cytoreductive surgery, and can also be utilised along with specialised chemotherapy, such as the HIPEC in the case of peritoneal surface malignancies, which is considered a curative approach for the hitherto fatal disease.

Advancements in chemotherapy

Chemotherapy has improved significantly with the introduction of newer drugs, improved dosage regimens, targeted formulations, adjuvant and neoadjuvant administration, as well as combinatorial therapeutic strategies. An example of a novel delivery system is the widely used liposomal formulation of paclitaxel, which improves efficacy with a reduction in the side effects of chemotherapy. Chemotherapy can be administered during surgery in the hyperthermic form as HIPEC for the treatment of peritoneal surface malignancies, and the novel drug delivery system, pressurised intraperitoneal aerosol chemotherapy (PIPAC) is under development as a neoadjuvant treatment before cytoreductive surgery for the treatment of peritoneal metastasis. An example of newer combinatorial therapies includes the recent approval of dostarlimab-gxly along with paclitaxel and carboplatin for endometrial cancer. Another example is the recent approval of tipiracil and trifluridine along with bevacizumab for the treatment of metastatic colorectal cancer.

Advancements in radiation therapy

Radiotherapy has also been improved significantly with the development of targeted brachytherapy, precision radiotherapy, and proton therapy. Targeted brachytherapy has been utilised as an adjuvant in the treatment of endometrial cancers. The yttrium-90 internal radiation therapy utilises resin/glass microspheres embedded with yttrium-90 to target cancers such as liver metastasis of colorectal cancer, as well as neuroendocrine tumours. Proton therapy is a precise and targeted radiotherapy utilising proton beams, ensuring high energy radiation dose destroying the tumour cells while sparing the nearby tissues and organs, especially the vital organs, significantly minimising the adverse and harmful effects of radiotherapy, and is used in the treatment of several cancers. The radiosurgery known as gamma knife has been utilised in the treatment of brain tumours. Nuclear medicine witnessed a breakthrough with the development of radioligand imaging as well as therapy. The first radioligand therapy, pluvicto, utilising a radioisotope as well as a targeted ligand can target the radiation to specific cancer cells, minimising the damage to the nearby healthy tissue, got FDA approval in the past year for the treatment of prostate cancer.

Targeted/ biological therapy and immunotherapy

The advancements in therapeutic strategies such as immunotherapy and targeted therapy revolutionised cancer management, leading to progression-free survival and significantly improving the quality of life, especially in the case of advanced and incurable cancers. The advancements in omics techniques have resulted in the identification of several targets in cancer, and targeted therapy is now considered indispensable in the treatment of advanced cancers, and similar is the case with immunotherapy.

Immuno-oncology has developed rapidly, and immunotherapy is considered indispensable, particularly for the treatment of advanced cancers. The PD-1 inhibitor, monoclonal antibody Pembrolizumab revolutionised the treatment of several advanced cancers. Dostarlimab is also gaining importance in the treatment of multiple cancers. The immunotherapy Atezolizumab is an inhibitor of PD-L1, and tremelimumab is an inhibitor of CTLA-4. The targeted and biological drugs target specific pathways/proteins that are dysregulated in the particular cancer subtype and include anti-angiogenic drugs that prevent blood vessel formation in tumours, such as the widely used VEGF targeting bevacizumab. The mTOR inhibitors include drugs such as everolimus. The PI3K inhibitors include drugs such as alpelisib. Selpercatinib is a RET inhibitor, and lenvatinib is an example of a multiple tyrosine kinase receptor inhibitor. Trastuzumab deruxtecan, the antibody–drug conjugate, is a targeted therapy for HER2-positive cancers. The past year witnessed the approval of several breakthrough therapies in cancer, such as a new class in the immune checkpoint inhibitors, the LAG-3 inhibitor relatlimab, the first T cell receptor-based drug tebentafusp, and the first folate receptor-α targeting antibody-drug conjugate mirvetuximab soravtansine-gynx.

Local therapy

The locoregional therapies can be given in combination with surgery as well as chemotherapy or to provide a systemic therapy-free period to target and treat metastases, especially the liver and lung metastases, for long-term management of the disease, leading to progression-free survival. Thermal ablation, also known as laser interstitial thermal therapy, is utilised to treat liver metastasis, and other techniques include microwave ablation utilising microwaves and radiofrequency ablation utilising radio waves.Stereotactic body radiotherapy (SBRT) can also be utilised to manage liver and lung metastases, especially in the case of metastatic colorectal cancer. Transarterial radioembolisation is another technique to manage liver metastasis of colorectal cancer. Isolated Hepatic Perfusion (IHP) utilises high-dose heated chemotherapy targeting the liver metastasis. The transarterial chemoembolisation (TACE) combining the embolisation technique and local delivery of chemotherapeutic agents, as well as hepatic arterial infusion chemotherapy, which can deliver a high chemotherapy dose in the hepatic blood supply with the help of a pump, also targets the liver metastasis of colorectal cancer. Focal therapy, also called partial gland ablation, is a recent technique utilising real-time imaging to selectively destroy prostate tumours without destroying nearby healthy prostate tissue.

Personalised therapy

Several targeted therapies can be considered personalised therapy because, after the genetic testing, they identify and target the specific proteins and genes that are dysregulated in a particular cancer patient. The chimeric antigen receptor (CAR) T-cell therapy collects the patient’s immune cells, genetically altering them by introducing a new receptor that can identify the patient’s specific cancer cells and kill them without harming the normal cells. They are approved for the treatment of several cancers. Studies are also gaining momentum in developing personalised cancer vaccines as well as messenger RNA (mRNA) based cancer therapies after the success of COVID-19 vaccines, and many therapies are currently in the different stages of the drug development process.

Advancements in diagnostics and screening

The advancements in molecular as well as diagnostic technologies, including omics technologies, resulted in the development of various biomarkers aiding the diagnosis and surveillance of the disease, precise characterisation of the types and subtypes of the disease, treatment response prediction, and prognosis. Significant advancements have been made in endoscopic techniques, and scanning techniques have improved a lot, which can even be combined with treatment, as in the case of focal therapy. The utilisation of several approved biomarkers such as CA-125 (Ovarian), CA19-9 (Pancreatic), CA15-3, and CA27.29 (Breast), CEA, PSA (Prostate), thyroglobulin (Thyroid), α-fetoprotein (Testicular), circulating tumour cells such as cytokeratins 8, 18+, 19+, CD45, and EpCAM (Breast), DR-70 (Colorectal), AFP-L3 (Hepatocellular), p63 (Prostate), HE4 (Ovarian), OVA1 (Ovarian), Pro2PSA (Prostate), NMP22, and NuMA (Bladder), c-Kit (Gastrointestinal stromal), and fecal occult blood (Colorectal) revolutionised the landscape of cancer diagnostics, screening, and disease monitoring.

Table 1. FDA approved drugs in 2023 for the treatment of various cancers

FDA approved drugs

Date

Indication

Tucatinib+ trastuzumab

19-1-2023

RAS wild-type HER2-positive unresectable or metastatic colorectal cancer progressed following chemotherapy based on fluoropyrimidine, oxaliplatin, and irinotecan.

Zanubrutinib

19-1-2023

Small lymphocytic lymphoma (SLL) or Chronic lymphocytic leukemia (CLL)

Pembrolizumab

26-1-2023

In stage IB, II, or IIIA non-small cell lung cancer (NSCLC) as an adjuvant post resection and platinum-based chemotherapy

Pirtobrutinib

27-1-2023

In relapsed or refractory mantle cell lymphoma (MCL) post two lines of systemic therapy

Elacestrant

27-1-2023

ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer priorly received one line of endocrine-based therapy

Sacituzumab govitecan-hziy

3-2-2023

Unresectable locally advanced or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer priorly received endocrine-based therapy and in the metastatic setting, two additional systemic therapies

Dostarlimab-gxly

9-2-2023

dMMR recurrent or advanced endometrial cancer progressed on or post a prior platinum-containing regimen and ineligible for curative surgery or radiation

Abemaciclib+ endocrine therapy (tamoxifen or an aromatase inhibitor)

3-3-2023

HR-positive, HER2-negative, node-positive, early breast cancer at high risk of recurrence as an adjuvant therapy

Dabrafenib+ trametinib

16-3-2023

Low-grade glioma (LGG) with a BRAF V600E mutation in pediatric patients of 1 year age group who require systemic therapy

Retifanlimab-dlwr

22-3-2023

Metastatic or recurrent locally advanced Merkel cell carcinoma (MCC) in adults

Enfortumab vedotin-ejfv+pembrolizumab

3-4-2023

Locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy

Omidubicel-onlv

17-4-2023

Hematologic malignant pediatric or adult patients preparing for an umbilical cord blood transplantation post myeloablative conditioning

Polatuzumab vedotin-piiq+ rituximab, cyclophosphamide, doxorubicin,prednisone (R-CHP)

19-4-2023

High-grade B-cell lymphoma (HGBL), untreated diffuse large B-cell lymphoma (DLBCL)

Epcoritamab-bysp

19-5-2023

Relapsed or refractory DLBCL, HGBL post two or more lines of systemic therapy

Olaparib+abiraterone and prednisone

31-5-2023

BRCA-mutated, metastatic castration-resistant prostate cancer (mCRPC)

Glofitamab-gxbm

16-6-2023

Relapsed or refractory DLBCL, LBCL

Talazoparib+ enzalutamide

20-6-2023

Homologous recombination repair (HRR) gene-mutated mCRPC

Quizartinib+initially cytarabine and anthracycline followed by cytarabine alone

20-7-2023

Acute myeloid leukemia (AML)

Dostarlimab-gxly+ carboplatin and paclitaxel, followed by dostarlimab-gxly alone

31-7-2023

dMMR primary advanced or recurrent endometrial cancer

Trifluridine + tipiracil with bevacizumab

2-8-2023

Metastatic colorectal cancer which was previously treated with chemotherapy based on fluoropyrimidine, oxaliplatin and irinotecan

Pralsetinib

9-8-2023

Metastatic RET fusion-positive NSCLC

Talquetamab-tgvs

9-8-2023

Refractory or relapsed multiple myeloma adults received a minimum of four lines of therapy (proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody)

Niraparib + abiraterone acetate with prednisone

11-8-2023

BRCA-mCRPC

Elranatamab-bcmm

14-8-2023

Refractory or relapsed multiple myeloma adults received a minimum of four lines of therapy (proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody)

Melphalan      

14-8-2023

Uveal melanoma with hepatic metastases that is unresectable

Temozolomide

14-9-2023

Refractory anaplastic astrocytoma, newly diagnosed anaplastic astrocytoma adjuvant therapy, newly diagnosed glioblastoma treatment along with radiotherapy, and maintenance later on

 

Conclusion

With the advancements in therapeutic techniques, cancer, the hitherto considered deadly disease, is rapidly evolving towards achieving a status of chronic and manageable disease with a possibility of cure. But a major issue yet to be resolved is the development of acquired and adaptive resistance despite all the current therapeutic advancements. The advancements in therapeutic techniques, such as precision and personalized medicine for cancer, are also associated with exorbitant treatment costs, which a majority of society cannot afford, and are considered an emerging societal problem associated with the complexities of cancer care in the era of precision medicine. Addressing these specific issues, along with the rapid advancements in cancer therapeutics, makes the future promising for every cancer patient.

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Rajesh Kumar

Rajesh Kumar is an Assistant Professor of Pharmaceutical Sciences at Kerala University of Health Sciences, India. He has been teaching Diploma, Bachelor, and Doctor of Pharmacy students for several years and is actively involved in research. He has authored more than 19 papers and is a reviewer for Bentham Science Publishers. His research includes applying the principles of pharmaceutical sciences, omics technologies, computational biology, and bioinformatics in the broad areas of cancer research, ethnopharmacology, drug delivery, targeting, and formulations.

Seetha Harilal

Seetha Harilal is an Assistant Professor of Pharmacology at Kerala University of Health Sciences, India. She has several years of experience in teaching Diploma, Bachelor, and Doctor of Pharmacy students and is actively pursuing research. She has authored more than 22 papers and is a manuscript reviewer for Bentham Science Publishers, Frontiers in Public Health, Frontiers in Medicine, and Archives of Medical Research (Elsevier). Her research includes the diverse areas of pharmacology and therapeutics, phytopharmaceuticals, cancer research, neurological disorders, and the application of omics technologies, computational pharmacology, and bioinformatics.

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