№13 Sh. M. Khubiev

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CHERKESSK · 2026
Pharmacotherapy in
Oncology
Current Status and Future Directions
Sh. M. Khubiev, PhD (Medicine), Associate
Professor
Head of the Department of Pharmacology · North Caucasus State Academy

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0 · INTRODUCTION
OUTLINE
What we will cover
01
Foundations
1. Cancer burden and the evolution of therapy
02
New horizons
5. Antibody–drug conjugates, bispecific antibodies,
cellular and radioligand therapies
2. Cytotoxic and endocrine therapy
6. Clinical pharmacology and supportive care
3. Molecular diagnostics and targeted therapy
7. Future directions and conclusions
4. Immunotherapy
Sh. M. Khubiev · Pharmacotherapy in Oncology
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1 · CANCER BURDEN AND
EVOLUTION
EPIDEMIOLOGY · GLOBOCAN 2024
The scale of the challenge
20.6
9.8
34.4
+67%
million new cases, 2024
million deaths, 2024
million cases per year by
2050
increase by 2050
Sung H. et al. CA Cancer J Clin. 2026;76(4):e70090 (GLOBOCAN 2024)
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1 · CANCER BURDEN AND
EVOLUTION
EVOLUTION
From cytotoxic “poisons” to precision targets
1940s
1960s–1990s
2001
2011
2017–2025
Nitrogen mustards, antifolates
Platinum agents, taxanes
Imatinib
Ipilimumab
CAR-T, next-generation ADCs
Sh. M. Khubiev · Pharmacotherapy in Oncology
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1 · CANCER BURDEN AND
EVOLUTION
CLASSIFICATION
Five classes of anticancer agents
Modern treatment often combines agents from several classes.
Class
Mechanism of action
Examples
Cytotoxic agents
Disruption of DNA, mitosis or nucleotide synthesis
Cisplatin, paclitaxel, fluorouracil
Endocrine agents
Blockade of hormone signaling
Tamoxifen, letrozole, enzalutamide
Targeted agents
Inhibition of oncogenic drivers
Osimertinib, olaparib, trastuzumab
Immuno-oncology agents
Release of antitumor immune inhibition
Pembrolizumab, nivolumab
New platforms
Payload delivery, T-cell redirection
ADCs, bispecific antibodies, CAR-T cells,
radioligands
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2 · CONVENTIONAL THERAPY
CYTOTOXIC THERAPY
Chemotherapy remains
the backbone
• Backbone of neoadjuvant, adjuvant and palliative
treatment
• Basis for combinations with immunotherapy and
targeted agents
• Dose-dense and metronomic regimens
• De-escalation where safe
Sh. M. Khubiev · Pharmacotherapy in Oncology
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2 · CONVENTIONAL THERAPY
PHARMACOGENETICS
Genotyping before the first dose
01
DPYD → fluoropyrimidines
Enzyme deficiency: severe fluorouracil and capecitabine
toxicity; dose reduction
02
UGT1A1*28 → irinotecan
Risk of neutropenia and diarrhea; adjust the starting dose
03
TPMT / NUDT15 → thiopurines
Mercaptopurine-induced myelosuppression; genotypeguided dosing
CPIC: Amstutz U. et al. Clin Pharmacol Ther. 2018;103:210–216
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2 · CONVENTIONAL THERAPY
ENDOCRINE THERAPY
Hormone-dependent tumors
Breast cancer
Prostate cancer
Tamoxifen, aromatase inhibitors
Fulvestrant; elacestrant for ESR1 mutations
+ CDK4/6 inhibitors
+ PI3K/AKT inhibitors
Androgen deprivation
Abiraterone, enzalutamide
Apalutamide, darolutamide
Early combination therapy
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3 · TARGETED THERAPY
MOLECULAR DIAGNOSTICS
No targeted therapy without a biomarker
01
02
03
Sample
Analysis
Decision
Tissue biopsy or circulating tumor DNA analysis
Immunohistochemistry, PCR, sequencing;
target actionability assessed using ESCAT
Drug selection and resistance monitoring
Mateo J. et al. Ann Oncol. 2018;29:1895–1902 (ESCAT)
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3 · TARGETED THERAPY
TARGETED THERAPY · LUNG CANCER
NSCLC: a mosaic of molecular subtypes
Molecular profiling is standard before first-line treatment.
Target
Agents
Comment
EGFR
Osimertinib
FLAURA: PFS 18.9 vs 10.2 months
ALK
Alectinib, lorlatinib
Active against brain metastases
ROS1
Crizotinib, entrectinib
Rare but important driver
KRAS G12C
Sotorasib, adagrasib
Previously “undruggable” target
MET ex14 / RET
Capmatinib, tepotinib / selpercatinib
Essential components of sequencing panels
Soria J.C. et al. NEJM 2018; Skoulidis F. et al. NEJM 2021
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3 · TARGETED THERAPY
TARGETED THERAPY · BREAST CANCER AND BRCA
Key targets in breast cancer
Receptors, HER2
and DNA repair
guide treatment
CDK4/6 · HORMONE-DEPENDENT CANCER
Palbociclib, ribociclib, abemaciclib
PI3K/AKT
Alpelisib, capivasertib, inavolisib
HER2
Trastuzumab, pertuzumab, tucatinib
PARP
Olaparib, niraparib — BRCA1/2 mutations, DNA repair
deficiency
Sh. M. Khubiev · Pharmacotherapy in Oncology
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3 · TARGETED THERAPY
TARGETED THERAPY · HEMATOLOGIC MALIGNANCIES
Hematology: chemotherapy-free treatment
With imatinib, life expectancy in CML approaches that of the general population.
Target
Agents
Indications
BCR-ABL
Imatinib, dasatinib, nilotinib
Chronic myeloid leukemia
BTK
Ibrutinib, acalabrutinib, zanubrutinib
Chronic lymphocytic leukemia, lymphomas
BCL-2
Venetoclax
Chronic lymphocytic leukemia, acute myeloid
leukemia
FLT3 / IDH
Gilteritinib / ivosidenib, enasidenib
Acute myeloid leukemia
Sh. M. Khubiev · Pharmacotherapy in Oncology
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3 · TARGETED THERAPY
ANTIANGIOGENIC THERAPY
Targeting tumor vasculature
Antiangiogenic agents
Synergy with immunotherapy
Targets: VEGF and its receptors
Bevacizumab, ramucirumab
Sorafenib, lenvatinib, cabozantinib
Risks: hypertension, proteinuria, bleeding
Atezolizumab + bevacizumab — liver cancer
Lenvatinib + pembrolizumab — kidney cancer
Vascular normalization
Greater T-cell infiltration
Finn R.S. et al. NEJM 2020;382:1894–1905 (IMbrave150)
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3 · TARGETED THERAPY
TUMOR-AGNOSTIC THERAPY
Biomarkers matter more than tumor site
NTRK
MSI-H
BRAF
Larotrectinib, entrectinib
Pembrolizumab, dostarlimab
V600E: dabrafenib + trametinib
RET
HER2
Genome
Selpercatinib
Trastuzumab deruxtecan
Prerequisite: tumor sequencing
Sh. M. Khubiev · Pharmacotherapy in Oncology
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3 · TARGETED THERAPY
DRUG RESISTANCE
Tumors respond through evolution
01
Mechanisms
• Secondary target mutations: EGFR T790M, C797S;
ALK G1202R
02
Strategies
• Next-generation agents
• Rational combinations
• Bypass pathways: MET, HER2 amplification
• Repeat biopsy and circulating tumor DNA analysis
• Transformation to small-cell carcinoma
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4 · IMMUNOTHERAPY
IMMUNOTHERAPY
Immune checkpoint
inhibitors
• Release the PD-1/PD-L1, CTLA-4 and LAG-3
“brakes” on T cells
• Nivolumab, pembrolizumab, atezolizumab,
durvalumab, ipilimumab, relatlimab
• Melanoma, nivolumab + ipilimumab: median OS
71.9 vs 19.9 months
Wolchok J.D. et al. NEJM 2025;392:11–22 (CheckMate 067)
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4 · IMMUNOTHERAPY
IMMUNOTHERAPY IN EARLY-STAGE DISEASE
Improving the chance of cure
24%
100%
86.6%
complete tumor response, lung cancer
complete response, rectal cancer
5-year survival: breast cancer
Forde P.M. 2022, 2025; Cercek A. 2022, 2025; Schmid P. 2024 — NEJM
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4 · IMMUNOTHERAPY
IMMUNOTHERAPY BIOMARKERS
Who benefits from immunotherapy?
There is no perfect
biomarker yet
PD-L1
Different assays, scoring systems and cutoffs
MSI-H
The most reliable predictor of response
TUMOR MUTATIONAL BURDEN
More mutations — more neoantigens
THE FUTURE
Tumor microenvironment, microbiome, circulating
tumor DNA
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4 · IMMUNOTHERAPY
IMMUNOTHERAPY SAFETY
Immune-related adverse events
Early recognition is essential for safe continuation of treatment.
Organ
Manifestations
Management
Skin
Rash, pruritus, vitiligo
Topical treatments; systemic corticosteroids for
severe cases
Gut and liver
Colitis, hepatitis
Corticosteroids; for colitis: infliximab, vedolizumab
Endocrine system
Thyroiditis, hypophysitis
Hormone replacement, often lifelong
Lungs
Pneumonitis
Hold or discontinue immunotherapy; corticosteroids
Heart, muscles
Myocarditis, myositis
Urgent high-dose corticosteroids
Schneider B.J. et al. J Clin Oncol. 2021;39:4073–4126 (ASCO)
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5 · NEW PLATFORMS
NEW PLATFORMS
Antibody–drug conjugates: targeted delivery
01
Binding
Antibody recognizes an antigen: HER2, TROP-2, Nectin-4
02
Internalization
The complex is taken up by the cell
03
Release
The linker is cleaved; the payload kills the cell
04
Bystander effect
Also targets neighboring cells
EV-302: OS 31.5 vs 16.1 months · DESTINY-Breast04: the HER2-low category
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5 · NEW PLATFORMS
BISPECIFIC ANTIBODIES
T cells and tumors: direct contact
01
Agents
02
Risks and monitoring
• Blinatumomab — acute lymphoblastic leukemia
• Cytokine release syndrome
• Teclistamab — multiple myeloma
• Neurotoxicity
• Tarlatamab — small-cell lung cancer
• Infections, hypogammaglobulinemia
• Tebentafusp — uveal melanoma
• Step-up dosing
Mountzios G. et al. NEJM 2025;393:349–361 (DeLLphi-304)
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5 · NEW PLATFORMS
CELLULAR THERAPY
CAR-T: a “living drug”
01
02
03
Collection
Preparation
Infusion
Apheresis and genetic modification
Cell expansion, lymphodepletion
Single infusion; monitor for cytokine release
syndrome
Lymphomas, ALL, myeloma · Tumor-infiltrating lymphocytes: lifileucel (2024)
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5 · NEW PLATFORMS
RADIOLIGAND THERAPY
Theranostics: “see what you
treat”
Lutetium-177 agents are already in use; actinium-225 is on the horizon
Sartor O. et al. NEJM 2021;385:1091–1103 (VISION)
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6 · CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
Safety lies in the details
Managing
interactions and
adherence
CYP3A4 ENZYMES
Inhibitors and inducers alter targeted drug
concentrations
GASTRIC ACIDITY
Proton pump inhibitors reduce absorption of some
agents
MONITORING
Therapeutic drug monitoring
SPECIAL POPULATIONS
Older adults; renal and hepatic impairment
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6 · CLINICAL PHARMACOLOGY
SUPPORTIVE CARE
Keeping treatment on track
Supportive care determines whether patients receive the full planned treatment.
Problem
Interventions
Comment
Nausea and vomiting
Aprepitant + ondansetron + dexamethasone +
olanzapine
Highly emetogenic chemotherapy
Neutropenia
Filgrastim, pegfilgrastim
Prevention of febrile neutropenia
Cardiotoxicity
Ejection fraction monitoring, cardioprotection
Anthracyclines, anti-HER2 therapy
Thrombosis
Heparins, direct anticoagulants
Cancer-associated thrombosis
Pain and bone disease
Analgesics, zoledronate, denosumab
Bone metastases
Hesketh P.J. et al. JCO 2020 (ASCO); Lyon A.R. et al. Eur Heart J 2022 (ESC)
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7 · FUTURE DIRECTIONS AND
CONCLUSIONS
FUTURE DIRECTIONS
What comes next
01
New targets
Pan-RAS inhibitor daraxonrasib: doubled survival in
pancreatic cancer
02
New modalities
mRNA vaccine intismeran: 49% lower melanoma recurrence
risk at 5 years; PD-1×VEGF bispecifics
03
New approaches
Circulating tumor DNA-guided treatment; artificial
intelligence
O'Reilly E.M. NEJM 2026 (RASolute 302); Khattak A. JCO 2026 (KEYNOTE-942); Tie J. NEJM 2022 (DYNAMIC)
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7 · FUTURE DIRECTIONS AND
CONCLUSIONS
CONCLUSIONS
Key takeaways
01
From cytotoxicity to precision therapy
02
Immunotherapy delivers long-term survival and moves into early-stage disease
03
ADCs, bispecifics, CAR-T and radioligands are becoming new standards
04
Clinical pharmacology and pharmacogenetics play a growing role
05
The future: personalized combinations guided by liquid biopsy
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7 · FUTURE DIRECTIONS AND
CONCLUSIONS
REFERENCES
Key sources
EPIDEMIOLOGY
Sung H. et al., 2026 (GLOBOCAN 2024)
CA Cancer J Clin 76:e70090
TARGETED THERAPY
Soria 2018; Skoulidis 2021; Finn 2020
NEJM
IMMUNOTHERAPY
Wolchok 2025; Forde 2022, 2025; Cercek 2022, 2025
NEJM
NEW PLATFORMS
Modi 2022; Powles 2024; Mountzios 2025; Sartor 2021
NEJM
FUTURE DIRECTIONS
O'Reilly 2026; Khattak 2026; Tie 2022
NEJM; JCO
GUIDELINES
CPIC 2018; ASCO 2021; ESC 2022
RUSSCO; Russian Ministry of Health guidelines
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