Pancreatic Cancer: R&D Landscape, Market Analysis & Amplia Therapeutics (ASX: ATX) Deep Dive

As of March 2026

Table of Contents

1. Executive Summary
2. Epidemiology
3. Market Size & Forecasts
4. Diagnosis & Staging
5. Current Treatment Landscape by Line of Therapy
6. R&D Pipeline: Drugs in Active Development
7. The KRAS Revolution
8. Novel Modalities & Emerging Approaches
9. Unmet Needs & Biological Challenges
10. Surgical Landscape
11. Key Opinion Leader Views
12. Comparison with Other Cancers
13. Patient Journey & Burden
14. Regulatory Landscape
15. Amplia Therapeutics (ASX: ATX) — Deep Dive
16. Investment Implications

1. Executive Summary

Pancreatic cancer remains the deadliest major malignancy, with a 5-year survival rate stalled at 13% and over 80% of patients diagnosed at advanced stages when curative surgery is impossible. It is projected to become the second leading cause of cancer death in the US by 2030. The global therapeutics market is approximately $3–5 billion (2024–2025) and projected to reach $6–7 billion by 2030.

After decades of incremental progress, the field is experiencing its most active period of R&D innovation:

• NALIRIFOX (FDA approved Feb 2024) is the first new first-line approval for metastatic PDAC in over a decade
• Daraxonrasib (Revolution Medicines) — a RAS(ON) multi-selective inhibitor — is showing transformative Phase 1/2 data (47% ORR in first-line monotherapy) and has FDA Breakthrough Therapy Designation
• KRAS inhibitors broadly are finally making the "undruggable" target druggable, covering ~90% of PDAC mutations
• FAK inhibitors are emerging as a stromal remodeling strategy, with Verastem's defactinib receiving the first-ever FDA approval (May 2025, in LGSOC) and Amplia Therapeutics' narmafotinib showing compelling Phase 2a data in first-line PDAC
• AI-augmented imaging and liquid biopsy technologies are making early detection feasible for the first time
• mRNA vaccines, bispecific antibodies, ADCs, and radioligand therapies are all entering clinical testing

This note provides a comprehensive survey of the entire pancreatic cancer landscape — epidemiology, market dynamics, treatment paradigms, R&D pipeline, biological challenges, and the competitive field — followed by an in-depth analysis of Amplia Therapeutics (ASX: ATX), a micro-cap Australian biotech developing narmafotinib (AMP945), a "best-in-class" FAK inhibitor showing early but noteworthy signals in first-line metastatic PDAC.

2. Epidemiology

United States Incidence & Mortality (2025 Estimates)

Source: SEER Cancer Stat Facts; ACS Cancer Statistics 2025

Global Burden

The global burden of pancreatic cancer has more than doubled in recent decades, driven by aging populations, rising obesity, and increasing diabetes prevalence.

Source: PMC - Unraveling the Burden of Pancreatic Cancer

5-Year Survival Rate: Historical Trend

Key insight: The 5-year survival rate doubled from 6% to 12% between 2004-2015, but has plateaued at 13% as of the most recent ACS data (January 2025). For pancreatic ductal adenocarcinoma specifically (90% of cases), 5-year survival is only 8%.

Stage-specific survival trends (2004 to 2015): - Localized: 24% → 46% (major improvement driven by better surgical technique and adjuvant therapy) - Regional: 9% → 15% - Distant: 2% → 3% (minimal improvement — where most patients are diagnosed)

Source: PanCAN Press Release

Rising Incidence in Younger Populations

This is one of the most concerning epidemiological trends:

• Age-adjusted incidence rates have risen an average of 0.9% per year over 2013-2022 across all ages
• Between 2001-2018, incidence for people younger than 55 increased by 1.29% annually vs. 1.11% for those older than 55
• In the youngest age group (15-34 years), the annual average percentage change was 6.45% in women and 2.97% in men
• There is a striking gender disparity: incidence rise of 2.36% in young women vs. 0.62% in young men
• 25-30% of early-onset pancreatic cancer cases involve a germline mutation (BRCA1/2, CDKN2A, mismatch repair genes)
• Contributing factors: rising obesity rates, increasing type 2 diabetes in younger populations, and possibly environmental exposures

A 2024 study specifically demonstrated the disproportionate rise in younger women is indeed driven by adenocarcinoma, not neuroendocrine tumors.

Source: Dana-Farber - Rising Pancreatic Cancer Rates; Lancet Gastroenterology

Geographic Variation

Highest incidence regions (age-standardized rates): - Hungary: 13.7/100,000 (males), 9.2/100,000 (females) - Uruguay: 12.8/100,000 (males) - Western Europe, High-income North America, High-income Asia-Pacific: consistently highest rates

Lowest incidence regions: - Sub-Saharan Africa: ~0.5/100,000 in males - South Asia (India, Sri Lanka, Pakistan): lowest rates in females

Incidence is strongly correlated with the Socio-Demographic Index (SDI). The gap is narrowing as middle-income countries adopt Western dietary patterns.

3. Market Size & Forecasts

Global Pancreatic Cancer Therapeutics Market

Consensus range: The global pancreatic cancer therapeutics market was approximately $3-5 billion in 2024-2025 and is projected to reach $6-7 billion by 2030, representing a CAGR of approximately 7-13%.

US Market

• The US represents approximately 40-45% of the global market
• US market estimated at $1.5-2.2 billion in 2025, projected to reach $5.46 billion by 2035

Key Market Growth Drivers

1. Rising incidence: 0.9% annual increase in age-adjusted incidence
2. New drug approvals: NALIRIFOX (Feb 2024), KRAS inhibitors in pipeline
3. Earlier diagnosis potential: AI imaging, liquid biopsy technologies
4. Precision medicine: Genomic profiling identifying actionable mutations in ~26% of patients
5. Combination therapies: Expanding use of multi-agent regimens
6. Longer treatment duration: Maintenance therapy paradigm (e.g., olaparib in BRCA-mutated patients)

4. Diagnosis & Staging

Stage at Diagnosis

The fundamental problem: Over 80% of patients are diagnosed at regional or distant stages. Only ~12-14% present with localized, surgically resectable disease.

Why Late Diagnosis is So Common

1. Anatomical location: The pancreas is deep in the retroperitoneum
2. Asymptomatic early disease: Symptoms only appear when the tumor is large or has invaded adjacent structures
3. No validated screening test: Unlike breast, colorectal, lung, and cervical cancers
4. Non-specific symptoms: Jaundice, weight loss, pain mimic common GI conditions
5. Rapid progression: Can metastasize early, even when the primary tumor is small
6. CA 19-9 limitations: Elevated in only 70-80% of patients, not elevated in 5-10% who are Lewis antigen negative

Advances in Early Detection

Liquid Biopsy

• Multi-omic liquid biopsy (2025 ASCO data): Detection rates of 88% stage I, 94% stage II, 99% stage III, 95% stage IV
• Exosome-based liquid biopsy: Combined with CA 19-9, accurately identified 97% of early-stage patients
• microRNA-based liquid biopsy (NCI-supported): Accuracy of 93% (US cohort), 91% (Korean), 88% (Chinese)
• ctDNA: Can detect KRAS mutations and track them longitudinally

Source: ASCO 2025 - Multi-omic Liquid Biopsy

AI-Augmented Imaging

• Mayo Clinic AI model: Identifies pancreatic cancer in CT scans 475 days before clinical diagnosis with 92% accuracy
• Deep learning on CT: Achieved 91.8% sensitivity at diagnosis and 53.9% sensitivity on pre-diagnostic scans; 82.9% sensitivity for stage I disease
• PANDA model (Nature Medicine, 2023): Non-contrast CT deep learning approach with high accuracy
• Processing speed: Adds less than 1 second per case with ~2 false positives per 1,000 scans

High-Risk Population Screening

• CAPS5 study: Screening high-risk individuals detected 9 PDAC cases, 8 were resectable
• Median OS in screened cohort: 9.8 years vs. 1.5 years for patients diagnosed outside surveillance
• Only ~10% of patients have identifiable high-risk factors

Emerging Biomarkers

• CA 19-9: Standard of care for monitoring; limited for screening
• KRAS mutations in ctDNA: Detectable in blood; useful for monitoring
• Multi-cancer early detection (MCED) tests: Grail's Galleri includes pancreatic cancer but sensitivity for early-stage PDAC remains limited
• New-onset diabetes: Recognized as a potential early signal — the "3-year window" of new diabetes onset is an area of active research

5. Current Treatment Landscape by Line of Therapy

5A. First-Line Metastatic Pancreatic Cancer

This is the largest treatment segment, as ~55% of patients present with metastatic disease.

Preferred Regimens (NCCN Category 1, Fit Patients, ECOG 0-1)

NALIRIFOX (liposomal irinotecan + 5-FU/leucovorin + oxaliplatin): - FDA approved February 2024 — first new first-line approval for metastatic PDAC in over a decade - NAPOLI-3 trial (n=770): mOS 11.1 mo vs. 9.2 mo for Gem/NabP (HR 0.84, p=0.04) - The relative efficacy of NALIRIFOX vs. FOLFIRINOX/mFOLFIRINOX has not been tested head-to-head - More expensive than generic FOLFIRINOX, creating payer/access debates

FOLFIRINOX / modified FOLFIRINOX: - mFOLFIRINOX (without bolus 5-FU) is preferred due to better tolerability - Remains widely used globally, especially outside the US - A 2025 Phase II trial raised questions about whether mFOLFIRINOX is truly superior in real-world settings

Gemcitabine + nab-paclitaxel: - Preferred for patients with ECOG PS 2 or borderline fitness - Backbone for many combination trials

Estimated Market Share (1L Metastatic, US, ~2025)

• mFOLFIRINOX: ~35-40% (declining with NALIRIFOX entry)
• Gemcitabine + nab-paclitaxel: ~35-40%
• NALIRIFOX: ~15-20% (growing rapidly)
• Other (gemcitabine mono, clinical trials): ~5-10%

5B. Adjuvant Therapy (Post-Surgical Resection)

Only 15-20% of patients are eligible for curative-intent surgery.

Modified FOLFIRINOX is the current standard of care in the adjuvant setting: PRODIGE 24 showed mOS of 54.4 mo vs. 35.0 mo for gemcitabine alone — a landmark result.

5C. Neoadjuvant Therapy

The paradigm is shifting toward neoadjuvant-first approaches:

Borderline Resectable: Neoadjuvant therapy is now the preferred approach per NCCN guidelines. R0 resection rates after neoadjuvant: 60-70%.

Locally Advanced (Unresectable): Conversion rates of 20-40% achieve macroscopic resection. Median OS with neoadjuvant + pancreatectomy: ~31 months vs. ~12-15 months without surgery.

Upfront Resectable: Neoadjuvant vs. upfront surgery is being actively debated. Some centers favor neoadjuvant for all patients to test tumor biology.

5D. Second-Line and Beyond (2L+)

Liposomal irinotecan + 5-FU/LV (Onivyde) is the only FDA-approved 2L regimen (approved 2015).

5E. Maintenance Therapy

Olaparib (Lynparza) — the only approved maintenance therapy: - FDA approved December 2019 for gBRCA-mutated metastatic PDAC - POLO trial: mPFS 7.4 mo vs. 3.8 mo (HR 0.53, p=0.004) - Applies to only ~5-7% of PDAC patients (those with gBRCA1/2 mutations)

5F. Molecularly Targeted / Precision Medicine

Actionable mutations found in ~26% of PDAC patients: - KRAS G12C (~1-2%): Sotorasib, adagrasib (ORR ~21% in 2L) - BRCA1/2 mutations (~5-7%): Olaparib maintenance; platinum sensitivity - MSI-H/dMMR (~1-2%): Pembrolizumab (FDA approved, tumor-agnostic) - NTRK fusions (<1%): Larotrectinib, entrectinib (FDA approved, tumor-agnostic) - NRG1 fusions (<1%): Zenocutuzumab-zbco (FDA accelerated approval Dec 2024) - BRAF V600E (~1%): Dabrafenib + trametinib - HER2 amplification (~1-2%): Under investigation

NCCN now recommends germline testing and somatic tumor profiling for ALL PDAC patients.

6. R&D Pipeline: Drugs in Active Development

Recently Approved Treatments (2024-2026)

Optune Pax (Novocure) — the newest approval: - FDA approved February 2026 based on the PANOVA-3 trial - Tumor Treating Fields: low-intensity, intermediate-frequency alternating electric fields delivered via transducer arrays worn on the abdomen - PANOVA-3 (n=556): TTFields + Gem/NabP vs. Gem/NabP alone — significant OS and PFS improvement - Non-invasive, device-based approach — represents a new treatment modality in PDAC - Compliance and tolerability challenges: patients must wear the device for ≥18 hours/day

Phase 3 Trials (Active or Planned)

Phase 2 Trials (Selected Key Programs)

Phase 1 Trials (Notable Early-Stage Programs)

7. The KRAS Revolution

KRAS is the dominant oncogenic driver of pancreatic cancer, mutated in >90% of PDAC cases. For decades it was considered "undruggable" due to its smooth protein surface and picomolar GTP affinity. The development of KRAS inhibitors represents the most significant therapeutic breakthrough in PDAC in years.

KRAS Mutation Distribution in PDAC

Daraxonrasib (RMC-6236) — Revolution Medicines

This is the most important pipeline drug in pancreatic cancer:

Mechanism: RAS(ON) multi-selective inhibitor targeting active (GTP-bound) KRAS — covers G12D, G12V, G12R, G12C, and other RAS variants. Unlike earlier KRAS G12C-only inhibitors, daraxonrasib addresses ~90% of KRAS mutations in PDAC.

Clinical Data:

Regulatory Status: - FDA Breakthrough Therapy Designation (June 2025) — most significant BTD in PDAC - FDA Orphan Drug Designation (October 2025) - Phase 3 trials: RASolute 302 (2L+), RASolute 303 (1L + Gem/NabP), RASolute 304 (1L + NALIRIFOX)

Safety: Rash (90%), mucositis (>50%); grade 3+ events in ~33%. Toxicity is class-related and manageable but notable.

KOL consensus: If Phase 3 results confirm Phase 1/2 data, daraxonrasib could fundamentally change the PDAC treatment paradigm. The combination with Gem/NabP (55% ORR, 90% DCR) is particularly striking.

Source: Revolution Medicines; Targeted Oncology

Other KRAS Inhibitors in Development

KRAS + Immunotherapy Combinations

Penn Medicine / MD Anderson preclinical data (March 2025): Adding immunotherapy to RAS(ON) multi-selective inhibitors kept pancreatic cancer at bay significantly longer than targeted therapy alone.

Mechanism: KRAS inhibition remodels the TME, reducing immunosuppressive cells and increasing T-cell infiltration, creating a window for checkpoint inhibitors to work. Multiple trials evaluating daraxonrasib + anti-PD-1 are planned or underway.

KRAS Vaccines

ELI-002 2P (Elicio Therapeutics): Phase 1 data in Nature Medicine showed immune responses in ~two-thirds of patients; higher T-cell responses correlated with longer DFS and OS. Targets KRAS-mutated cells (G12D, G12V, G12R). May be most useful in the adjuvant/MRD setting.

8. Novel Modalities & Emerging Approaches

mRNA-Based Personalized Neoantigen Vaccines

Autogene cevumeran (BioNTech/Genentech): - Individualized mRNA neoantigen vaccine — each patient receives a custom vaccine encoding up to 20 patient-specific neoantigens - Phase 1 (n=16 adjuvant PDAC): Patients with vaccine-responsive T cells had significantly longer recurrence-free survival (median not reached vs. 13.4 months) - Phase 2 ongoing in adjuvant PDAC - Represents the most advanced application of mRNA vaccine technology in solid tumors

Antibody-Drug Conjugates (ADCs)

Multiple ADC programs are in early clinical development targeting PDAC-relevant antigens: - Mesothelin-targeted ADCs: Mesothelin is overexpressed in >90% of PDAC - CEACAM5-targeted ADCs: Targeting carcinoembryonic antigen-related cell adhesion molecule 5 - Claudin 18.2-targeted ADCs: Leveraging the restricted expression of CLDN18.2 in GI cancers - ADCs have been transformative in breast cancer (T-DXd) and are being explored across solid tumors

Radioligand and FAPI-Targeted Therapy

• FAPI-targeted radioligand therapy: Fibroblast Activation Protein (FAP) is highly expressed in PDAC's desmoplastic stroma, making it an ideal target for radioligand therapy
• Multiple FAPI-PET imaging agents are in clinical development
• Therapeutic FAPI radioligands (labeled with lutetium-177 or actinium-225) are in early clinical testing
• Potential to deliver radiation directly to the stromal compartment — addresses the fundamental drug delivery challenge

Alpha DaRT (Alpha Tau Medical)

• Intratumoral alpha radiation using diffusing alpha-emitter seeds
• Being tested in locally advanced pancreatic cancer
• Alpha particles have high linear energy transfer (LET), causing irreparable DNA damage
• Early clinical data in other solid tumors shows local tumor control

Tumor Treating Fields (TTFields)

• Optune Pax (Novocure): FDA approved February 2026 for 1L mPDAC with Gem/NabP
• Non-invasive, device-based approach delivering alternating electric fields
• Disrupts mitosis and cellular organization
• Adds a new modality to the PDAC treatment armamentarium

Bispecific Antibodies

• Spevatamig (PT886): Anti-CLDN18.2/CD47 bispecific antibody — FDA Fast Track for CLDN18.2+ mPDAC
• Simultaneously blocks "don't eat me" signal (CD47) and targets tumor antigen (CLDN18.2)
• Represents the next generation of immunotherapy approaches beyond checkpoint inhibitors

Fascin Inhibitors

• NP-G2-044 (Prilukae, MiNT Therapeutics): First-in-class fascin inhibitor
• FDA Orphan Drug Designation for PDAC
• Fascin is an actin-bundling protein essential for cancer cell motility and metastasis
• Targets the metastatic dissemination machinery rather than the primary tumor

Stromal Modulation Strategies

The field has learned from early failures (Infinity Pharmaceuticals' IPI-926 Hedgehog inhibitor paradoxically worsened outcomes by depleting stroma). Current approaches focus on reprogramming rather than destroying the stroma:

• FAK inhibitors (narmafotinib, defactinib, IN10018): Remodel stroma, increase immune infiltration
• Hyaluronidase (PEGPH20): Failed in Phase 3 (HALO 109-301) — depleting hyaluronic acid alone was insufficient
• Vitamin D receptor agonists: Reprogram pancreatic stellate cells from activated to quiescent state
• CD40 agonists (mitazalimab): Activate macrophages to remodel stroma and present antigens

9. Unmet Needs & Biological Challenges

Why Pancreatic Cancer Remains So Deadly

Pancreatic cancer is often called the "graveyard of oncology" due to the near-total failure of therapeutic advances that have transformed other cancers.

9A. The Tumor Microenvironment (TME) Problem

The PDAC TME is uniquely hostile and is the single biggest biological barrier to treatment:

Desmoplasia (Dense Stromal Reaction): - The stroma can constitute up to 80% of the total tumor volume — far more than any other solid tumor - Composed of activated pancreatic stellate cells (PSCs), cancer-associated fibroblasts (CAFs), dense extracellular matrix (ECM), and collagen - Creates a physical barrier that prevents drug delivery and immune cell infiltration - Generates high interstitial fluid pressure that collapses blood vessels, reducing perfusion - Acts as a biological shield that sequesters growth factors and cytokines

Immunosuppressive Microenvironment: - PDAC is considered an "immunologically cold" tumor with very low mutational burden (median TMB ~1 mut/Mb) - Abundant immunosuppressive cells: TAMs, MDSCs, regulatory T cells - Scarcity of cytotoxic CD8+ T cells - Result: Single-agent checkpoint inhibitors have been virtually ineffective (ORR <5% in unselected patients)

Hypoxic and Nutrient-Depleted Milieu: - Desmoplasia disrupts blood flow, creating hypoxia and acidosis - Metabolic reprogramming: cancer cells adopt autophagy, macropinocytosis

9B. Early Metastatic Dissemination

• Pancreatic cancer metastasizes very early — often before the primary tumor is detectable
• Mathematical modeling suggests metastatic seeding may occur years before diagnosis
• Common sites: liver (most common), peritoneum, lungs

9C. KRAS Dominance

• >90% of PDAC harbors oncogenic KRAS mutations
• Only KRAS G12C (~1-2%) had approved inhibitors until recently
• Pan-KRAS and G12D-selective inhibitors are now changing this landscape (see Section 7)

9D. Therapeutic Resistance

• Intrinsic chemoresistance: dense stroma limits drug delivery
• Rapid adaptive resistance: tumor heterogeneity and clonal evolution
• No effective biomarker-guided therapy for the majority of patients

9E. Clinical Trial Challenges

• Patients often have poor performance status at diagnosis
• Rapid clinical decline means many patients cannot complete treatment
• High attrition rate in clinical trials
• Small patient subgroups for molecularly targeted approaches

10. Surgical Landscape

Resectability Categories

Surgical Procedures

Pancreaticoduodenectomy (Whipple Procedure): - For tumors in the head/uncinate process (~70% of resectable cases) - Operative mortality at high-volume centers: <1-4% (from historical 20-25%) - Morbidity: ~30-50% complication rate

Distal Pancreatectomy: For body/tail tumors (~20-25% of resectable cases). Lower morbidity than Whipple.

Total Pancreatectomy: Rarely performed; results in brittle diabetes and exocrine insufficiency.

Modern Trends

• Neoadjuvant-first approach increasingly standard for borderline resectable
• Minimally invasive surgery (laparoscopic/robotic): increasing adoption
• Vascular resection and reconstruction: increasingly performed for venous involvement
• R0 resection is the strongest prognostic factor: mOS ~20-25 months with R0 + adjuvant therapy

11. Key Opinion Leader Views

Most Promising Approaches (KOL Consensus)

1. KRAS inhibitors (especially daraxonrasib): Most transformative pipeline drug in years. Combinations with chemo, IO, and related pathway drugs (SHP2, MEK, ERK) will be key to durable responses
2. KRAS + Immunotherapy combinations: KRAS inhibition remodels the TME, creating a window for checkpoint inhibitors
3. Early detection revolution: AI imaging + liquid biopsy could enable population screening within 5-10 years
4. Stromal modulation: Reprogramming CAFs and normalizing vasculature (FAK inhibitors, CD40 agonists)
5. Bispecific antibodies: PT886 (CLDN18.2 x CD47) — FDA Fast Track
6. mRNA neoantigen vaccines: BioNTech autogene cevumeran in adjuvant setting
7. ctDNA-guided therapy: MRD testing to guide adjuvant treatment decisions
8. FAK inhibitors in combination: Narmafotinib, defactinib addressing the stromal barrier

12. Comparison with Other Cancers

5-Year Survival Rate Comparison

Why Pancreatic Cancer Has Lagged

The fundamental gap: Pancreatic cancer is the only major cancer with a 5-year survival rate below 20% and the only top-5 deadliest cancer without a standard screening strategy.

13. Patient Journey & Burden

Symptom Burden at Diagnosis

• Pain: Present in ~80% of patients
• Weight loss: Occurs in >80%, often the presenting complaint
• Jaundice: In ~50-60% (head-of-pancreas tumors)
• New-onset diabetes: In ~25-40% in the 1-3 years before diagnosis
• Fatigue: Near-universal
• Depression and anxiety: 30-50% — among the highest rates of any cancer

Cachexia: The Defining Complication

• Affects up to 80% of PDAC patients at diagnosis
• Characterized by involuntary weight loss, skeletal muscle wasting, systemic inflammation
• Cannot be fully reversed by nutritional support alone
• Independent predictor of mortality

Pain Management

• 70-80% seek medical attention initially for pain
• Two mechanisms: pancreatic ductal obstruction; perineural invasion
• Celiac plexus nerve block / neurolysis effective in 70-90% of patients

Exocrine and Endocrine Insufficiency

• Pancreatic exocrine insufficiency (PEI): Present in 60-90% of patients
• Requires pancreatic enzyme replacement therapy (PERT) — often underprescribed

Palliative Care Integration

• Early palliative care has been shown to lengthen survival, reduce symptom burden, improve QoL
• ASCO and NCCN recommend concurrent palliative care from diagnosis for advanced PDAC
• Despite guidelines, palliative care remains underutilized

14. Regulatory Landscape

Recent FDA Approvals in Pancreatic Cancer

Key Regulatory Designations

Regulatory Environment

• The FDA has been increasingly receptive to expedited pathways in PDAC given severe unmet need
• BTD for daraxonrasib signals the FDA views KRAS multi-selective inhibitors as a potential paradigm shift
• Tumor-agnostic approvals have expanded options for small PDAC subsets
• Real-world evidence and surrogate endpoints increasingly accepted given difficulty of large trials
• The orphan drug pathway is increasingly leveraged for PDAC sub-indications

15. Amplia Therapeutics (ASX: ATX) — Deep Dive

15A. Company Overview

Amplia Therapeutics Limited is an Australian clinical-stage pharmaceutical company developing proprietary, orally bioavailable, small-molecule Focal Adhesion Kinase (FAK) inhibitors for the treatment of cancer and fibrotic diseases. Headquartered in Melbourne, Australia.

Corporate History: - Incorporated: 2000 (Auckland, New Zealand) - Original Name: Innate Immunotherapeutics Limited (April 2009), focused on MIS416 for multiple sclerosis - MIS416 Failure: June 2017 — Phase 2 trial failed to show benefit in SPMS - Strategic Pivot: Pivoted to FAK inhibitor oncology - Rebranded: September 2018 to Amplia Therapeutics (ASX: ATX) - OTCQB Listing: December 2025 (ticker: INNMF)

15B. Key Financial Metrics

15C. Core Technology: FAK Inhibitors

What is FAK?

Focal Adhesion Kinase (FAK, also called PTK2) is a non-receptor tyrosine kinase that sits at the intersection of multiple critical cellular signaling pathways. It is found at "focal adhesions" — points where cells attach to the extracellular matrix.

FAK plays critical roles in: - Cell survival and proliferation: Activated FAK promotes cancer cell survival through PI3K/AKT and RAS/MAPK - Cell migration and invasion: Essential for metastasis - Angiogenesis: Contributes to tumor blood vessel formation - ECM remodeling: Drives fibroblast activation and collagen deposition - Immune evasion: Nuclear FAK1 drives CD8+ T-cell exhaustion and recruits Tregs/MDSCs

Why FAK Matters in PDAC:

1. Dense Desmoplastic Stroma: PDAC has the densest stroma of any solid tumor — FAK inhibition reduces stromal cell proliferation by up to 87%
2. Immunosuppressive TME: FAK activity correlates with low CD8+ T-cell infiltration — FAK inhibition dramatically increases CD8+ T cells and reduces Tregs/MDSCs
3. KRAS Synergy: Treatment with KRAS inhibitors induces FAK hyperactivity as a resistance mechanism — narmafotinib blocks this
4. Chemosensitization: FAK inhibition "primes" tumors for chemotherapy by reducing stiffness and improving drug delivery

Preclinical Evidence (Jiang et al., Nature Medicine 2016): In the aggressive KPPC mouse model, FAK inhibition + checkpoint therapy + low-dose gemcitabine showed a >2.5-fold increase in median survival, with some animals remaining disease-free at six months.

15D. Lead Drug: Narmafotinib (AMP945)

"Best-in-Class" Positioning: - Defactinib: Inhibits FAK + PYK2 + 9 other kinases — broader profile contributes to toxicity - IN10018 (ifebemtinib): More selective, co-targeting 4 other kinases - Narmafotinib: Described as a "pure play" FAK inhibitor with superior specificity

15E. ACCENT Trial (Phase 1b/2a) — Lead Program

Phase 2a Results (through March 2026):

Key Milestones: - June 2025: First pathological complete response (pCR) — "extremely rare" in metastatic PDAC - December 2025: 5 confirmed complete responses (CR rate 7.8%) — described as "unprecedented" - January 2026: Data presented at ASCO GI 2026 - March 2026: Updated OS data showing 11.1-month median overall survival

15F. AMPLICITY Trial (Phase 1b/2a)

Tests narmafotinib with the other major first-line backbone, covering both dominant treatment paradigms.

15G. Planned Phase 2b/3 Registration Trial

• Positive FDA feedback from Type D meeting
• Two-dose comparison planned for Phase 2b, followed by pivotal Phase 3
• Protocol being prepared for FDA review in H1 2026; trial initiation targeted H2 2026

15H. Pipeline Overview

KRAS Combination Data (March 2026): Collaboration with Next & Bio (South Korea). Poster at AACR RAS Conference showed narmafotinib enhances KRAS inhibitor activity across pancreatic, lung, and ovarian cancer models. Treatment with KRAS G12C inhibitors induces FAK hyperactivity and fibrogenesis — narmafotinib blocks this resistance pathway.

15I. Competitive Landscape: FAK Inhibitors

Defactinib + Avutometinib (Verastem): - FDA Approved May 8, 2025 as Avmapki/Fakzynja Co-pack for KRAS-mutated recurrent LGSOC - First-ever FAK inhibitor FDA approval — validation event for FAK as a drug target - Different indication (LGSOC) than Amplia's focus (PDAC)

Ifebemtinib (IN10018, InxMed): - BTD in China for platinum-resistant ovarian cancer AND KRAS G12C-mutant NSCLC - FDA Fast Track for platinum-resistant ovarian cancer - Phase 3 registrational trial ongoing in China - Focused on ovarian/NSCLC, not PDAC

Amplia's competitive position: Only FAK inhibitor in clinical development specifically for first-line pancreatic cancer. Differentiated by selectivity, PDAC focus, and dual-backbone strategy.

15J. Financial History & Funding

Current runway: A$31.5M cash at Dec 31, 2025. Guided into 2027. Quarterly net cash consumption ~A$1.8M (excluding grants), but will increase as AMPLICITY scales and Phase 2b/3 preparation begins.

R&D Tax Incentive Refunds: A$3.18M (FY2023/2024) — significant income source for Australian biotechs.

15K. Management Team

• Dr Christopher Burns — CEO & Managing Director (appointed Dec 2022). Co-founder; 25+ years drug discovery
• Dr Jason Lickliter — CMO (appointed 2025). Presented ACCENT data at ASCO GI 2026
• Dr Rhiannon Jones — COO
• Dr Mark Devlin — CSO
• Dr Warwick Tong — Non-Executive Chairman
• Prof. Paul Timpson (Garvan Institute) — Key scientific collaborator

15L. Bear Case

1. Historical Failures of FAK Inhibitors: - Defactinib failed in mesothelioma (Phase 2, no OS/PFS benefit vs. placebo) - Defactinib showed limited activity in KRAS-mutant NSCLC - Earlier MEK + FAK combinations abandoned due to toxicity - FAK inhibition may only work in carefully selected combinations

2. Single-Arm Trial Limitations: - ACCENT is open-label, single-arm, Phase 2a vs. historical benchmarks - The comparison to NAPOLI-3 (NALIRIFOX: ORR 36.2%, OS 11.1 months) shows ACCENT's results are comparable to NALIRIFOX — not clearly superior - Raises the question: does narmafotinib add meaningful benefit, or is the population simply performing to modern standards?

3. Funding Risk and Dilution: - Pre-revenue ~A$56M market cap attempting Phase 2b/3 pivotal trials - Pivotal PDAC trials likely cost A$50-100M+ - Already 513M shares outstanding after significant dilution - Each capital raise at small market cap is highly dilutive

4. Small Company Execution Risk: - Tiny team (<20 FTEs estimated) - Multi-country clinical trials across Australia, South Korea, and US - Competing against much larger companies for patients and investigators

5. Competitive Threats: - InxMed could beat Amplia to market and expand into PDAC - Verastem has cash and infrastructure to expand defactinib into PDAC - If KRAS inhibitors alone become effective enough, FAK combination need may diminish - Big pharma could develop/acquire a FAK program and out-resource Amplia

6. Binary Outcomes: - Single-program company — any clinical setback would be catastrophic - Entire thesis rests on Phase 2b/3 success in the "graveyard of oncology"

15M. Bull Case

1. Genuinely Compelling Clinical Signal: - 35.9% ORR vs. 23% historical benchmark with the same chemo backbone - 7.8% CR rate — unprecedented in metastatic PDAC - PFS and OS improvements meaningful in this lethal disease

2. Mechanism Validation: - Verastem's defactinib FDA approval validates FAK as a druggable target - InxMed's BTDs further validate the class - Growing understanding of FAK's role in TME remodeling, chemosensitization, and immune modulation

3. KRAS Combination Opportunity: - KRAS inhibitor resistance creates demand for FAK combination - March 2026 preclinical data shows narmafotinib enhances KRAS inhibitor activity - If KRAS inhibitors become standard, FAK inhibitors could be essential add-ons

4. Regulatory Pathway: - FDA Fast Track designation - Positive FDA Type D meeting feedback for Phase 2b/3 - Expedited pathways available given PDAC unmet need

5. Funding Secured Through Critical Milestones: - A$31.5M cash, runway into 2027 - Strong institutional support in recent capital raises - OTCQB listing expands US investor access

6. Partnership/Acquisition Potential: - Positive clinical data in PDAC from a "best-in-class" FAK inhibitor could attract pharma interest - The KRAS combination story is particularly compelling for companies developing KRAS inhibitors

15N. Recent News Timeline

2025: | Date | Event | |------|-------| | June 16 | First pathological complete response (pCR) in ACCENT | | July 23 | A$27.5M capital raise | | ~Aug | Top-line ACCENT data with strong interim results | | Sep 19 | FDA Fast Track Designation | | Dec | OTCQB uplisting (INNMF) | | Dec 12 | ORR reaches 35% (19/55 patients) | | Dec 19 | Second agreement with Next & Bio for KRAS combinations |

2026: | Date | Event | |------|-------| | Jan 12 | ACCENT data presented at ASCO GI 2026 | | Jan 30 | Quarterly report: A$31.5M cash | | Feb 11 | US sites opened for AMPLICITY (UC Irvine, Cleveland Clinic) | | ~Feb | 5 confirmed complete responses (CR rate 7.8%) | | Mar 6 | AACR RAS Conference: narmafotinib + KRAS inhibitor data | | Mar | Updated OS: 11.1-month median overall survival | | H1 (planned) | Phase 2b/3 protocol submission to FDA | | H2 (planned) | Registration-enabling Phase 2b/3 trial initiation |

16. Investment Implications

Near-Term Catalysts (2025-2027)

1. Daraxonrasib (Revolution Medicines): Phase 3 readouts will be pivotal. Positive data could support $3-5B+ peak sales given ~90% KRAS-mutant addressable population
2. Narmafotinib (Amplia): Phase 2b/3 initiation (H2 2026) and ongoing data from ACCENT/AMPLICITY. Watch for Phase 2b/3 design details and enrollment rate
3. NALIRIFOX uptake trajectory: Monitoring adoption vs. mFOLFIRINOX and Gem/NabP
4. AI early detection FDA clearances: Companies building pancreatic cancer-specific AI models
5. Liquid biopsy validation: Grail, Exact Sciences, Freenome pursuing pancreatic-inclusive MCED tests
6. TTFields (Novocure): Real-world uptake and compliance data for Optune Pax

Structural Long-Term Thesis

• Pancreatic cancer is transitioning from an era of nihilism to cautious optimism
• The convergence of (1) KRAS druggability, (2) AI-enabled early detection, (3) liquid biopsy screening, and (4) TME remodeling (FAK inhibitors) creates a potential inflection point
• The market is projected to roughly double by 2030, but transformative therapies could push it well beyond current projections
• Rising incidence, especially in younger populations, expands the addressable population over time

Key Companies: Prices & Positioning (as of March 20, 2026)

Notable Price Movements (Week Ending March 20, 2026)

• Erasca (ERAS) +9.15% on Mar 19 — Analyst price target hike; ERAS-0015 (pan-RAS molecular glue) showing ongoing partial responses across multiple RAS-mutant tumors. Stock near 52-week high ($16.41) after trading at $1.01 a year ago. Remarkable run.
• Verastem (VSTM) — RAMP 205 Update: 83% ORR (10/12 patients) in front-line metastatic PDAC with avutometinib + defactinib + Gem/NabP. If this holds in expansion cohort (29 patients at RP2D, data 1H26), a Phase 3 PDAC registration trial will initiate in 2026. This is directly competitive with Amplia's narmafotinib.
• Revolution Medicines (RVMD) — Announced 9 presentations at AACR 2026 Annual Meeting (April 17-22, San Diego), including two Phase 1/2 datasets for daraxonrasib in 1L mPDAC. Stock pulled back from $124 high but remains well supported at ~$96.
• Novocure (NVCR) — Optune Pax FDA approved Feb 11, 2026. PANOVA-3 showed mOS 16.2 mo vs 14.2 mo (Gem/NabP alone); median time to pain progression 15.2 mo vs 9.1 mo. Stock surged 19% on approval but has given back most gains — 2026 revenue estimates revised down.
• Actuate (ACTU) near 52-wk low despite positive Phase 2 data — elraglusib + Gem/NabP reduced risk of death by 38% (HR 0.62); mOS 10.1 mo vs 7.2 mo; 12-mo survival 44.4% vs 22.3%. Launched RAS inhibitor combination research initiative Mar 9. Classic micro-cap disconnect between data quality and share price.
• Incyte (INCY) down ~8.5% over the month — Despite strong INCB161734 Phase 1 data (34% ORR in PDAC at 1200mg), stock weighed down by FDA Complete Response Letter for Zynyz (retifanlimab) in lung cancer. Jefferies downgraded to Hold.
• Alligator (ATORX.ST) at SEK 0.185 — Effectively a distressed micro-cap. Phase 3 mitazalimab planning for 550-patient 1L PDAC trial but appears entirely partnership-dependent at this valuation.

Competitive Implications for Amplia (ATX)

The Verastem RAMP 205 data (83% ORR in 1L PDAC) is the most important competitive development for Amplia. If Verastem's avutometinib + defactinib + Gem/NabP combination produces durable results in the expansion cohort, it could reach Phase 3 in PDAC before Amplia's narmafotinib — using a FAK inhibitor (defactinib) with an already FDA-approved pedigree. Amplia's differentiation rests on narmafotinib's superior selectivity profile, but Verastem has substantially more resources, a broader pipeline, and an established regulatory relationship from the LGSOC approval.

Research compiled March 23, 2026. Prices as of market close March 20, 2026 (most recent trading day). Data sourced from SEER, ACS, NCCN, FDA, peer-reviewed publications (NEJM, Lancet, JCO, JAMA Oncology, Nature Medicine), clinical trial registries, company filings, Yahoo Finance, and market research reports. All survival, price, and market data should be validated against primary sources for investment decisions.