Towards efficient therapies for small cell long cancer dr. n. haraszkiewicz-birkemeier

Towards efficient therapies for
Small Cell Lung Cancer (SCLC).
Potential therapeutic targets.
Clinical research. Market analysis.
Dr Natalia Haraszkiewicz-Birkemeier
Credentials: IASLC

SCLC Therapies - Dr. N. Haraszkiewicz-Birkemeier
Small Cell Lung Cancer – SCLC
www.madscape.comwww.madscape.com

Small Cell Lung Cancer (SCLC)
Overview
Causes
Diagnostic criteria
Comparison with other cancers
Wikimedia Commons, SCLC - cytology

Small Cell Lung Cancer (SCLC)
represents ca. 15 % of all types of lung cancer
the cancer cells are small compared with other types of lung cancer
almost always caused by smoking
the most aggressive subtype of lung cancer
is difficult to detect in the early stages of the disease
5-year survival rate of <7% (poor long-term survival diagnosis)
many patients with SCLC respond to initial chemotherapy
the majority of the patients are diagnosed when the cancer has spread and
cannot be removed by surgery.

What distinguishes small cell lung
cancer from other cancer types?
SCLC vs NSCLC: different rate of growth, rate of spread, reaction to treatment and
association with other syndromes. SCLC affects 25 % of all lung cancer patients.
SCLC grows rapidly as the time from development of symptoms to the initial
diagnosis typically occurs in less than 90 days. 75 % of SCLC patients have the cancer
in other parts of their body by the time a diagnosis is made.
SCLC responds well to both chemotherapy and radiation treatments. Non-small cell
lung cancer grows slower, spreads less, and is harder to treat.
SCLC typically starts in the center of the chest within the bronchi of the lungs
Large-cell carcinoma, contrary to other large-cell lung cancers, grows fast, starts in
the center of the lungs and shows similar signs of small-cell lung cancer.
Ca. 40 % of all lung cancers are adenocarcinomas, or a type of non-small cell lung
cancer found in outer portions of lungs that grows slower and is normally detected
before it leaves the lungs.
Source: American Cancer Society, eMedicineHealth, WebMD

Diagnostic criteria and grading of
lung neuroendocrine tumors
Source: Translation Lung Cancer Res. 2016

Small Cell Long Cancer (SCLC)
Global therapeutic market
Treatment size market forecast
Vendors & regions

Global LC Therapeutics Market
Source: Business Wire 2015

SCLC – treatment market size forecast
dramatical rise from $198 million in 2014 to $2.29 billion by 2024, representing a
high Compound Annual Growth Rate (CAGR) of 27.7%
seven major markets: US, France, Germany, Italy, Spain, the UK, and Japan, will
primarily be driven by the launch of premium-priced therapies including anti-PD-1
and anti-CTLA-4 immunotherapies and targeted agents.
novel SCLC therapies will experience strong and rapid adoption during the
forecast period in combination with generic, chemotherapy-only regimens in the
early lines of therapy, and extend the number of lines of treatment available for
patients.
SCLC treatment sales will also be bolstered by an increase in rates of the disease
across the five European markets and Japan, at a CAGR of 1.49% over the forecast
period.

Global vendors and regions
Bristol Myer Squibb
Glaxo Smith Kline
Boehringer-Ingelheim
Sanofi
Novartis
Amgen
Roche/Genentech
Merck
Americas
EMEA
APAC

Potential targets
Genomics

Potential targets for Small Cell Long
Cancer (SCLC)
Source: Translation Lung Cancer Res. 2016

Genomic analyses and mutations
There is a panel of several genes that appear
mutated/abnormal in nearly all SCLCs: p53, Rb and Myc
family members as well as in PI3K pathway and NOTCH
Oncogene mutations such as KRAS are rare or non-existent
Predominant mutations observed in SCLC include loss-of-
function mutations in the Rb and p53 genes
Overexpression of proto-oncogenes by amplification of
distinct chromosomal regions include L-myc or C-myc

Targeted therapies
Clinical Trials

Targeted Therapies for SMLC in CT

New therapies for SCLC ?
Immune checkpoint inhibitors (immunotherapy) are explored in
seemingly every type of cancer, including SCLCT
Two clinical trials:
CheckMate-032, patients with pretreated SCLC received either
the PD-1 inhibitor nivolumab (Opdivo) or a combination of
Opdivo and the CTLA-4 inhibitor ipilimumab (Yervoy).
KEYNOTE-028 clinical trial, 24 SCLC patients received the PD-1
inhibitor pembrolizumab (Keytruda).

New therapies for SCLC – next steps
Combining PD-1 inhibitors with other treatments
(chemotherapy, radiotherapy, or targeted drugs) is
the next step in improvements of the efficacy of PD-
1 blockers in SCLC
Several clinical trials are already testing this:
(NCT02402920, NCT02481830, NCT02472977,
NCT02331251, NCT02551432)

SCLC - Clinical trials
clinical research study to find the highest tolerable dose of pembrolizumab (MK-3475) and radiation
therapy (either with chemotherapy or alone). Trial of MK-3475 and Concurrent Chemo/Radiation for the
Elimination of Small Cell Lung Cancer; Phase I
Sponsor: M.D. Anderson Cancer Center
Collaborator: Merck Sharp & Dohme Corp.
Estimated enrollment: 80 patients
clinical research study to compare the overall survival of nivolumab versus chemotherapy in patients with
relapsed SCLC. Study of Nivolumab or Chemotherapy in Subjects With Relapsed Small-cell Lung Cancer
After Platinum-based First Line Chemotherapy (CheckMate 331: CHECKpoint Pathway and nivoluMAb
Clinical Trial Evaluation 331); Phase III
Sponsor: Bristol-Myers Squibb
Estimated enrollment: 149 sites
Collaborator: Ono Pharmaceutical Co. Ltd
clinical research study to determine whether the combination of Ulocuplumab and Nivolumab is safe and
effective in the treatment of pancreatic cancer and small cell lung cancer. A Phase I / II Study of the Safety
and Efficacy of Ulocuplumab Combined With Nivolumab in Subjects With Advanced or Metastatic Solid
Tumors.
Sponsor: Bristol-Myers Squibb
Estimated Enrollment: 195 patients

SCLC - Clinical trials
A Phase Ib/II Study of Pembrolizumab Plus Chemotherapy in Patients With Advanced Cancer
(PembroPlus)
Sponsor: Western Regional Medical Center
Estimated Enrollment:90 patients
Patients with refractory SCLC. Patients will be treated with paclitaxel and pembrolizumab, phase II,
Phase II Study of Pembrolizumab and Paclitaxel in Refractory Small Cell Lung Cancer
Sponsor: Seoul National University Hospital
Estimated Enrollment:26 patients
Source: https://clinicaltrials.gov

Examples promising therapies
EMA

Two-Drug Immunotherapy -
Nivolumab+Ipilimumab
Nivolumab blocks the activity of a molecule PD-1 found on T cells, and is approved
for advanced non-small cell lung cancer, melanoma and renal cell carcinoma
patients. Ipilimumab targets a molecule called CTLA-4 on T cells and is approved for
advanced melanoma patients.
Phase 1/2 international study (Checkmate 032) to assess the activity and safety of
nivolumab and ipilimumab in 216 patients with SCLC who developed progressive
disease after prior standard chemotherapy. Patients received either nivolumab
therapy as a single agent, or two different combination regimens of nivolumab plus
ipilimumab.
The researchers reported that nivolumab and the combination regimen were
active in SCLC patients and resulted in responses that lasted longer than many other
investigational agents. Ten percent of patients treated with single-agent nivolumab
responded to therapy, while approximately 20 percent of patients treated with
nivolumab combined with ipilimumab responded. Furthermore, 16 patients
maintained their response for longer than 6 months.
Source: Lancet Oncology 2016

EMA Orphan designation for Rova-T
On 30 May 2016, orphan designation (EU/3/16/1667) was granted by the European
Commission to Aceso Biologics Consulting Ltd, United Kingdom, for rovalpituzumab tesirine
(Rova-T) for the treatment of small cell lung cancer.
Opinions on orphan medicinal product designations are based on the following three criteria:
• the seriousness of the condition;
• the existence of alternative methods of diagnosis, prevention or treatment;
• either the rarity of the condition (affecting not more than 5 in 10,000 people in the EU) or
insufficient returns on investment.
Designated orphan medicinal products are products that are still under investigation and are
considered for orphan designation on the basis of potential activity. An orphan designation is not
a marketing authorisation. As a consequence, demonstration of quality, safety and efficacy is
necessarybefore a product can be granted a marketing authorisation.
http://www.ema.europa.eu/

Promissing results with a new class of
drugs that target cancer stem cells
(CSCs) - Rova-T
Rovalpituzumab tesirine (aka
SC16LD6.5) is an ADC drug - an
antibody-drug conjugate, in which the
antibody part recognizes and binds to
a protein called DLL3, which is found in
70% of SCLC tumors.
The antibody part is linked to the
cytotoxic (cell-killing) drug tesirine.
When the antibody part binds to DLL3,
the drug is absorbed into the cancer
cell, where it damages DNA and kills
the cell.
Source: Science of Translational Medicine 2015
Journal of Thoracic Oncology 2016

Clinical development - CPA
https://www.ncbi.nlm.nih.gov/pmc

Interested and need more info?
For more information and a complete presentation
don't hesitate to contact me. Presentations in
different languages: English, German, Polish, Dutch
are available.
Email: natalia.haraszkiewicz@gmail.com
Tel. mobile: +31 (0)641883606
Contacts preferably via SMS and/or What's App ツ

Towards efficient therapies for small cell long cancer dr. n. haraszkiewicz-birkemeier

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