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


Small Cell Long Cancer (SCLC)� 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


Small Cell Long Cancer (SCLC)� 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


Small Cell Long Cancer (SCLC)� 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


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