Treatment for Lung Cancer: Drug Therapy

Transcription

1 Treatment for Lung Cancer: Drug Therapy Living in the Molecular Age: Advances Drug Therapy of Lung Cancer John C. Morris, M.D. Division of Hematology-Oncology November 1, 2014

2 Non-small cell lung cancer: Stage at diagnosis Stage IV 40% Stage I 10% Stage II 20% Stage IIIB 15% Stage IIIA 15% Ettinger, et al. Oncology. 1996;10:

3 Types of Drug Therapy for Lung Cancer Chemoprevention- Drug treatment to reduce the risk of developing lung cancer in an at risk patient without cancer. Retinoids (vitamin A analogs)- Unsuccessful. Metformin (anti-diabetes drug)- Studies ongoing. Adjuvant Chemotherapy- Used after the initial treatment (usually surgery and/or radiation) to eliminate undetectable cancer cells that may be left behind. High-risk stage I and stages II and III NSCLC Neoadjuvant Chemotherapy- Drugs used upfront sometimes with radiation before surgery. Stage IIIA NSCLC, Pancoast s tumors Palliative Chemotherapy- Drugs given to relieve lung cancer symptoms and maybe extend life, but are not for cure.

4 History of Drug Therapy for Lung Cancer s- First Generation- Alkylating agents, antimetabolities, antitumor antibiotics Cyclophosphamide, CCNU, doxorubicin (Adriamycin ), 5-fluorouracil, methotrexate 1980 s- Second Generation- Multi-agent chemotherapy Carboplatin, cisplatin, etoposide, mitomycin C, vinblastine 1990 s- Third Generation- Platinum-based doublets Carboplatin, cisplatin, docetaxel (Taxotere ), gemcitabine (Gemzar ), paclitaxel (Taxol ), vinorelbine (Navelbine ) 2000 s- Fourth Generation- Targeted agents Tyrosine kinase inhibitors: Gefitinib (Iressa ), erlotinib (Tarceva ), afatinib (Gilotrif ) Monoclonal antibodies: Bevacizumab (Avastin ), cetuximab (Erbitux ) Pemetrexed (Alimta ) 2010 s- Fifth Generation- Immunotherapy Negative-immune checkpoint blockade Cancer vaccines

5 Important Questions Does chemotherapy cure or improve the survival of patients with lung cancer? Answer: Yes, but it depends. Does chemotherapy relieve symptoms associated with lung cancer? Answer: Yes sometimes.

6 LACE Meta-analysis of Adjuvant Chemotherapy: Chemotherapy Benefit by Stage Category No. Deaths/ No. Patients HR for Overall 5-Yr. Survival (Chemotherapy vs. Control) Stage IA 104/ ( )* Stage IB 515/ ( ) Stage II 893/ ( ) P =.04 Stage III 878/ ( ) Pignon JP, et al. J Clin Oncol. 2008; 26: Chemotherapy Better Control Better

7 Patient Survival (%) By the early 2000 s we had reached a plateau for cytotoxic chemotherapy in advanced NSCLC ECOG 1594 Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel Months Schiller JH, et al. N Engl J Med. 2002

8 Platinum-doublet Chemotherapy in Advanced NSCLC Overall response 20-25% Time-to-progression 4-6 months Median survival 8-9 months 1-year survival 20-25% 2-year survival 10-15% Failed strategies: Triplet chemotherapy 2,3 Non-platinum-based chemotherapy Single agent chemotherapy 1. NCCN Non-small Cell Lung Cancer Clinical Practice Guideline, v Available at: 2. Frasci et al. J Clin Oncol. 1999;17: Kelly et al. Clin Cancer Res. 2000;6:

9 Strategies to improve effectiveness of treatment Better Treatments: Less toxic More specific Better Predictive Biomarkers: Which ones? Better Patient Selection: What criteria?

10 Bevacizumab Blocks Angiogenesis Recombinant humanized monoclonal antibody to VEGF-A

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12 Maintenance Chemotherapy for Lung Cancer The continuation of reduced intensity chemotherapy to reduce the risk of tumor Progression in patients whose lung cancers have responded or remained stable when treated with initial standard chemotherapy. Pemetrexed (Alimta ) Bevacizumab (Avastin ) Erlotinib (Tarceva )

13 The Molecular Age: Thymidylate synthtase (TS) expression in lung cancer SCLC High TS Squamous High TS Adeno Low TS TS Bhattacharjee, et al. PNAS. 2001

14 Survival Probability Survival Probability Selecting Chemotherapy by Molecular Analysis Non-squamous* (n = 1252) Squamous (n = 473) HR=0.844 (95% CI: ) p=0.011 HR=1.229 (95% CI: ) p=0.051 Pemetrexed + cisplatin Gemcitabine + cisplatin Gemcitabine + cisplatin Pemetrexed + cisplatin Survival Time (months) Survival Time (months) *Non-squamous- adenocarcinoma, large cell carcinoma, and other/indeterminate histology. Scagliotti, et al. J Clin Oncol 2008.

15 Driver mutations in adenocarcinoma of the lung Harris T. Disc Med; 2010.

16 Inhibitors of Epidermal Growth Factor Receptor (EGFR) afatinib, erlotinib, gefitinib

17 Effect of EGFR mutations on response to Tarceva

18 Structure of the EGFR-ATP Binding Site Exons# 18, 19, 20 and 21- tyrosine kinase domain. Deletions and missense mutations Allow drugs like Tarceva to bind more tightly and inactivate EGFR Lynch TJ, et al. N Engl J Med. 2004; 350:

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20 Targeted Agents for Treatment of Lung Cancer EGFR overexpression (90%+) Cetuximab (Erbitux )- Not approved for lung cancer in U.S. EGFR sensitizing mutations (11-17%) Gefitinib (Iressa ), erlotinib (Tarceva ), afatinib (Gilotrif ) T790M Resistance- Clovis COO-1686, AZD9291- Still investigational. EML-4/ALK translocations and ROS-1 rearrangements (3-6%) Crizotinib (Xalkori ), ceritinib (Zykaydia ). BRAF (V600E) mutations (1-4%) Vemurafenib (Zelboraf ), Debrafinib (Tafinlar )- Not approved for lung cancer. HER-2/neu overexpression (1-3%) Trastuzumab (Herceptin ), pertuzumab (Perjeta ), ado-trastuzumab emtansine (Kadcyla )- All not approved for lung cancer.

21 PI3k P P P P IGF-1R/ IR HER C-MET P P P P P P P P EGFR HGF IGF-1/ Insulin Src Ras Ras Raf MEK Erk PIP3 PTEN PIP2 PDK-1 Akt raptor mtor rictor mtor p70s6k 4EBP Hif-1α Protein Translation FoxO3a Transcription Angiogenesis Cell Cycle Progression Proliferation Differentiation BAD Apoptosis Anti-HER Lapatinib BMS BMS PF XL647 BIBH2992 ARRY Anti-cMET XL880 ARQ197 PF JNJ388 MGCD265 SU11274 PHA HGF mab AMG102 OA5D5 IGF-1 mab CP AMG479 IMC-A12 R1507 BIIB022 Anti-IGF-1R XL228 OSI906 NDGA Anti-Src Bosutinib XL999 AZD0530 KX Anti-mTOR Everolimus Deforolimus UCN01 Anti-Akt Perifosine GSK Anti-PI3k PI103 BGT226 BEZ235 XL765 XL147 Anti-Ras Tipifarnib Lonafarnib BMS Anti-Raf Sorafenib RAF265 XL281 PLX4032 Anti-MEK AZD6244 RDEA119 XL518 IRS Anti-DNMT 5-azacitadine 5-aza-2 -deoxycitidine Anti-HDAC SNDX275 CI994 Apicidin Desipeptide Trapoxin Depeudecin SK7068 vorinostat

22 Immunotherapy of Lung Cancer: Negative Checkpoint Blockade

23 03/08/12 04/23/12 06/04/12

24 Tergenpumatucel-L

25 Pre-HAL vaccination 64 Months Post-HAL vaccination

26 Eligibility and Randomization (1:1:1) (n = 480) Docetaxel Tergenpumatucel-L Q1 wk Tergenpumatucel-L Q2 wks Progression Progression Progression Gemcitabine or Pemetrexed Docetaxel or Gemcitabine or Pemetrexed with Tergenpumatucel-L Q1 wk Docetaxel or Gemcitabine or Pemetrexed with Tergenpumatucel-L Q2 wks

27 Improvement in survival in patients with metastatic NSCLC over time Time Period Median Survival (months) 1-Yr. Survival (%) 2-Yr. Survival (%)

28 Number of Annual Deaths Cancer Deaths and NIH Research Spending (per Death) ($1,796) ($6,812) ($2,682) ($15,775) ($5,294) Washington Post, Feb. 18, Cancer Site

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