The Four Percent Lung Cancer Solution

A small group of lung cancer patients, who carry EML4-ALK marker in their tumor genome, can now look forward to a cancer-free future, thanks to a new drug crizotinib being developed by Pfizer.  This group of patients are generally nonsmokers or had given up smoking long ago, but still have the misfortune of coming down with lung cancer. 
The saving grace for them is the diagnosis of ALK-rearranged NSCLC and crizotinib on pharmacy shelves.

Pfizer’s crizotinib (also known as PF-02341066 or 1066) is a potent, ATP-competitive, small-molecule inhibitor of ALK kinase.  In this week's ASCO Chicago meeting (June 3-7, 2011), Pfizer presented two major abstracts (#2501 and #7514) on crizotinib trial.  The first abstract provided additional details from the Phase I clinical study (preliminary data was reported at the last year’s ASCO meeting.)  The overall response rate in this open-label trial with 116 patients was 61%, with two patients reaching complete response (complete elimination of tumors) and 69 patients (59%) showing partial response at 11 months.  The progression-free survival was 10 months (range 8-15 months).  Interestingly, this drug has been so effective, that most patients are alive today and the investigators have yet to determine the median overall survival time.  The second abstract presented by Pfizer disclosed preliminary data from an ongoing Phase II trial on ALK-rearranged NSCLC patients with recurrent, advanced, or metastatic disease.  The trial is being conducted at 57 sites spread across 12 countries.  This trial covers a broad cross-section of patients; half of the participants are females and 68% are nonsmokers.  Pfizer reports, “on a waterfall plot of tumor measurements in evaluable pts, 63 of 76 pts (83%) had target lesion shrinkage (41 pts had ≥30% shrinkage). Seven patients experienced objective progression by RECIST” [“pts” stands for patients.] 

Crizotinib development has provided great hope to a EL4-ALK subset of lung cancer patients, and the data backs up this enthusiasm beautifully.  Pfizer received an orphan drug status for crizotinib in October 2010 because ALK-rearranged NSCLC constitute just 2-7% of all lung cancer patients; crizotinib was granted fast track status two month later in December.  Pfizer filed for FDA approval on May 18th, 2011, and is now under FDA priority review—we should hear from the FDA within the next six months.  Abbott Molecular also filed a companion diagnostic (CDx) application for a FISH-based ALK-rearrangement test on May 18th, 2011.  Crizotinib story has drawn parallels to the dawn of personalized medicine in cancer care (see WSJ Online article).  Another milestone was the simultaneous regulatory approval filing in US (FDA) and Japan, the first ever simultaneous filing by any non-Japanese pharma. The timeline is also very impressive—filing for approval within three years of the start of clinical trial.  The EML4-ALK mutation was discovered just four years ago (see pie chart below)

(Numbers in brackets are years mutations discovered.

Figure from: Ladanyi M, Pao W. Mod Path. 200;21:S16–S22 | DOI | Fulltext |)

The future of crizotinib 

ALK stands for anaplastic large-cell lymphoma (ALL) kinase.  Therefore, it was expected that somebody would also look into ALL, a rare form of lymphoma.  In a recent study reported in New England Journal of Medicine, crizotinib completely wiped out tumors in ALL patients.  Crizotinib is also being studied in brain cancer.  This drug has a potential to become the standard-of-care in several ALK-rearranged or over-expressed cancers.  Crizotinib also inhibits MET/HGF receptor tyrosine kinases which may further expand it's use.  One analysis quoted in Bloomberg, expects the sales of crizotinib to top $755 million by 2015.  But there is no time to sit and relax, researchers have already begun to develop models to understand and address potential resistance to crizotinib (Read PNAS article here).

Lung cancer 

The shift in lung cancer care towards personalized therapy model is the new norm.  The results of the BATTLE (which stands for "Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination") trial published in this month’s issue of the AACR journal Cancer Discovery summarizes that molecular stratification of a patient's tumor based on EGFR, KRAS and VEGFR mutations or amplifications was key to making decision on best drug choice.  Patients with EGFR mutations respond best to erlotinib (Tarceva™) or gefitinib (Iressa™), and those with EGFR amplification to erlotinib plus bexarotene (Targretin™); high Cyclin D1 to erlotinib plus bexarotene combination; high VEGFR-2 expression to vandetanib; KRAS/BRAF marker for sorafenib (Nexavar™).  To this panel of biomarkers, we can add ALK-rearranged tumors.  However, as shown in the figure below, we have work cut out for us—no good options are available to over half of all lung cancer patients.  Still, the four percent solution is better than none, and we are on the right track.

(Figure from: Harris T. Discov Med. 2010 August:10(51):144-150 | FullText |)

References and Further Readings

• EML4-ALK fusion lung cancer: a rare acquired event. Perner S, Wagner PL, Demichelis F. Neoplasia. 2008 Mar;10(3):298-302. | PubMed | Fulltext | 
• Inhibition of ALK Signaling for Cancer Therapy. Mossé YP, Wood A, Maris JM. Clin Cancer Res. 2009 Sept. 15;15:5609 | PubMed | DOI | FullText |
• Crizotinib in Anaplastic Large-Cell Lymphoma. Gambacorti-Passerini C, Messa C, Pogliani EM. N Engl J Med. 2011 February 24;364:775-776 | FullText |
• Early Accelerated Approval for Highly Targeted Cancer Drugs. Chabner BA. N Engl J Med. 2011 March 24;364:1087-1089 | FullText |

BATTLE trial

• The BATTLE Trial: Personalizing Therapy for Lung Cancer. Kim ES, Herbst RS, Wistuba II, et al. Cancer Discovery. 2011 June;1:44 | DOI | FullText |
• The BATTLE Trial: A Bold Step toward Improving the Efficiency of Biomarker-Based Drug Development. Rubin EH, Anderson KM, Gause CK. Cancer Discovery. 2011 June;1:17 | DOI | FullText |

ASCO 2011 presentations

• Initial phase II results with crizotinib in advanced ALK-positive non-small cell lung cancer (NSCLC): PROFILE 1005.  Crinò L, Kim D, Riely GJ, et al. J Clin Oncol 29: 2011 (suppl; abstr 7514) | Link |
  
• Progression-free survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive non-small cell lung cancer (NSCLC).  Camidge DR, Bang Y, Kwak EL, et al. J Clin Oncol 29: 2011 (suppl; abstr 2501) | Link | 
• Impact of crizotinib on survival in patients with advanced, ALK-positive NSCLC compared with historical controls. Shaw AT, Yeap BY, Solomon BJ. J Clin Oncol 29: 2011(suppl; abstr 7507) | Link |
  

Drug resistance issues

• Crizotinib Continues to Show Promise for Some Lung Tumors, Faces Challenge of Drug Resistance. Reynolds S. NCI Cancer Bulletin. 2010 November 2. Available at http://www.cancer.gov/ncicancerbulletin/110210/page2 . Accessed June 08, 2011.
• Inflaming resistance to Tarceva. Cain C. SciBX. 2010 Sep. 9;3(35). | DOI | FullText |
• Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Katayama R, Khan TM, Benes C, et al. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7535-40. | PubMed | DOI | FullText |

Blogs and misc 

• Crizotinib and ALK rearrangements in lung cancer: an interview with Dr Ross Camidge.  Sally Church.  PharmaStratgyBlog. 2010, November 30 Available at http://pharmastrategyblog.com/2010/11/crizotinib-and-alk-rearrangements-in-lung-cancer-an-interview-with-dr-ross-camidge.html/ . Accessed June 08, 2011. 
• Major Shift in War on Cancer. Drug Studies Focus on Genes of Individual Patients; Testing Obstacles Loom.  Winslow R. Wall St J Online. 2011, June 5. Available at http://online.wsj.com/article/SB10001424052702304432304576367802580935000.html . Accessed  June 08, 2011.

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