Targeting Oncogenic Driver Mutations for Cancer Therapy

The Journal of Targeted Therapies in Cancer, August 2013, Volume 1, Issue 8

The dependence of cancer cells on the continued activity of specific oncogenes for proliferation and survival can be explored for drug development.

Daniel Morgensztern, MD

Division of Oncology, Department of Medicine,

Washington University School of Medicine, and Alvin J.

Siteman Cancer Center at Washington University School

of Medicine, St Louis, MO

Corresponding Author:

Ramaswamy Govindan, MD

Division of Medical Oncology, Washington University

School of Medicine, St. Louis, MO;


The dependence of cancer cells on the continued activity of specific oncogenes for proliferation and survival can be explored for drug development. This new era of targeted therapy started with the initial studies of imatinib in patients with chronic myeloid leukemia. Since then, multiple targeted drugs have been tested, particularly in patients with gastrointestinal stromal tumors (GISTs), melanoma, and lung adenocarcinomas. This review highlights some of the approved tyrosine kinase inhibitors (TKIs), including their mechanism of action, activity in early studies, and comparison with standard chemotherapy in phase III trials.


Historically, the treatment approach to patients with cancer has been based largely on empirically designed clinical studies. This approach has traditionally been associated with modest clinical benefit, high frequency of adverse events, and substantial healthcare costs.1,2With a better understanding of the biology of several malignancies and discovery of novel targets for therapy, there is now considerable hope for improving the outcomes of patients with cancer.

The DNA in normal cells is constantly damaged by environmental and normal cellular processes. Although the majority of the damage is repaired, a small fraction is converted into fixed mutations.3Unlike germline mutations, which are present in the fertilized eggs inherited from the parents and transmitted to the offspring, somatic mutations are acquired after conception and occur during cell division.4Although somatic mutations are usually randomly distributed throughout the genome, a subset occurs in key genes with potential to initiate and maintain cancer phenotype (oncogenes). Oncogenes contain driver mutations, which are implicated in oncogenesis by deregulating the control of normal cell proliferation, differentiation, and death, leading to growth advantage for the malignant clone. In contrast, passenger mutations often are present within the genome prior to the development of driver mutations, being carried along the clonal expansion, and not implicated in oncogenesis.

The vast majority of malignancies are sporadic and occur due to the accumulation of genomic alterations, leading to dysregulation of protein-encoding genes. As normal cells evolve to a neoplastic state, they acquire several essential complementary capabilities, including sustained proliferative signaling, resistance to apoptosis, evasion of growth suppressors, and induction of angiogenesis, invasion, and metastases.5Cancer cells are often physiologically dependent on the continued activity of specific oncogenes, where inactivation of a single critical oncogenic gene may induce them to differentiate into normal cells or undergo apoptosis.6This cancer cell dependency on single oncogenes has been recently explored for drug discovery, with the development of targeted therapies.

The pivotal phase I studies conducted by Druker and colleagues7showed that the oral BCR-ABL tyrosine kinase inhibitor (TKI) imatinib was well tolerated in patients with chronic myeloid leukemia, and associated with remarkable response rates in patients in the chronic phase who had already progressed on interferon alfa. A total of 53 out of 54 patients treated with daily doses of 300 mg or more achieved complete hematologic response, with 29 cytogenetic responses (54%). Among patients with myeloid blast crisis, 21 out of 38 (55%) patients had a decrease in bone marrow blast to 15% or less, with four patients (11%) achieving complete hematologic response.8For patients with lymphoid blast crisis, 14 out of 20 (70%) achieved bone marrow blast decrease to 15% or less, with four (20%) complete hematologic responses.


Since then, several studies have been conducted, leading to the approval of targeted therapies against a variety of driver mutations. Among the solid tumors, targeted therapies directed against driver mutations with TKIs have been approved for patients with gastrointestinal stromal tumors (GISTs), melanoma, and non-small cell lung cancer (NSCLC), where randomized clinical trials in the latter two diseases showed a significant benefit compared with standard chemotherapy (Table).GISTs are mesenchymal tumors of the gastrointestinal tract, arising usually in the stomach or small bowel. Approximately 75% to 80% haveKITmutations. The second most common mutation in GIST, representing 10% of the cases, occurs in the platelet- derived growth factor receptor alpha (PDGFRα), whereas 10% to 15% of the tumors lack detectable mutations in either oncogene.9

Because the response rates with chemotherapy were typically very low, there were no effective therapies for GIST prior to the use of targeted therapy. Imatinib mesylate is an oral small-molecule, competitive inhibitor of multiple tyrosine kinases, including the intracellular ABL kinase resulting from the chimeric BCR-ABL fusion oncoprotein, KIT, and PDGFR.

In the phase I trial evaluating the use of imatinib in GIST, dose-limiting toxicities occurred at 500 mg twice daily, and 25 out of 36 (70%) patients with GIST achieved an objective response, including 19 confirmed partial responses (PRs) and six patients with tumor reduction between 20% and 29%.10

In the phase II trial, 147 patients were randomized to imatinib 400 mg or 600 mg once daily.11Seventy- nine patients (53.7%) had a PR and 41 (27.9%) had stable disease (SD), with median duration of response not reached by the time of report and without significant differences between the arms. The treatment was well tolerated, with edema, nausea, and diarrhea, mostly grades 1-2, as the most common toxicities.


In the phase III study, 746 patients with incurable GIST were randomized to 400 mg once or twice daily.12The overall response rates (ORRs) were 45% for both arms, with median progression-free survival (PFS) and median overall survival (OS) of 18 months and 55 months, respectively, in the standard arm, and 20 months and 51 months, respectively, in the high-dose arm. In a study of imatinib by Heinrich et al,13the presence of aKITmutation in exon 11 was associated with a significant improvement in the outcomes compared with exon 9 mutations and wild-typeKIT.Approximately 50% of patients with cutaneous melanoma harbor a mutation inBRAF, leading to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway.14Among theBRAFmutations, 80% to 90% consist of the substitution of glutamic acid for valine at amino acid 600 (V600E), with a smaller fraction represented by other subtypes such asV600KandV600R. Vemurafenib (Zelboraf) was shown in preclinical studies to have potent antitumor effect againstBRAF V600E-mutated melanoma cell lines, with minimal activity in wild-type BRAF cells.15

The phase I trial with vemurafenib showed response rates in 11 of 16 patients (68%) receiving at least 240 mg orally twice daily, whereas in the expansion cohort at the recommended phase II dosage of 960 mg twice daily, 26 of 34 patients (76%) had complete or partial responses, with an estimated PFS of 7 months.16

In a phase II trial enrolling 132 patients with previously treated melanoma harboring the BRAF mutation, the ORR was 53%, with 6% complete response, a median PFS of 6.8 months, and a median OS of 15.9 months.17The encouraging results led to the BRAF Inhibitor in Melanoma 3 (BRIM-3) phase III trial comparing vemurafenib to dacarbazine in 675 patients with previously untreatedBRAF V600E-mutated metastatic melanoma.18Vemurafenib and dacarbazine were administered at 960 mg orally twice daily and 1000 mg/m2 intravenously every 3 weeks, respectively. Response rates (48% vs 5%;P< .001), median PFS (5.3 months vs 1.6 months; hazard ratio [HR] = 0.26;P< .001), and OS at 6 months (84% vs 64%; HR = 0.37;P< .001) were significantly better for patients treated with vemurafenib. Vemurafenib was well tolerated, with arthralgia, rash, and fatigue as the most common side effects, in addition to the unique development of keratoacanthomas and cutaneous squamous cell carcinomas in 8% and 12% of patients, respectively, with all lesions treated by simple excision.

TABLE. Selected Randomized Clinical Trials Comparing TKIs to Standard Chemotherapy











Vemurafenib vs Dacarb

48% vs 5% (P< .001)

5.3 vs 1.6 mo (P< .001)

84% vs 64%a (P< .001)




Trametinib Dacarb or Pac

22% vs 8% (P< .01)

4.8 vs 1.5 mo (P< .001)

81% vs 67%a (P< .01)




Gefitinib CisDoc

62% vs 32% (P< .0001)

9.2 vs 6.3 mo (P< .0001)





Gefitinib CarbPac

73% vs 30% (P< .001)

10.8 vs 5.4 mo (P< .001)

30.5 vs 23.6 m (P= .31)




Erlotinib CarbGem

83% vs 36% (P< .0001)

13.1 vs 4.6 mo (P< .0001)





Erlotinib CisDoc or CisGem

64% vs 18% (P< .0001)

9.7 vs 5.2 mo (P< .0001)



PROFILE 100734


Crizotinib Pem or Doc

65 vs 20% (P< .001)

7.7 vs 3 mo (P< .0001)


a 6-month OS.

RR = relative risk; PFS = progression-free survival; OS = overall survival; mo = months; NA = not applicable; carb = carboplatin; Cis = cisplatin; Dacarb = dacarbazine; Doc = docetaxel; Gem = gemcitabine; Pac = paclitaxel; Pem = pemetrexed; WJTOG = West Japan Thoracic Oncology Group; NEJ = North-East Japan Study Group.


Another approach for patients with the BRAF mutation is the use of MEK inhibitors. In the phase III METRIC study, 322 patients with metastatic melanoma harboringBRAF V600EorBRAF V600Kwere randomized 2:1 to receive the oral selective MEK inhibitor trametinib 2 mg daily or chemotherapy with dacarbazine or paclitaxel.19Patients on chemotherapy were to cross over and receive trametinib at progression. Trametinib was associated with an improvement in response rates (22% vs 8%;P= .01), improved median PFS (4.8 vs 1.5 months;P< .001), and OS at 6 months (81% vs 67%;P= .01). Based on the results of this study, trametinib was approved on May 29, 2013, for the treatment ofBRAF V600E- orBRAF V600K-mutated melanoma.Several driver mutations have been detected in patients with NSCLC. Among them, targeted therapy has been shown to be particularly effective in patients with epidermal growth factor receptor (EGFR) mutations and the anaplastic lymphoma kinase (ALK) fusion gene.

The most common activatingEGFRmutations include the deletions in exon 19 and the substitution of arginine for leucine at position 858 (L858R).20-22Although initial trials with EGFR TKIs in unselected populations showed modest response rates,23,24studies in patients with theEGFRmutation showed significant improvements in response rates and PFS.25In the Iressa Pan-Asia Study (IPASS), 1217 previously untreated patients with advanced pulmonary adenocarcinoma who were either nonsmokers or light smokers were randomized to gefitinib or chemotherapy with carboplatin plus paclitaxel.26There was a significant interaction between the treatment arm and the presence of theEGFRmutation, with gefitinib associated with a significant improvement in PFS among patients withEGFR-mutant disease (HR = 0.48; 95% CI, 0.36-0.64;P< .001) and significant decrease in PFS for those with wild-typeEGFR(HR = 2.85; 95% CI, 2.05-3.98;P< .001).

Since then, several studies have shown improved response rate and PFS for EGFR TKIs, including gefitinib and erlotinib, compared with standard chemotherapy.27-30The most common toxicities from EGFR TKIs in all studies have been rash and diarrhea.

TheEML4-ALKfusion oncogene results from the fusion of the N-terminal portion of the protein encoded by the echinoderm microtubule-associated protein-like 4 (EML4) gene with the intracellular signaling portion of the ALK receptor tyrosine kinase on the short arm of chromosome 2.31In the initial study evaluating the ALK inhibitor crizotinib in 82 patients with advanced NSCLC and ALK rearrangement by fluorescence in situ hybridization (FISH), the treatment was well tolerated with 47 responses (53%; 46 partial responses, 1 complete response); 27 (33%) achieved SD, and six (7%) had progressive disease (PD).32The estimated probability of PFS at 6 months was 72%, with median PFS not reached at the time of the report.

Based on these results, crizotinib received accelerated FDA approval for patients with advanced NSCLC and ALK-positive tumors. In an update of the phase I trial, 87 of 143 patients had an objective response (60.8%; 95% CI, 52.3-68.9), including three complete responses and 84 partial responses. Median PFS was 9.7 months, and estimated 1-year OS was 74.8%.33

In the phase III study in patients with advanced NSCLC previously treated with a platinum-based doublet, crizotinib was associated with a significant improvement compared with chemotherapy (pemetrexed or docetaxel), with higher response rates (65% vs 20%; P < .001) and median PFS (7.7 months vs 3 months;P< .001).34The most common side effects with crizotinib were visual disorders, gastrointestinal problems, and elevated transaminases.

PROFILE 1014 (NCT01154140) is a phase III trial comparing crizotinib to platinum plus pemetrexed as first-line therapy in patients with translocation or inversion involving the ALK gene locus.


ROS1 is a receptor tyrosine kinase recently found to be a driver mutation in NSCLC.35ROS rearrangements are found in approximately 1% of lung adenocarcinomas and have been associated with response to crizotinib. Ou and colleagues36reported the initial results of crizotinib in 25 patients with advanced NSCLC andROS1rearrangements, with response rates of 56% and probability of PFS by 6 months of 71%.Progress in the treatment of cancer can only be achieved with a better understanding of the pathophysiology of the tumors and development of more effective drugs that are capable of inducing durable responses with minimal toxicity. Recent studies have shown that targeted therapies are capable of producing dramatic response rates in selected patients based on the presence of driver mutations. Nevertheless, not all eligible patients achieve tumor reduction, and virtually all patients develop progressive disease, usually within less than one year. Therefore, further studies are needed to establish more potent drugs and combinations in an attempt to prolong the benefits, and hopefully transform at least some malignancies into chronic disorders.

Author Disclosures

Dr. Morgensztern has no conflicts of interest to report.

Dr. Govindan has been a consultant/advisory board member and received honoraria from Pfizer Inc., Genentech, Bristol-Myers Squibb Company, Merck & Co., Inc., Boehringer Ingelheim, Abbott Laboratories, and Covidien.


  1. Simon R. The use of genomics in clinical trial design.Clin Cancer Res. 2008;14(19):5984-5993.
  2. Gonzalez-Angulo AM, Hennessy BT, Mills GB. Future of personalized medicine in oncology: a systems biology approach.J Clin Oncol. 2010;28(16):2777-2783.
  3. Stratton MR, Campbell PJ, Futreal PA. The cancer genome.Nature. 2009;458(7239):719-724.
  4. Stratton MR. Exploring the genomes of cancer cells: progress and promise.Science. 2011;331(6024):1553-1558.
  5. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation.Cell. 2011;144(5):646-674.
  6. Weinstein IB. Cancer. Addiction to oncogenes--the Achilles heal of cancer.Science. 2002;297:63-64.
  7. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.N Engl J Med. 2001;344(14):1031-1037.
  8. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.N Engl J Med. 2001;344(14):1038-1042.
  9. Joensuu H, Hohenberger P, Corless CL. Gastrointestinal stromal tumour [published online ahead of print April 23, 2013].Lancet. 2013. doi:10.1016/S0140-6736(13)60106-3.
  10. van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study.Lancet. 2001;358(9291):1421-1423. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors.N Engl J Med. 2002;347(7):472-480.
  11. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033.J Clin Oncol. 2008;26(4):626- 632.
  12. Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group.J Clin Oncol. 2008;26(33):5360-5367.
  13. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer.Nature. 2002;417(6892):949-954.
  14. Tsai J, Lee JT, Wang W, et al. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.Proc Natl Acad Sci USA. 2008;105(8):3041-3046.
  15. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma.N Engl J Med. 2010;363(9):809-819.
  16. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600- mutant advanced melanoma treated with vemurafenib.N Engl J Med. 2012;366(8):707-714.
  17. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation.N Engl J Med. 2011;364(26):2507-2516.
  18. Flaherty KT, Robert C, Hersey P, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma.N Engl J Med. 2012;367(2):107- 114.
  19. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N Engl J Med. 2004;350(21):2129-2139.
  20. Paez JG, J&auml;nne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.Science. 2004;304(5676):1497-1500.
  21. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from &ldquo;never smokers&rdquo; and are associated with sensitivity of tumors to gefitinib and erlotinib.Proc Natl Acad Sci USA. 2004;101(36):13306-13011.
  22. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial).J Clin Oncol. 2003;21(12):2237-2246.
  23. Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.JAMA. 2003;290(16):2149-2158.
  24. Fong T, Morgensztern D, Govindan R. EGFR inhibitors as first-line therapy in advanced non-small cell lung cancer.J Thorac Oncol. 2008;3(3):303- 310.
  25. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.N Engl J Med. 2009;361(10):947-957.
  26. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial.Lancet Oncol. 2010;11(2):121-128.
  27. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.N Engl J Med. 2010;362:2380-2388.
  28. Zhou C, Wu YL, Chen G, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-smallcell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study.Lancet Oncol. 2011;12(8):735-742.
  29. Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.Lancet Oncol. 2012;13(3):239-246.
  30. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.Nature. 2007;448 (7153):561-566.
  31. Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.N Engl J Med. 2010;363(18):1693- 1703.
  32. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012;13(10):1011-1019.
  33. Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK positive lung cancer [published online ahead of print June 1, 2013].N Engl J Med. 2013. DOI:10.1053/NEJMoa1214886.
  34. Bergethon K, Shaw AT, Ou S-HI, et al. ROS 1 rearrangements define a unique molecular class of lung cancers.J Clin Oncol. 2012;30(8):863-870.
  35. Ou S-HI, Bang Y-H, Camidge DR, et al. Efficacy and safety of crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC).J Clin Oncol. 2013;31:abstr 8032.