Targeted Cancer Therapies

 

Am Fam Physician. 2021 Feb 1;103(3):155-163.

Author disclosure: No relevant financial affiliations.

Targeted cancer therapies involve chemotherapeutic agents that attack, directly or indirectly, a specific genetic biomarker found in a given cancer. Targeted oncology includes monoclonal antibodies, small molecule inhibitors, antibody-drug conjugates, and immunotherapy. For example, the monoclonal antibodies trastuzumab and pertuzumab target human epidermal growth factor receptor 2 (HER2) and are used when treating HER2-positive breast cancer. Although targeted oncology has improved survival by years for some incurable cancers such as metastatic breast and lung cancer, as few as 8% of patients with advanced cancer qualify for targeted oncology medications, and even fewer benefit. Other limitations include serious adverse events, illustrated by a 20% to 30% rate of heart attack, stroke, or peripheral vascular events among patients taking ponatinib, which is used in treating chronic myelogenous leukemia. Immune checkpoint inhibitor therapy–related adverse effects such as hypothyroidism are common, and more severe adverse events such as colitis and pneumonitis can be fatal and require immediate intervention. Drug interactions with widely prescribed medications such as antacids and warfarin are common. Additionally, financial toxicities are a problem for patients with cancer who are using costly targeted therapies. Future directions for targeted oncology include tumor-agnostic drugs, which target a given mutation and could be used in treating cancers from multiple organ types. An overview of indications, mechanism of action, and toxicities of targeted cancer therapies is offered here.

Targeted cancer therapy involves testing various types of cancer for genetic biomarkers that can predict the response to chemotherapeutic agents that attack the biomarkers directly or indirectly.1,2 In the past decade, the U.S. Food and Drug Administration (FDA) has approved approximately 40 new targeted therapies for 12 different cancers36  (Table 1). Despite this innovation, the percentage of patients with cancer who are eligible for such therapies is small. In 2018, an estimated 8.3% of 610,000 patients with advanced or metastatic cancer were eligible for targeted therapy.7 The number of patients who benefit from these drugs is even smaller and ranges widely, depending on the tumor and drug. Targeted oncology has mainly shown benefit in the metastatic (incurable) setting, with rare success for patients treated with surgery in the local or regional setting.

WHAT'S NEW ON THIS TOPIC

Targeted Cancer Therapies

In the past decade, the U.S. Food and Drug Administration has approved approximately 40 new targeted therapies for 12 different cancers.

Patients with metastatic epidermal growth factor receptor–mutated lung cancer who are treated with osimertinib (Tagrisso) live a median of 39 months, more than double the survival of similar patients who were treated with the first epidermal growth factor receptor inhibitor, erlotinib (Tarceva), between 2007 and 2011.

In 2020, the average patient out-of-pocket cost for a course of oral cancer therapy was $5,663. According to one large analysis, 20% of patients with cancer take less medication than prescribed, 19% only partially fill oral cancer therapy prescriptions, and 24% avoid filling a prescription at all.

 Enlarge     Print

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendationEvidence ratingComments

Patients with metastatic non–small cell lung cancer should receive genomic testing for epidermal growth factor receptor and anaplastic lymphoma kinase alterations and, if positive, receive targeted therapy.14,23

A

Consistent evidence from RCTs showing reduced mortality

Patients with metastatic colorectal cancer should receive expanded RAS testing and be evaluated for mismatch repair deficiency.26

A

Consistent evidence from RCT showing reduced mortality

Patients taking ponatinib (Iclusig) should also be taking low-dose aspirin as long as no contraindications exist.28

C

Expert opinion and consensus guideline in the absence of clinical trials

Patients and caregivers should receive education about immunotherapies and the clinical profile of possible immune-mediated adverse effects before initiation and throughout treatment and survivorship.37

C

Expert opinion and consensus guideline in the absence of clinical trials

Physicians should maintain a high level of suspicion for immune therapy–related adverse effects and consider whether prompt treatment with corticosteroids is indicated.37

C

Expert opinion and consensus guideline in the absence of clinical trials

Patients taking small molecule inhibitors should undergo careful medication review and may require dosage modification if they are taking other medications metabolized by CYP3A enzymes.33

C

Expert opinion and consensus guideline in the absence of clinical trials


CYP3A = cytochrome P450, family 3A; RCT = randomized controlled trial.

A = consistent, good-quality

The Authors

show all author info

CLAIRE ELIZABETH POWERS SMITH, MD, is an assistant professor of medicine in the Hematology and Oncology department at Boston (Mass.) University Medical Center. At the time this article was written, she was a fellow in hematology and medical oncology at Oregon Health & Science University, Portland....

VINAYAK PRASAD, MD, MPH, is an associate professor in the Division of Epidemiology and Biostatistics at the University of California, San Francisco. At the time this article was written, he was a professor in the Department of Epidemiology/Biostatistics with a secondary appointment in hematology and oncology at Oregon Health & Science University.

Address correspondence to Claire Elizabeth Powers Smith, MD, Boston Medical Center, 820 Harrison Avenue, FGH 1002, Boston, MA 02118 (email: Claire.smith@bmc.org). Reprints are not available from the authors.

Author disclosure: No relevant financial affiliations.

References

show all references

1. Prasad V, Gale RP. The ASCO Post. What precisely is precision oncology—and will it work? January 25, 2017. Accessed March 1, 2020. https://www.ascopost.com/issues/january-25-2017/what-precisely-is-precision-oncology-and-will-it-work/...

2. Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372(9):793–795.

3. U.S. Food and Drug Administration. 2010 notifications. Updated February 13, 2018. Accessed December 18, 2019. https://www.fda.gov/drugs/resources-information-approved-drugs/2010-notifications

4. U.S. Food and Drug Administration. 2011 notifications. Updated February 13, 2018. Accessed December 18, 2019. https://www.fda.gov/drugs/resources-information-approved-drugs/2011-notifications

5. U.S. Food and Drug Administration. Hematology/oncology (cancer) approvals and safety notifications; 2016. Updated December 19, 2016. Accessed December 18, 2019. http://wayback.archive-it.org/7993/20170111064250/http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm

6. U.S. Food and Drug Administration. Hematology/oncology (cancer) approvals and safety notifications; 2020. Updated August 3, 2020. Accessed October 10, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications

7. Marquart J, Chen EY, Prasad V. Estimation of the percentage of US patients with cancer who benefit from genome-driven oncology [published correction appears in JAMA Oncol. 2018;4(10):1439]. JAMA Oncol. 2018;4(8):1093–1098.

8. Singh S, Kumar NK, Dwiwedi P, et al. Monoclonal antibodies: a review. Curr Clin Pharmacol. 2018;13(2):85–99.

9. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–712.

10. Wolff AC, Hammond MEH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36(20):2105–2122.

11. Bang Y-J, Van Cutsem E, Feyereislova A, et al.; ToGA Trial Investigators. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastrooesophageal junction cancer (ToGA) [published correction appears in Lancet. 2010;376(9749):1302]. Lancet. 2010;376(9742):687–697.

12. Qin S, Li J, Wang L, et al. Efficacy and tolerability of first-line cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX-4) versus FOLFOX-4 in patients with RAS wild-type metastatic colorectal cancer: the open-label, randomized, phase III TAILOR trial. J Clin Oncol. 2018;36(30):3031–3039.

13. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722–731.

14. Ramalingam SS, Vansteenkiste J, Planchard D, et al.; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41–50.

15. Rosell R, Carcereny E, Gervais R, et al.; Spanish Lung Cancer Group in collaboration with Groupe Français de Pneumo-Cancérologie and Associazione Italiana Oncologia Toracica. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC). Lancet Oncol. 2012;13(3):239–246.

16. Alecensa (alectinib) [package insert]. Chugai Pharmaceutical; 2017. Updated June 2018. Accessed May 1, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208434s004lbl.pdf

17. Wiggans AJ, Cass GK, Bryant A, et al. Poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of ovarian cancer. Cochrane Database Syst Rev. 2015;(5):CD007929.

18. Thomas A, Teicher BA, Hassan R. Antibody-drug conjugates for cancer therapy. Lancet Oncol. 2016;17(6):e254–e262.

19. Haslam A, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open. 2019;2(5):e192535.

20. Yarchoan M, Albacker LA, Hopkins AC, et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight. 2019;4(6):e126908.

21. Schmid P, Adams S, Rugo HS, et al.; IMpassion130 Trial Investigators. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–2121.

22. Paz-Ares L, Luft A, Vicente D, et al.; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040–2051.

23. National Comprehensive Cancer Network. NCCN guidelines in oncology. Non small cell lung cancer version 8. 2020. Accessed October 13, 2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

24. Mok TSK, Wu Y-L, Kudaba I, et al.; KEYNOTE-042 Investigators. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042). Lancet. 2019;393(10183):1819–1830.

25. National Comprehensive Cancer Network. NCCN guidelines in oncology. Colon cancer version 4. 2020. Accessed October 13, 2020. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf

26. Iclusig (ponatinib) [package insert]. Ariad Pharmaceuticals; 2012. Accessed May 9, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203469lbl.pdf

27. Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381(17):1632–1643.

28. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393–404.

29. Kim J, Nair A, Keegan P, et al. Evaluation of serious postmarket safety signals within 2 years of FDA approval for new cancer drugs. Oncologist. 2020;25(4):348–354.

30. Prasad V, Mailankody S. The accelerated approval of oncologic drugs: lessons from ponatinib. JAMA. 2014;311(4):353–354.

31. Sprycel (dasatinib) [package insert]. Bristol-Myers Squibb. Accessed May 9, 2020. https://packageinserts.bms.com/pi/pi_sprycel.pdf

32. Tarceva (erlotinib) [package insert]. Schwarz Pharma. Accessed May 9, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021743s14s16lbl.pdf

33. Segal EM, Flood MR, Mancini RS, et al. Oral chemotherapy food and drug interactions. J Oncol Pract. 2014;10(4):e255–e268.

34. Opdivo (nivolumab) injection [package insert]. Bristol-Myers Squibb; 2014. Updated June 2020. Accessed August 6, 2020. https://packageinserts.bms.com/pi/pi_opdivo.pdf

35. Keytruda (pembrolizumab) injection [package insert]. Merck and Co.; 2014. Updated June 2020. Accessed August 6, 2020. https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf

36. Yervoy (ipilimumab) injection [package insert]. Bristol-Myers Squibb; 2011. Updated June 2020. Accessed August 6, 2020. https://packageinserts.bms.com/pi/pi_yervoy.pdf

37. Brahmer JR, Lacchetti C, Schneider BJ, et al.; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy. J Clin Oncol. 2018;36(17):1714–1768.

38. Johnson DB, Sullivan RJ, Ott PA, et al. Ipilimumab therapy in patients with advanced melanoma and preexisting autoimmune disorders. JAMA Oncol. 2016;2(2):234–240.

39. Offin M, Liu D, Drilon A. Tumor-agnostic drug development. Am Soc Clin Oncol Educ Book. 2018;38:184–187.

40. Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520.

41. Drilon A, Siena S, Ou S-HI, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib. Cancer Discov. 2017;7(4):400–409.

42. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations [published correction appears in N Engl J Med. 2018;379(16):1585]. N Engl J Med. 2015;373(8):726–736.

43. Prasad V. Our best weapons against cancer are not magic bullets. Nature. 2020;577(7791):451.

44. Dusetzina SB, Keating NL. Mind the gap: why closing the doughnut hole is insufficient for increasing Medicare beneficiary access to oral chemotherapy. J Clin Oncol. 2016;34(4):375–380.

45. Zafar SY, Peppercorn JM, Schrag D, et al. The financial toxicity of cancer treatment. Oncologist. 2013;18(4):381–390.

46. Ramsey SD, Bansal A, Fedorenko CR, et al. Financial insolvency as a risk factor for early mortality among patients with cancer. J Clin Oncol. 2016;34(9):980–986.

47. Verma V, Sprave T, Haque W, et al. A systematic review of the cost and cost-effectiveness studies of immune checkpoint inhibitors. J Immunother Cancer. 2018;6(1):128.

48. Gong J, Pan K, Fakih M, et al. Value-based genomics. Oncotarget. 2018;9(21):15792–15815.

49. Gerber DE. Targeted therapies: a new generation of cancer treatments. Am Fam Physician. 2008;77(3):311–319. Accessed August 4, 2020. https://www.aafp.org/afp/2008/0201/p311.html

 

 

Copyright © 2021 by the American Academy of Family Physicians.
This content is owned by the AAFP. A person viewing it online may make one printout of the material and may use that printout only for his or her personal, non-commercial reference. This material may not otherwise be downloaded, copied, printed, stored, transmitted or reproduced in any medium, whether now known or later invented, except as authorized in writing by the AAFP. Contact afpserv@aafp.org for copyright questions and/or permission requests.

Want to use this article elsewhere? Get Permissions

CME Quiz

More in AFP


Editor's Collections


Related Content


More in Pubmed

MOST RECENT ISSUE


May 1, 2021

Access the latest issue of American Family Physician

Read the Issue


Email Alerts

Don't miss a single issue. Sign up for the free AFP email table of contents.

Sign Up Now

Navigate this Article