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https://www.gene.com/patients/medicines/phesgo

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Timeline created using information and images from gene.com ⁹ and cancer.gov ¹⁰, as well as timeline template from powerpointschool.com ¹⁸

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"If it were not for the great variability among individuals, medicine might as well be a science, not an art." ⁹
Sir William Osler, 1892

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Anti-HER2 Mechanisms of Approved HER2 Inhibitors

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About 1/4 breast cancers are HER2+, while the mean frequency of HER2+ cancer in gastric cancers is 17.9%¹⁶

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Cancer is the second leading cause of death worldwide ¹⁷

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In this short video about Herceptin clinical trials, keep an eye out for...

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In this short video about Herceptin clinical trials, keep an eye out for...

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- The incredibly promising and groundbreaking results
- Mention of the ASCO meeting
- The goal to make Herceptin more widely accessible!²²

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The HERA Breast Cancer Clinical Trial - Breast Cancer Trials

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Roche's Herceptin vs. Phesgo

Roche developed a new product, Phesgo, which comes in a single-dose vial and can be administered in a treatment center or at home. Each treatment requires about five minutes to administer, with eight minutes as an initial loading process, lending it a competitive advantage over Herceptin in the form of convenience²⁸

In the midst of the COVID-19 pandemic, patients with weak immune systems, such as those with breast cancer, may benefit from Phesgo, as it allows them to avoid treatment centers²⁸

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Demetra Economopoulos: Background & Introduction, Featured Anecdote, What Made Herceptin Successful, The Road to Personalized Medicine Timeline, Sir William Osler Quote, Clinical Trials Video, Gene.com Mechanism Image, Article Images, Alternatives, Market, Formatting, Editing and Revisions of Padlet

Ding Wang: Preclinical Studies & Mechanism (disease target & Herceptin Mechanism),
Mechanism video, breast cancer cell,  revision

Ouye Chen: Drug Development, Clinical Trials, Biosimilars, First Research of HER2, Applying Monoclonal Antibody inhibiting HER2 + Cancer

Ting Ting Cai: Combination Chemotherapy,  Alternatives, Market , Side Effect

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Side effects with Herceptin are common, but not all are serious. Most are non life-threatening.                   Potential side effects include:
1. Infusion-related reaction
Herceptin is administered intravenously, which can cause fever, chills, headache, nausea and shortness of breath. These symptoms are among the most commonly experienced in Herceptin patients.
2. Allergic reaction
Hypersensitivity reactions or anaphylactic allergic reactions have been observed in patients treated with Herceptin.
3. Heart problems (with or without symptoms)
Potential heart complications include congestive heart failure and reduced heart function.

Patients should contact their doctors if they:
- Become or are at risk of becoming pregnant
- Have severe lung problems
- Have low white blood cell counts

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Analysis and Future Outlook - Alternatives

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Analysis and Future Outlook - Alternatives

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Perjeta (Pertuzumab): As an alternative, Herceptin is often given with another targetted treatment, called Perjeta. Both Herceptin and Perjeta are designed to target breast cancer cells with excess HER-2 receptors, however each employ a unique mechanism in pursuit of this goal. While both drugs attach to HER2 overexpressing cells and block growth signals, Perjeta targets a different area on the HER2 receptor compared to Herceptin²⁵

Docetaxel: Pertuzumab and Trastuzumab may also be combined with Docetaxel, which is a chemotherapy drug. This trio of drugs may be given before surgery²⁷

Kadcyla:  Kadcyla is also a good example of combining targetted chemotherapy with personalized medicine²⁰

Tykerb: Tykerb may be used in later lines of therapy in cases where the cancer has stopped responding to Herceptin, anthracyclines and taxanes. Tykerb is a dual tyrosine kinase inhibitor²⁶

Aside from these targetted treamtemts, there are also traditional treatment options chemotherapy, radiation therapy and surgery ²⁶

Additionally, the biosimilars mentioned in the "Biosimilars" section also make for competitive alternatives to Herceptin.

The figure bellow illustrates Herceptin and Perjeta working to block growth signals in a cancer cell.²⁴

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1. DoTokuda, Y, et al. “In Vitro and in Vivo Anti-Tumour Effects of a Humanised Monoclonal Antibody against c-ErbB-2 Product.” British Journal of Cancer, vol. 73, no. 11, 1996, pp. 1362–1365., doi:10.1038/bjc.1996.259.

2. Ferguson, K. M. (2008). Structure-Based View of Epidermal Growth Factor Receptor Regulation. Annual Review of Biophysics, 37(1), 353-373. doi:10.1146/annurev.biophys.37.032807.125829

3. CA;, Hudis. “Trastuzumab--Mechanism of Action and Use in Clinical Practice.” The New England Journal of Medicine, U.S. National Library of Medicine, 5 July 2007, pubmed.ncbi.nlm.nih.gov/17611206/.

4. Anti-HER2 Mechanisms of Approved HER2 Inhibitors [Video file]. (2013, April 30).

5. Kwong Glover, Z. W., Gennaro, L., Yadav, S., Demeule, B., Wong, P. Y., & Sreedhara, A. (2013). Compatibility and stability of pertuzumab and trastuzumab admixtures in i.v. infusion bags for coadministration. Journal of Pharmaceutical Sciences, 102(3), 794–812.

6. Kirschbrown, W. P., Kågedal, M., Wang, B., Lindbom, L., Knott, A., Mack, R., . . . Garg, A. (2019). Pharmacokinetic and exploratory exposure–response analysis of pertuzumab in patients with operable HER2-positive early breast cancer in the APHINITY study. Cancer Chemotherapy and Pharmacology, 83(6), 1147-1158.

7. Schechter, A. L. et al. The neu oncogene: an erb-B-related gene encoding a 185,000-Mr tumour antigen. (1984). Nature (London) 312, 513-516.

8. Jeffrey A. Drebin, Victoria C. Link, Robert A. Weinberg & Mark I. Greene. Inhibition of Tumor Growth by a Monoclonal Antibody Reactive with an Oncogene-Encoded Tumor Antigen. (1986). Proceedings of the National Academy of Sciences - PNAS 83, 9129-9133.

9. The HER2 Journey. Erin Biba. https://www.gene.com/stories/her2/

10. Milestones in Cancer Research and Discovery. National Cancer Institute. https://www.cancer.gov/research/progress/250-years-milestones

11. Precision Medicine in Cancer Treatment. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/precision-medicine

12. Cameron, D. et al. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. (2017). The Lancet (British edition) 389, 1195-1205 .

13. Global Trastuzumab Biosimilar Market Research Report 2020: Industry Trends & Technological Advancements, COVID 19 Impact, Market Share Analysis, Revenue Forecast 2019-2028. (2020) https://www.medgadget.com/2020/06/global-trastuzumab-biosimilar-market-research-report-2020-industry-trends-technological-advancements-covid-19-impact-market-share-analysis-revenue-forecast-2019-2028.html

14. Herceptin (Trastuzumab): Side Effects, How it Works, and More. (2020). https://www.breastcancer.org/treatment/targeted_therapies/herceptin

15. Supporting you along the Herceptin journey. (2020). https://www.herceptin.com/

16. Long-Term Results Show 1 Year of Herceptin Best for Lowering Recurrence Risk of Early-Stage, HER2-Positive Disease. (2017). https://www.breastcancer.org/research-news/1-yr-of-herceptin-best-for-reducing-recur-risk

17. Cancer. World Health Organization. (2018). https://www.who.int/news-room/fact-sheets/detail/cancer#:~:text=Cancer%20is%20a%20leading%20cause,Breast%20(2.09%20million%20cases)

18. Animated Powerpoint Timeline Template. https://powerpointschool.com/animated-powerpoint-timeline-template/

19. A Secret to Tell: The Journey of My Wife's Breast Cancer. (2020). https://www.curetoday.com/view/a-secret-to-tell-the-journey-of-my-wifes-breast-cancer-part-2

20. How Kadcyla is Thought to Work. https://www.kadcyla.com/patient/how-kadcyla-works.html

21. Abelson, D., Collins P.A. Media Hyping and the “Herceptin Access Story”: An Analysis of Canadian and UK Newspaper Coverage. (2009). Health Policy, 4(3), 113-128.

22. The HERA Breast Cancer Clinical Trial - Breast Cancer Trials, Breast Cancer Trials. (2017). https://www.youtube.com/watch?v=zlj_-JunajI

23. Fast Track Approvals for Drugs, 1998-2007, including PEPFAR. FDA. (2007). https://www.fda.gov/media/124350/download

24. Possible Link Between Childbirth And Risk of Certain Types of Breast Cancer. https://tefalhead.wordpress.com/2011/02/24/possible-link-between-childbirth-and-risk-of-certain-types-of-breast-cancer/

25. How Perjeta is Thought to Work. https://www.perjeta.com/

26. Taking the Good With the Bad: Mitigating Heart Problems With Breast Cancer Medication. Meeri Kim. (2016). https://www.curetoday.com/view/taking-the-good-with-the-bad-mitigating-heart-problems-with-breast-cancer-medication

27. Docetaxel. http://chemocare.com/chemotherapy/drug-info/docetaxel.aspx

28. Phesgo. Genentech. https://www.gene.com/patients/medicines/phesgo

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Combination Chemotherapy:
It has been shown that adding Perjeta to Herceptin and chemotherapy is beneficial to patients with early stages of HER2 positive breast cancer
APHINITY study
Early result in 2017:
Adding Perjeta to Herceptin and chemotherapy slightly improved survival. The standard of care for most stage II to stage III HER2-positive breast cancers became Herceptin, Perjeta, and chemotherapy after surgery.⁶
APHINITY process:
- 4805 patients were randomly assigned to one of two treatment regimens after surgery:
1. Herceptin and placebo plus chemotherapy
2. Herceptin and Perjeta plus chemotherapy

- Results in 2019, after 6 years:

90.6% of women treated with Herceptin, Perjeta, and chemotherapy were alive with no cancer recurrence⁶

87.8% of women treated with Herceptin and chemotherapy were alive with no cancer recurrence⁶

- Considering the survival rate:

94.8% of women treated with Perjeta, Herceptin, and chemotherapy were alive after 6 years⁶

93.9% of women treated with Herceptin and chemotherapy were alive after 6 years⁶

Conclusion:
Addition of Perjeta to Herceptin reduces the risk of disease recurrence for patients with HER2-positive breast cancer.⁶

However, since the data is still immature, a longer follow-up may be required to observe the significant survival benefits.

The figure below illustrates two different treatment options for HER2-positive breast cancer patients who have previously undergone surgery.⁶

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Herceptin Molecular Mechanism:

Herceptin delivers continuous inhibition to the HER2 receptors by working on both the intracellular and extracellular domains of the receptor ³

Herceptin has two antigen-specific sites that bind to the extracellular domain of the HER2 receptor and a humanized Fc domain that can be recognized by immune effector cells.(figure B) ³

Herceptin binds to the extracellular domain & reduces HER2 signaling by inhibiting either homodimerization or heterodimerization of the tyrosine kinase domain (figure C & D)³

Herceptin also functions by recruiting immune effector cells that are responsible for antibody-dependent cytotoxicity (flags tumor cells for destruction by immune system) (figure E)³

The figure below shows the molecular mechanism of Trastuzumab³.

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Disease Target: HER-2 Receptor

Human Epidermal Growth Factor 2 is a transmembrane tyrosine kinase receptor which normally regulates cell growth and survival

The Tyrosine Kinase domain is activated by both homodimerization and heterodimerization, which refer to ligand binding ²

Compared to other members of the HER family, the HER2 receptor has a special extracellular domain which can resemble a ligand-activated state and permits its dimerization without the presence of a ligand ²

Over-expression of the HER2 Receptor leads to uncontrolled cell proliferation

The figure below shows the extracellular domain and the tyrosine kinase domain of the HER-2 receptor².

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First Discovery:

Experiments conducted by Genentech revealed anti-tumor activity of murine monoclonal antibodies directed against the HER2 receptor extracellular domain, both in vivo and in vitro

Major Problem:

The human anti-mouse antibody response could potentially limit the progress and effectiveness of the drug in clinical trials

Goal of Preclinical Study and Resolution of the Problem:

Demonstrate effectiveness of a humanized antibody against the HER2 receptor, yielding anti-tumor effects similar to its murine counterpart

The murine antibody Mu4D5 could be grafted onto a human antibody, cleverly disguising it from the immune system and, thus "humanizing" it to Rhu4D5

Method:

In vitro experiment: Human tumor cell lines (Eg. SK-BR3) were cultured for 3 days with various concentrations of both Rhu4D5 and Mu4D5 in micro plates to test  their anti-proliferative activity¹

Fresh peripheral blood mononuclear cells (PBMC) from normal donors were mixed with tumor cells from nude mice to test cytotoxicity with the presence of Rhu4D5 and Mu4D5¹

In vivo experiment: Human gastric carcinoma xenografts 4-1St and St-15 were maintained by serial inoculation in SCID mice, and both Rhu4D5 and Mu4D5 were tested for anti-tumor effects ¹

Results:

The binding capacity of Rhu4D5 to the HER2 receptor was comparable to that of Mu4D5¹

In vitro anti-proliferative activity of Rhu4D5 against SK-BR3 human tumor cell lines was slightly reduced compared with Mu4D5, but the result was still comparable (figure 2)¹

The cytotoxicity of human PBMC against a variety of HER2 positive cells lines was significantly augmented in the presence of Rhu4D5 (figure 3 & figure 6)¹

In vivo, Rhu4D5 showed a significantly better anti-tumor effect on 4-1ST transplanted in mice (figure 4) 1

Conclusion:

In the in vitro experiment, the antibody-dependent cell-mediated cytotoxicity of human PBMC was significantly augmented with Rhu4D5, but not Mu4D5¹

In vivo experimental research showed that Rhu4D5 had anti-tumor effects, even without the presence of human effector cells¹

These results provided evidence to suggest that Rhu4D5 possesses similar anti-tumor activity to Mu4D5 and, moreover, that Rhu4D5 may have greater anti-tumor potency in clinical trials¹

The figures below show results of in vivo and vitro experiments of Mu4D5 and Rhu4D5¹.

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The phase II clinical trial focused on comparing fixed dosages versus dosages calculated based on body weight. The researchers were able to recruit over 300 volunteers. For the 222 patients who were given a weekly calculated dosage of trastuzumab as the single-agent treatment, the response rate (24%) was significantly higher compared to those with fixed dosage (11.6%), and even better than fixed dosage combined with cisplatin (22%). These findings demonstrated a very high tumor targeting ability¹².
The figure below shows a schematic for the Phase II clinical trial¹².

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Analysis and Future Outlook - Biosimilars

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Analysis and Future Outlook - Biosimilars

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Before the end of 2019, Herceptin's patent had expired in both the United States of America and Europe. Upward of 20 biosimilars have been approved, the most competitive of which include:
- Mylan and Biocon’s Ogivri
- Celltrion’s Herzuma
- Samsung Biologics' Ontruzant
- Pfizer's Trazimera
- Amgen's Kanjinti
The figure below illustrates the biosimilar market report for 2020, indicating the popularity of Herceptin and its related biosimilars¹³.

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Across a treatment period of 14 months, the patients treated with Herceptin received an overall 163% increase in anti-cancer response compared with the group that received chemotherapy alone. In addition, researchers observed a 25% increase in the survival rate of patients (20.3 month to 25.4 month), further demonstrating that the addition of trastuzumab to chemotherapy strongly increases HER2+ breast cancer patients' survival rate and quality of life¹².

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The phase III clinical trial aimed to compare the therapeutic effects of chemotherapy compared to trastuzumab in combination with chemotherapy, in HER2+ breast cancer patients. The 469 patients were separated based on their chemotherapy history, and then further divided into the 2 treatment groups. Chemotherapy was repeated every three
weeks for six cycles, and the trastuzumab was given in a fixed dosage on the same day of chemotherapy¹².
The figure below shows a schematic for the Phase III clinical trial¹².

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Applying Monoclonal Antibody and Inhibiting HER2+ Tumor Growth:
Weinberg later cooperated with Mark I. Greene from Harvard in developing an antibody to target neu (HER2) and inhibit tumor growth. The selected antibody, Mu4D5, is a type 2a IgG incubated in hybridoma cells⁸.

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Applying Monoclonal Antibody and Inhibiting HER2+ Tumor Growth, Continued:
Mu4D5 demonstrated high efficiency in inhibiting tumor progression in multiple sarcoma cell lines as well as mice models⁸. The limitation of Mu4D5, however, is the human immunogenic response mentioned under "Drug Development."
The figure below shows the effectiveness of Mu4D5 in inhibiting neuro-blastoma progression in mice⁸.

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Phase I Clinical Trial for Trastuzumab (Herceptin)

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Phase I Clinical Trial for Trastuzumab (Herceptin)

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The Phase I clinical trial was conducted in 1992, with limited volunteers recruited and separated into 3 treatment groups: single dose trastuzumab alone, weekly dose trastuzumab alone, and weekly trastuzumab combined with chemotherapy drug cisplatin.
Applied with varying dosages, the maximum tolerance dosage was not reached, indicating a strong pharmacokinetics profile for trastuzumab. The half life of the drug was about two weeks in the patients circulatory system and had no effect on cisplatin treatment¹².
The figure below shows a schematic for the Phase I clinical trial¹².

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Initial Research of HER2, continued:
The researchers then discovered that neu is a homolog of human erb-B, an EGF receptor. Further assays demonstrated that EGF receptor antibody recognizes neu, proving such homology⁷.
The figure below shows antibody recognition of neu gene product⁷.

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Initial Research of HER2:
In 1984, Robert A. Weinberg's lab from MIT discovered a novel oncogene "neu," later dubbed "HER2." The experiment began with monitoring multiple ras-associated oncogenes. Researchers noted that inducing the neu gene resulted in tumor progression, and that the gene product had a tumor antigen property⁷.

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Barbara Bradfield's breast cancer had been in remission two years after her double mastectomy when she discovered a lump on her throat. She had stage IV cancer that had spread to her lungs, and had run out of hope. Rather than seek additional treatment and undergo chemotherapy again, Barbara went on vacation and prepared to say her goodbyes. Her husband then convinced her to participate in a clinical trial, and she became one of the first women in the world to be treated with Herceptin, later becoming a "miracle cancer survivor."⁹

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Herceptin targets HER2+ breast and gastric cancers in the early or advanced stages.¹⁵ Cancers are HER2+ if they overexpress the HER2 gene, which makes HER2, or Human Epidermal Growth Factor 2, protein. HER2 protein receptors stimulate cell growth and division and, in over abundance, can cause cancer.¹⁴

HER2+ breast cancer is aggressive and historically has been very difficult to treat... but with Herceptin, HER2+ patients may actually have a better prognosis than HER2- patients!⁹

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Analysis and Future Outlook - What Made Herceptin Successful?

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Analysis and Future Outlook - What Made Herceptin Successful?

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Urgent need: HER2 positive breast cancer is relatively common and difficult to treat¹⁶

Ground breaking: Herceptin was at the forefront of a personalized medicine revolution⁹

Broad applications: Herceptin can treat a variety of cancer types, including adjuvant breast cancer, metastatic breast cancer and gastric cancer (stomach or gastroesophageal junction)¹⁵

Can be used in combination with a variety of other treatments, for instance, chemotherapy (paclitaxel, doxorubicin, and cyclophosphamide) and Perjeta¹⁹

Ongoing research and innovation, for instance, successfully linking antibody to chemotherapy with Kadcyla, thereby reducing chemotherapy's off target effects²⁰

New and emerging cancer therapies receive great media interest and coverage²¹:

In 2005, clinical trial results were presented at the American Society for Clinical Oncology (ASCO) and received front-page Canadian news coverage

Herceptin's efficacy was praised and there was public outcry regarding lack of public funding, which several Canadian provinces quickly provided, a response which earned them even greater coverage and a national newspaper award

The FDA granted fast track approval for Herceptin²²

Herceptin is referred to as a "miracle drug"²³

Recent studies suggest that Herceptin does not negatively impact quality of life longterm, or cause longterm cardiac damage (side effects are a major concern for cancer therapies)²³

In 2011, Herceptin was still the only FDA-approved therapeutic antibody for HER2-positive breast cancer²²

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Breast cancer and stomach cancer are among the most common cancers in the world ¹⁷

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A short video demonstration of Herceptin mechanism ⁴.

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https://tefalhead.wordpress.com/2011/02/24/possible-link-between-childbirth-and-risk-of-certain-types-of-breast-cancer/