Swinging for the Fences

Most experiments fail. Many well-respected scientists spend their entire careers without seeing any of their projects become approved treatments. And for all the highly celebrated wins in medicine, most researchers live with many more quiet defeats. Nevertheless, these moments are still a crucial part of the scientific process, because even in failure, we answer important questions that help us to move forward.

Mark Sliwkowski, distinguished staff scientist, molecular oncology, recalls a moment when a medicine he’d been working on returned disappointing results … and the surprising story of what happened next.


AT THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY MEETING IN 2005, DATA FROM TRIALS OF TWO MEDICINES YOU WERE WORKING ON WERE PRESENTED, WITH VERY DIFFERENT RESULTS. WHAT WAS THAT MEETING LIKE FOR YOU?

MARK SLIWKOWSKI: That time was an emotional roller coaster. On the one hand, I was delighted because we saw promising results with Herceptin® (trastuzumab) Indication and Important Safety Information in combination with chemotherapy that would change the treatment landscape for early HER2-positive breast cancer and have an impact on patients facing this aggressive disease.

But at that same conference, there were also some disappointing results from another potential medicine we were exploring in several other types of cancer. Back then it was known as omnitarg (now Perjeta Indication and Important Safety Information )—a second-generation antibody we believed blocked the activity of some of the HER family of receptors, which are responsible for the proliferation of certain cancer cells.1 We had been working on this molecule for several years and had high hopes that what we’d seen in the lab might ultimately translate into something that could help cancer patients.

Unfortunately, the results of those trials did not meet our expectations, and it was very depressing for the team.2 It’s such a long, painstaking process to get a molecule into clinical trials, and the stakes are high. Despite the success we’d seen with Herceptin, there was—and is still—so much more to be done. As someone who worked on both medicines, I was at the highest point with one and the lowest with the other.



In November 2006, the Food and Drug Administration approved Herceptin for treating early-stage HER2-positive breast cancer when given with chemotherapy (doxorubicin, cyclophosphamide and paclitaxel) after surgery. Herceptin carries a boxed warning for serious cardiac risks associated with the medicine, as well as potential infusion reactions, risk for severe lung problems, and the potential to harm an unborn baby. Indication and Important Safety Information


WHAT'S THAT LIKE, WHEN YOU'VE INVESTED YEARS IN SOMETHING YOU BELIEVE IN THAT DOESN'T WORK AS YOU'D HOPED?

MARK SLIWKOWSKI: Scientists are optimists, but also realists, and the reality is that it’s relatively rare in our industry to work on a molecule that you see cross the finish line. Most of us went into science because we enjoy the process, but we also dream big dreams. You always hope you’ll work on projects that get approved and can ultimately help patients, especially in a devastating disease like cancer. When something you’d hoped would make a significant difference in the fight against this disease does not, at that moment, you can feel like all that work was for nothing. And that’s how we felt about Perjeta at that point in 2005.

WHAT HAPPENS WHEN THE DREAM DOESN'T COME TRUE?

MARK SLIWKOWSKI: At Genentech, we’re focused on translating science into medicines for serious diseases, so we try to swing for the fences. When you do that, you’re going to strike out a lot, and that’s part of the deal. There’s no question that you get depressed and go through all the stages of grief. There’s a lot of denial and anger. But you have to be willing to have your heart broken. The key is to make sure it doesn’t break your spirit, motivation and drive. Whenever there’s a failure, you’ve got to get up, brush yourself off, and move on.

DID YOU THINK THAT WAS THE END OF THE STORY FOR PERJETA AT THAT POINT?

MARK SLIWKOWSKI: To some degree yes, it felt like it was circling the drain. Given the Phase II results we’d seen, we had to put Perjeta on the back burner, especially here at Genentech.

However, we were already collaborating closely with Roche on developing the medicine. The team there, in consultation with physician investigators including Luca Gianni and José Baselga, was still bullish on the idea of testing it further. Only this time, it would be Perjeta in combination with Herceptin and chemotherapy in patients whose HER2-positive metastatic breast cancer had progressed after receiving Herceptin and chemotherapy. We hypothesized that the two medicines might work together, in complementary ways, to slow HER2-positive breast cancer more effectively than either medicine alone.1 So the Roche team persevered with Perjeta in really what was a last-ditch effort, and that partnership turned out to be key in this story.

WHAT HAPPENED NEXT?

MARK SLIWKOWSKI: Quite simply, the last-ditch effort worked! Early data presented in 2007 were very promising for Perjeta.3 This then led to a pivotal Phase III trial that eventually showed the Perjeta regimen extended the time people lived without their disease worsening or death by a median of six months (median 18.5 vs. 12.4 months). Perjeta was ultimately approved in combination with Herceptin and docetaxel chemotherapy for previously untreated HER2-positive metastatic breast cancer (in 2012).1,4 When I first saw these data on July 13, 2011, it was truly the best day of my career and quite a turnaround for a medicine that almost never came to be. Indication and Important Safety Information

Later, in 2014, we presented overall survival results for Perjeta in previously untreated HER2-positive metastatic breast cancer. The study showed the Perjeta regimen extended the lives of those who received it by almost 16 months compared to Herceptin and chemotherapy alone (median 56.5 vs. 40.8 months).1,6 It’s important to note that receiving Perjeta-based therapy can also result in serious side effects, such as cardiac risks and the potential to harm an unborn baby.1,5



The most common side effects of Perjeta are diarrhea, hair loss, low levels of white blood cells with or without a fever, nausea, feeling tired, rash and damage to the nerves (numbness, tingling, pain in hands/feet). Indication and Important Safety Information


WHAT HAVE YOU LEARNED FROM THE PERJETA EXPERIENCE?

MARK SLIWKOWSKI: Our fundamental laboratory studies on HER2 activation as well as our partnership and perseverance were key factors in Perjeta’s success. Without the scientific collaboration from Roche and physician investigators, without the bravery and dedication of patients who were willing to participate in clinical trials, we might not have seen such progress in the fight against this disease. I feel I’ve been lucky to be at the right place at the right time. We scientists expect to strike out a lot along the way, but it’s a lot better when the ball goes over the fence.

Important Safety Information

What it Treats

Perjeta® (pertuzumab) is a prescription medicine approved for use in combination with Herceptin® (trastuzumab) and docetaxel in people who have HER2-positive breast cancer that has spread to different parts of the body (metastatic) and who have not received anti-HER2 therapy or chemotherapy for metastatic breast cancer.

Important Safety Information and Serious Side Effects

What should I know about side effects with PERJETA?

  • Not all people have serious side effects; however, side effects with PERJETA therapy are common. It is important to know what side effects may happen and what symptoms you should watch for
  • Your doctor may stop treatment if serious side effects happen. Be sure to contact your healthcare team right away if you have questions or are worried about any side effects

What are the most serious side effects?

PERJETA may cause heart problems, including those without symptoms (such as reduced heart function) and those with symptoms (such as congestive heart failure).

  • Your doctor may run tests to monitor your heart function before and during treatment with PERJETA
  • Based on test results your doctor may hold or discontinue treatment with PERJETA

Receiving PERJETA during pregnancy can result in the death of an unborn baby and birth defects.

  • Birth control should be used while receiving PERJETA and for 7 months after your last dose of PERJETA. If you are a mother who is breastfeeding, you should talk with your doctor about either stopping breastfeeding or stopping PERJETA
  • If you think you may be pregnant, you should contact your healthcare provider immediately
  • If you are exposed to PERJETA during pregnancy, or become pregnant while receiving PERJETA or within 7 months following the last dose of PERJETA in combination with Herceptin, you are encouraged to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 or visiting http://www.motherpregnancyregistry.com/ and report PERJETA exposure to Genentech at 1-888-835-2555

What are other possible serious side effects?

  • PERJETA should not be used in patients who are allergic to pertuzumab or to any of the ingredients in PERJETA
  • Infusion-related reactions: PERJETA is a medicine that is delivered into a vein through a needle. This process can cause reactions known as infusion-related reactions. The most common infusion-related reactions when receiving PERJETA, Herceptin, and docetaxel were feeling tired, abnormal or altered taste, allergic reactions, muscle pain, and vomiting. The most common infusion-related reactions when receiving PERJETA alone were fever, chills, feeling tired, headache, weakness, allergic reactions, and vomiting
  • Severe allergic reactions: Some people receiving PERJETA may have severe allergic reactions, called hypersensitivity reactions or anaphylaxis. This reaction may be severe, may happen quickly, and may affect many areas of the body

How will my doctor and I know if PERJETA is right for me?

PERJETA has only been shown to work in people with HER2-positive breast cancer. You must have a HER2 test to know if your breast cancer is HER2-positive before receiving an anti-HER2 treatment, such as PERJETA.

What are the most common side effects?

The most common side effects of PERJETA when given with Herceptin and docetaxel for treatment of breast cancer that has spread to other parts of the body (metastatic) are:

  • Diarrhea
  • Hair loss
  • Low levels of white blood cells with or without a fever
  • Nausea
  • Feeling tired
  • Rash
  • Damage to the nerves (numbness, tingling, pain in hands/feet)

Report side effects to Genentech and the FDA. Report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. Report side effects to Genentech at (888) 835-2555.

Please see PERJETA full Prescribing Information including Most Serious Side Effect for additional Important Safety Information at www.perjeta.com.

What it Treats

Adjuvant Breast Cancer

Herceptin is approved for the treatment of early-stage breast cancer that is Human Epidermal growth factor Receptor 2-positive (HER2+) and has spread into the lymph nodes, or is HER2-positive and has not spread into the lymph nodes. If it has not spread into the lymph nodes, the cancer needs to be estrogen receptor/progesterone receptor (ER/PR)-negative or have one high-risk feature.* Herceptin can be used in several different ways:

  • As part of a treatment course including the chemotherapy drugs doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel. This treatment course is known as “ACTH
  • With the chemotherapy drugs docetaxel and carboplatin. This treatment course is known as “TCH
  • Alone after treatment with multiple other therapies, including an anthracycline (doxorubicin) based therapy (a type of chemotherapy)

Patients are selected for therapy based on an FDA-approved test for Herceptin

*High-risk is defined as ER/PR-positive with one of the following features: tumor size >2 cm, age <35 years, or tumor grade 2 or 3.

Metastatic Breast Cancer

Herceptin has 2 approved uses in metastatic breast cancer:

  • Herceptin in combination with the chemotherapy drug paclitaxel is approved for the first line treatment of Human Epidermal growth factor Receptor 2-positive (HER2+) metastatic breast cancer
  • Herceptin alone is approved for the treatment of HER2-positive breast cancer in patients who have received one or more chemotherapy courses for metastatic disease

Patients are selected for therapy based on an FDA-approved test for Herceptin

Gastric Cancer

Herceptin is approved, in combination with chemotherapy (cisplatin and either capecitabine or 5-fluorouracil), for the treatment of HER2-positive metastatic cancer of the stomach or gastroesophageal junction (where the esophagus meets the stomach) in patients who have not received prior treatment for their metastatic disease.

Patients are selected for therapy based on an FDA-approved test for Herceptin.

Important Safety Information

Possible Serious Side Effects With HERCEPTIN

Not all people have serious side effects, but side effects with HERCEPTIN therapy are common.

Although some people may have a life-threatening side effect, most do not.

Your doctor will stop treatment if any serious side effects occur.

HERCEPTIN is not for everyone. Be sure to contact your doctor if you are experiencing any of the following:

HEART PROBLEMS

These include heart problems—such as congestive heart failure or reduced heart function—with or without symptoms. The risk for and seriousness of these heart problems were highest in people who received both HERCEPTIN and a certain type of chemotherapy (anthracycline). In a study of adjuvant (early) breast cancer, one patient died of significantly weakened heart muscle. Your doctor will check for signs of heart problems before, during, and after treatment with HERCEPTIN.

INFUSION REACTIONS, including:

  • Fever and chills
  • Feeling sick to your stomach (nausea)
  • Throwing up (vomiting)
  • Pain (in some cases at tumor sites)
  • Headache
  • Dizziness
  • Shortness of breath

These signs usually happen within 24 hours after receiving HERCEPTIN.

Be sure to contact your doctor if you:

Are a woman who could become pregnant, or may be pregnant

HERCEPTIN may result in the death of an unborn baby or birth defects. Contraception should be used while receiving HERCEPTIN and for 7 months after your last dose of HERCEPTIN. If you are or become pregnant while receiving HERCEPTIN or within 7 months after your last dose of HERCEPTIN, you should immediately report HERCEPTIN exposure to Genentech at 1-888-835-2555.

Have any signs of SEVERE LUNG PROBLEMS, including:

  • Severe shortness of breath
  • Fluid in or around the lungs
  • Weakening of the valve between the heart and the lungs
  • Not enough oxygen in the body
  • Swelling of the lungs
  • Scarring of the lungs

Your doctor may check for signs of severe lung problems when he or she examines you.

Have LOW WHITE BLOOD CELL COUNTS

Low white blood cell counts can be life threatening. Low white blood cell counts were seen more often in patients receiving HERCEPTIN plus chemotherapy than in patients receiving chemotherapy alone.

Your doctor may check for signs of low white blood cell counts when he or she examines you.

Side Effects Seen Most Often With HERCEPTIN

Some patients receiving HERCEPTIN for breast cancer had the following side effects:

  • Fever
  • Feeling sick to your stomach (nausea)
  • Throwing up (vomiting)
  • Infusion reactions
  • Diarrhea
  • Infections
  • Increased cough
  • Headache
  • Feeling tired
  • Shortness of breath
  • Rash
  • Low white and red blood cell counts
  • Muscle pain

Some patients receiving HERCEPTIN for metastatic stomach cancer had the following side effects:

  • Low white blood cell counts
  • Diarrhea
  • Feeling tired
  • Low red blood cell counts
  • Swelling of the mouth lining
  • Weight loss
  • Upper respiratory tract infections
  • Fever
  • Low platelet counts
  • Swelling of the mucous membranes
  • Swelling of the nose and throat
  • Change in taste

You should contact your doctor immediately if you have any of the side effects listed above.

You are encouraged to report side effects to Genentech and the FDA. You may report side effects to the FDA at 1–800–FDA–1088 or http://www.fda.gov/medwatch.

You may also report side effects to Genentech at 1–888–835–2555.

Please see additional select Important Safety Information throughout, and the accompanying full Prescribing Information, including Boxed WARNINGS.

1. Perjeta [package insert]. South San Francisco, Calif.: Genentech, Inc. 2016.
2. Genentech. Data From Omnitarg Clinical Program Presented at American Society of Clinical Oncology Meeting. May 15, 2005. Retrieved May 11, 2017 from http://www.gene.com/media/press-releases/8431/2005-05-15/data-from-omnitarg-clinical-program-pres.
3. Genentech. Genentech Provides Update on Pipeline Agents at The American Society of Clinical Oncology Meeting. June 3, 2007. Retrieved May 11, 2017 from http://www.gene.com/media/press-releases/10729/2007-06-03/genentech-provides-update-on-pipeline-ag.
4. Genentech. FDA Approves Perjeta (Pertuzumab) for People With HER2-Positive Metastatic Breast Cancer. June 8, 2012. Retrieved May 11, 2017 from /http://www.gene.com/media/press-releases/14007/2012-06-08/fda-approves-perjeta-pertuzumab-for-peop.
5. Herceptin [package insert]. South San Francisco, Calif.: Genentech, Inc. 2017.
6. Genentech. Genentech’s Perjeta Regimen Extended the Lives of People With an Aggressive Type of Metastatic Breast Cancer By 15.7 Months Compared to Herceptin and Chemotherapy. September 28, 2014. Retrieved May 11, 2017 from http://www.gene.com/media/press-releases/14574/2014-09-28/genentechs-perjeta-regimen-extended-the-.