A Door Opens

“Heads up, we got incoming!!!”

For Drs. Ira Mellman and Dan Chen, May 18, 2016 started out like any other day—the usual bustle and rush of the morning routine, the commute to the Genentech campus in South San Francisco and, in Chen’s case, a 7 a.m. meeting. Then, at 9:38 a.m., his cell phone started buzzing.

The “Heads up” text was from Dr. O. Daejin Abidoye. Abidoye is a member of the atezolizumab team, serving as the clinical filing lead for the multi-year effort toward the U.S. Food and Drug Administration (FDA) approval of Genentech’s first cancer immunotherapy. Normally, Chen wouldn’t keep checking his phone during a meeting, but these weren’t normal circumstances. The team had been told to expect news on the FDA’s decision any day now. That was last week. After anxious days of silence, Chen knew this might be history in the making.

Until recently, the notion that the immune system could be effectively enlisted to fight cancer may have been considered, at best, wishful thinking. Now it represented a scientific cutting edge in cancer treatment—the breakthrough that Chen, an oncologist, immunologist and vice president in charge of Genentech’s late stage global cancer immunotherapy development program, and Mellman, a well-respected cell biologist, immunologist and Genentech’s vice president of research cancer immunology, had been searching for their entire professional lives.

Their cancer medicine, atezolizumab (now known as TECENTRIQ®) Indication and Important Safety Information, was poised to be Genentech’s first cancer immunotherapy. The clinical trials also indicated it had potential to be the first significant drug development for people with previously treated advanced bladder cancer in more than 30 years. Now, all they needed was FDA approval.

Even after years of work, time was of the essence.

At 9:41 a.m., Chen’s pocket was still buzzing. Abidoye was texting emoticons now—smiley faces with gritted teeth. Did that mean nervous? The data were impressive, they’d worked tirelessly, but as Chen had cautioned his team, no outcome was ever certain. And so despite his confidence, he wondered—was there something to be nervous about?

“Stay tuned …” Abidoye had written. But by 9:45 a.m., Chen had already excused himself from the room and was jogging toward the stairs.

For the previous six months, the 4th floor of a building on the Genentech campus had been cordoned off for the team working to prepare the FDA submission for the investigational molecule. Now Chen emerged from the stairwell to find the filing team’s office already crowded with members of the atezolizumab team, including Dr. Gregg Fine, genitourinary global development lead, Kathleen Winson, global regulatory leader and Cathi Ahearn, life cycle team leader. Like many on the team, they had worked hard—years of days and nights and weekends—and now they were electric with anticipation and staring at Abidoye and his colleague, Jerald Grace, Pharm.D., the U.S. regulatory filing lead.

Grace stared at his email inbox, hitting the refresh button and waiting.

“Even after years of work, time was of the essence,” Chen explains. “Every day, we’d been racing against the clock. It was intense, because every day patients are struggling with this disease.”

The estimated 8,000 people diagnosed with advanced bladder cancer in the U.S. in 2016 had few options besides radical surgery and chemotherapy.1,2

“We intend to change this,” Chen had said to his team.

“There was an urgent need for new treatment options for advanced bladder cancer,” Chen explains. “We based our research decisions on scientific observation and had a strong hypothesis—but really, nobody knew what would happen. In my opinion, advanced bladder cancer was considered to be a minefield.”

Chen and Mellman had worked together at Genentech since 2007 when Mellman relocated from a professorship at Yale Medical School. Together, they helped guide Genentech’s research and drug development in immunotherapy and provided the foundational framework for cancer immunotherapy research, known as The Cancer-Immunity Cycle.

Starting from scratch, they’d quickly ramped up Genentech’s focus on a promising and unique target for drug development, which could impact many cancer types, including advanced bladder cancer, an underserved form of bladder cancer.

“In only a few years, cancer immunotherapy has evolved to become a key area of the oncology landscape,” Mellman explains. “The whole process has been so exciting—it’s not just one moment or development, it’s the progress made across the whole field of immunotherapy. How often do you get to experience a paradigm shift of this magnitude?”

In the spring of 2013, the atezolizumab team received the first indication that perhaps they had changed things.

Less than two weeks after some advanced bladder cancer patients received an initial dose of atezolizumab in the first Phase I clinical trial, investigators saw early evidence that the medicine appeared to be working. The team knew they had to get atezolizumab through clinical trials and to patients quickly.

While some advanced bladder cancer patients may have been involved in the Phase I and II studies of the medicine at major health centers, “those studies touch just a tiny fraction of advanced bladder cancer patients,” Fine explains. Most advanced bladder cancer patients are treated by local oncologists, often far from clinical trial sites where they might receive investigational medicines; in fact, Ahearn says, the cancer immunotherapy field was moving so fast, many had no idea atezolizumab was even being studied.

It was excitement and relief, reflection and forward-looking, all at once!

The promising early results prompted the FDA to grant atezolizumab Breakthrough Therapy Designation in May of 2014, expediting the development and review of the medicine. But only FDA approval would allow atezolizumab to be made available to the many patients in need Indication and Important Safety Information. Within 24 hours of approval, the medicine would be loaded onto planes en route to hospitals and clinics across the country; within 48 hours, the first patients would begin infusion. For the teams huddled anxiously at Genentech, and for patients in the U.S., there was no time to lose.

“DING.”

At 10:06 a.m., Grace blinked at the familiar sound of mail hitting his inbox. It was from the FDA. He leaned forward.

“In reference to your Biologics License Application …”

TECENTRIQ® (atezolizumab) Indication and Important Safety Information received accelerated approval for the treatment of people with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-based chemotherapy, or whose disease has worsened within 12 months of receiving platinum-based chemotherapy before surgery (neoadjuvant) or after surgery (adjuvant). TECENTRIQ is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.3



Possible serious side effects with TECENTRIQ include, but are not limited to, lung problems (pneumonitis), liver problems (hepatitis), intestinal problems (colitis), hormone gland problems (especially the pituitary, thyroid, adrenal glands and pancreas), nervous system problems (neuropathy, meningitis and encephalitis), eye problems (inflammation of the eyes), severe infections and severe infusion reactions. Additional information on these and other side effects can be found below.




There in the images, caught in camera flashes and phone video: the hoots and cheers and high fives and hugs. For Chen, news of the accelerated approval4 brought a “powerful release of emotion.” The steps that built up to the ultimate moment of approval—the research, the very first cancer patient to respond, finishing the pivotal trials—they all flashed rapid-fire before his eyes, like a slideshow.

“It was excitement and relief, reflection and forward-looking, all at once!” Chen remembers. “It was a very powerful moment—and a mark in Genentech’s history.”

But amazingly, looking back, Mellman doesn’t really remember that moment at all—he was already thinking ahead.

“I’m one of the most impatient people I know—that’s my personal affliction,” he laughs. “Usually, in drug development, you work on a drug, and if you’re successful, that’s the end of the story,” he explains. “But with cancer immunotherapy, it’s the opposite. We knew this would be just the beginning. With every breakthrough, right away, the question becomes ‘OK, that’s good—so what can we do next?’”

The coming days would be full of whoops and claps, speeches and balloons, and grown men and women, including Chen and Abidoye, leaping with raw joy. Even Mellman would allow himself a moment, joyfully ringing a little celebratory bell.

It was a remarkable moment. But, everyone knew, it was only a moment. A door had opened, for researchers and patients alike.

Read the companion piece: The Simplicity of It.


What it Treats

What is TECENTRIQ?

TECENTRIQ is a prescription medicine used to treat:

Adults with a type of lung cancer called non-small cell lung cancer (NSCLC).

  • TECENTRIQ may be used alone as a treatment for your lung cancer:
    • to help prevent your lung cancer from coming back after your tumor(s) has been removed by surgery and you have received platinum-based chemotherapy, and
    • you have stage 2 to stage 3A NSCLC (talk to your healthcare provider about what these stages mean), and
    • your cancer tests positive for “PD-L1”.
  • TECENTRIQ may be used alone as your first treatment when your lung cancer:
    • has spread or grown, and
    • your cancer tests positive for “high PD-L1”, and
    • your tumor does not have an abnormal “EGFR” or “ALK” gene.
  • TECENTRIQ may be used with the medicines bevacizumab, paclitaxel, and carboplatin as your first treatment when your lung cancer:
    • has spread or grown, and
    • is a type called “non-squamous NSCLC”, and
    • your tumor does not have an abnormal “EGFR” or “ALK” gene.
  • TECENTRIQ may be used with the medicines paclitaxel protein-bound and carboplatin as your first treatment when your lung cancer:
    • has spread or grown, and
    • is a type called “non-squamous NSCLC”, and
    • your tumor does not have an abnormal “EGFR” or “ALK” gene.
  • TECENTRIQ may be used alone when your lung cancer:
    • has spread or grown, and
    • you have tried chemotherapy that contains platinum, and it did not work or is no longer working.
    • If your tumor has an abnormal “EGFR” or “ALK” gene, you should have also tried an FDA-approved therapy for tumors with these abnormal genes, and it did not work or is no longer working.

Adults with a type of lung cancer called small cell lung cancer (SCLC). TECENTRIQ may be used with the chemotherapy medicines carboplatin and etoposide as your first treatment when your lung cancer:

  • is a type called “extensive-stage small cell lung cancer,” which means that it has spread or grown.

Adults with a type of liver cancer called hepatocellular carcinoma (HCC). TECENTRIQ may be used with the medicine bevacizumab when your liver cancer:

  • has spread or cannot be removed by surgery, and
  • you have not received other medicines by mouth or injection through your vein (IV) to treat your cancer.

Adults with a type of skin cancer called melanoma. TECENTRIQ may be used with the medicines cobimetinib and vemurafenib when your melanoma:

  • has spread to other parts of the body or cannot be removed by surgery, and
  • has a certain type of abnormal “BRAF” gene. Your healthcare provider will perform a test to make sure this TECENTRIQ combination is right for you.

Adults and children 2 years of age and older with a type of soft tissue tumor (cancer) called alveolar soft part sarcoma (ASPS). TECENTRIQ may be used when your sarcoma:

  • has spread to other parts of the body or cannot be removed by surgery.

It is not known if Tecentriq is safe and effective when used:

  • in children younger than 2 years of age for the treatment of ASPS.
  • In children for the treatment of NSCLC, SCLC, HCC or melanoma.

Important Safety Information

What is the most important information about TECENTRIQ?

TECENTRIQ can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. You can have more than one of these problems at the same time. These problems may happen anytime during your treatment or even after your treatment has ended.

Call or see your healthcare provider right away if you develop any new or worse signs or symptoms, including:

Lung problems

  • cough
  • shortness of breath
  • chest pain

Intestinal problems

  • diarrhea (loose stools) or more frequent bowel movements than usual
  • stools that are black, tarry, sticky, or have blood or mucus
  • severe stomach-area (abdomen) pain or tenderness

Liver problems

  • yellowing of your skin or the whites of your eyes
  • severe nausea or vomiting
  • pain on the right side of your stomach area (abdomen)
  • dark urine (tea colored)
  • bleeding or bruising more easily than normal

Hormone gland problems

  • headaches that will not go away or unusual headaches
  • eye sensitivity to light
  • eye problems
  • rapid heartbeat
  • increased sweating
  • extreme tiredness
  • weight gain or weight loss
  • feeling more hungry or thirsty than usual
  • urinating more often than usual
  • hair loss
  • feeling cold
  • constipation
  • your voice gets deeper
  • dizziness or fainting
  • changes in mood or behavior, such as decreased sex drive, irritability, or forgetfulness

Kidney problems

  • decrease in your amount of urine
  • blood in your urine
  • swelling of your ankles
  • loss of appetite

Skin problems

  • rash
  • itching
  • skin blistering or peeling
  • painful sores or ulcers in mouth or nose, throat, or genital area
  • fever or flu-like symptoms
  • swollen lymph nodes

Problems can also happen in other organs.

These are not all of the signs and symptoms of immune system problems that can happen with TECENTRIQ. Call or see your healthcare provider right away for any new or worse signs or symptoms, including:

 

  • Chest pain, irregular heartbeat, shortness of breath, or swelling of ankles
  • Confusion, sleepiness, memory problems, changes in mood or behavior, stiff neck, balance problems, tingling or numbness of the arms or legs
  • Double vision, blurry vision, sensitivity to light, eye pain, changes in eyesight
  • Persistent or severe muscle pain or weakness, muscle cramps
  • Low red blood cells, bruising

 

Infusion reactions that can sometimes be severe or life-threatening. Signs and symptoms of infusion reactions may include:

  • chills or shaking
  • itching or rash
  • flushing
  • shortness of breath or wheezing
  • dizziness
  • feeling like passing out
  • fever
  • back or neck pain

Complications, including graft-versus-host disease (GVHD), in people who have received a bone marrow (stem cell) transplant that uses donor stem cells (allogeneic). These complications can be serious and can lead to death. These complications may happen if you underwent transplantation either before or after being treated with TECENTRIQ. Your healthcare provider will monitor you for these complications.

Getting medical treatment right away may help keep these problems from becoming more serious. Your healthcare provider will check you for these problems during your treatment with TECENTRIQ. Your healthcare provider may treat you with corticosteroid or hormone replacement medicines. Your healthcare provider may also need to delay or completely stop treatment with TECENTRIQ if you have severe side effects.

Before you receive TECENTRIQ, tell your healthcare provider about all of your medical conditions, including if you:

  • have immune system problems such as Crohn’s disease, ulcerative colitis, or lupus
  • have received an organ transplant
  • have received or plan to receive a stem cell transplant that uses donor stem cells (allogeneic)
  • have received radiation treatment to your chest area
  • have a condition that affects your nervous system, such as myasthenia gravis or Guillain-Barré syndrome
  • are pregnant or plan to become pregnant. TECENTRIQ can harm your unborn baby. Tell your healthcare provider right away if you become pregnant or think you may be pregnant during treatment with TECENTRIQ. Females who are able to become pregnant:
    • Your healthcare provider should do a pregnancy test before you start treatment with TECENTRIQ.
    • You should use an effective method of birth control during your treatment and for at least 5 months after the last dose of TECENTRIQ.
  • are breastfeeding or plan to breastfeed. It is not known if TECENTRIQ passes into your breast milk. Do not breastfeed during treatment and for at least 5 months after the last dose of TECENTRIQ.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of TECENTRIQ when used alone include:

  • feeling tired or weak
  • decreased appetite
  • nausea
  • cough
  • shortness of breath

The most common side effects of TECENTRIQ when used in lung cancer with other anti-cancer medicines include:

  • feeling tired or weak
  • nausea
  • hair loss
  • constipation
  • diarrhea
  • decreased appetite

The most common side effects of TECENTRIQ when used in hepatocellular carcinoma (HCC) with bevacizumab include:

  • high blood pressure
  • feeling tired or weak
  • too much protein in the urine

The most common side effects of TECENTRIQ when used in melanoma with cobimetinib and vemurafenib include:

  • skin rash
  • joint, muscle, or bone pain
  • feeling tired or weak
  • liver injury
  • fever
  • nausea
  • itching
  • swelling of legs or arms
  • mouth swelling (sometimes with sores)
  • low thyroid hormone levels
  • sunburn or sun sensitivity

TECENTRIQ may cause fertility problems in females, which may affect the ability to have children. Talk to your healthcare provider if you have concerns about fertility.

These are not all the possible side effects of TECENTRIQ. Ask your healthcare provider or pharmacist for more information about the benefits and side effects of TECENTRIQ.

You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555.

Please see full Prescribing Information and Medication Guide for additional Important Safety Information.

 

1. National Cancer Institute. SEER Stat Fact Sheets: Bladder Cancer. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed September 9, 2016.
2. American Society of Clinical Oncology. Bladder Cancer: Treatment Options. http://www.cancer.net/cancer-types/bladder-cancer/treatment-options. Last updated 5/2016. Accessed October 3, 2016.
3. TECENTRIQ Prescribing Information. South San Francisco, Calif.: Genentech, Inc. 2016.
4. Genentech. FDA Grants Genentech’s Cancer Immunotherapy TECENTRIQ™ (atezolizumab) Accelerated Approval for People with a Specific Type of Advanced Bladder Cancer. May 18, 2016. Retrieved October 11, 2016 from: https://www.gene.com/media/press-releases/14626/2016-05-18/fda-grants-genentechs-cancer-immunothera