Monday, Feb 5, 2018

Phase III IMmotion151 Study Showed Genentech’s TECENTRIQ (Atezolizumab) and Avastin (Bevacizumab) Reduced the Risk of Disease Worsening or Death by 26 Percent in Certain People with Advanced Kidney Cancer

TECENTRIQ and Avastin met co-primary endpoint of investigator-assessed progression-free survival (PFS) compared with sunitinib for people whose disease expressed PD-L1

IMmotion151 is the second Phase III study to show positive PFS results for a treatment regimen including TECENTRIQ plus Avastin

Data will be discussed with global health authorities, including the U.S. Food and Drug Administration (FDA)

South San Francisco, CA -- February 5, 2018 --

Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced results from the positive Phase III IMmotion151 study of TECENTRIQ^® (atezolizumab) and Avastin^® (bevacizumab) as a first-line treatment for advanced or metastatic renal cell carcinoma (mRCC). The study met its co-primary endpoint of investigator-assessed progression-free survival (PFS) in people whose disease expressed the PD-L1 (programmed death-ligand 1: expression ≥ 1 percent) protein. Those who received TECENTRIQ plus Avastin had a 26-percent reduced risk of disease worsening or death (PFS) compared to people treated with sunitinib (median PFS [mPFS]: 11.2 vs. 7.7 months; HR=0.74; 95 percent CI 0.57, 0.96; p=0.02). Initial observations from the co-primary endpoint of overall survival (OS) in the overall study population (intention-to-treat, ITT) were encouraging, but are still immature. Safety for the TECENTRIQ and Avastin combination appeared consistent with the known safety profile of the individual medicines and what was previously reported in the Phase II IMmotion150 study. No new safety signals were identified with the combination. The rate of treatment-related Grade 3-4 adverse events was lower with the TECENTRIQ and Avastin combination (40 percent) than with sunitinib alone (54 percent) in all treated patients.

Observations of a pre-specified subgroup analysis of the TECENTRIQ and Avastin combination indicated that, in people whose disease expressed PD-L1, a numerical difference in PFS favoring TECENTRIQ was seen across all patient risk factor groups (favorable, intermediate and poor) compared to sunitinib. In addition, a pre-defined analysis of patient-reported outcomes (PRO) revealed that the combination of TECENTRIQ and Avastin markedly delayed the time to a worsening of disease symptoms that interfere with day-to-day life compared to sunitinib, (median time to deterioration: 11.3 vs. 4.3 months; HR=0.56; 95 percent CI: 0.46, 0.68) in the ITT population. Due to the study design, pre-defined subgroup analyses and pre-defined PRO analyses were not assessed for statistical significance and are descriptive only.

“This is the second positive Phase III study that includes TECENTRIQ and Avastin as part of a treatment regimen, providing further evidence to support the potential of this unique combination,” said Sandra Horning, M.D., chief medical officer and head of Global Product Development. “We are encouraged that initial treatment with TECENTRIQ and Avastin significantly reduced the risk of disease worsening or death in people with advanced kidney cancer, while also providing more time before disease symptoms interfered with day-to-day life compared with sunitinib, a current standard of care. We look forward to discussing these results with regulatory authorities worldwide.”

The late-breaking IMmotion151 data will be presented at the 2018 Genitourinary Cancers Symposium on Saturday, Feb. 10 from 1:00-2:00 p.m. Pacific Time (PT) (Abstract #578), and were highlighted as part of the conference’s official press program.

About the IMmotion151 study

IMmotion151 is a Phase III multicenter, randomized, open-label study to evaluate the efficacy and safety of TECENTRIQ and Avastin versus sunitinib in people with inoperable, locally advanced or metastatic renal cell carcinoma (RCC) who have not received prior systemic active or experimental therapy. It enrolled 915 people globally who were randomized 1:1 to receive TECENTRIQ and Avastin, or sunitinib alone.

People in the TECENTRIQ and Avastin arm received TECENTRIQ at a fixed dose of 1200 milligrams (mg) and Avastin at a dose of 15 milligrams per kilogram (mg/kg) via intravenous (IV) infusion every 3 weeks until loss of clinical benefit or unacceptable toxicity. People in the sunitinib arm received sunitinib 50 mg orally, once daily for 4 weeks followed by 2 weeks rest until loss of clinical benefit or unacceptable toxicity.

The co-primary endpoints were PFS, as determined by the investigator using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in people whose tumors expressed PD-L1 (expression ≥1 percent on immune cells [IC]), and OS in the overall study population (intention-to-treat, ITT). PD-L1 expression was prospectively assessed using an immunohistochemistry (IHC) test (SP142) developed by Roche Tissue Diagnostics. Secondary endpoints included OS in people whose tumors expressed PD-L1, PFS as determined by an Independent Review Facility (IRF) according to RECIST v1.1, investigator-assessed objective response rate (ORR) and median duration of response (mDOR), change from baseline in symptom interference and symptom severity as determined by M.D. Anderson Symptom Inventory (MDASI), and change from baseline in health-related quality of life as determined by European Quality of Life 5-Dimension (EQ-5D) Scores.

Stratification factors included the Memorial Sloan-Kettering Cancer Center (Motzer) prognostic scoring system, which predicts for OS based upon an individual’s baseline clinical and laboratory characteristics. Depending on the presence of one or several of five variables (risk factors), people are classified in one of the three risk groups: “Favorable” with 0 risk factors, “Intermediate” with 1-2 risk factors and “Poor” with ≥ 3 risk factors.

Phase III IMmotion151 Study Results: Investigator Assessed
Population	PD-L1+ (programmed death-ligand 1: Expression ≥1% on IC) n = 362			ITT (intent-to-treat) n = 915
Treatment Arm	Sunitinib n = 184	TECENTRIQ & Avastin n= 178		Sunitinib n = 461	TECENTRIQ & Avastin n= 454
PFS	Co-Primary			Secondary
mPFS (95% CI)	7.7 months (6.8, 9.7)	11.2 months (8.9, 15.0)		8.4 months (7.5, 9.7)	11.2 months (9.6, 13.3)
Stratified HR (95% CI)	0.74 (0.57, 0.96) P = 0.02			0.83 (0.70, 0.97)
ORR	Secondary			Secondary
ORR (95% CI)	35% (28, 42)	43% (35, 50)		33% (29, 38)	37% (32, 41)
mDOR (95% CI)	12.9 months (9.8, NE)	NE (12.4, NE)		14.2 months (11.3, NE)	16.6 months (15.4, NE)
Phase III IMmotion151 Study Results: IRF-Assessed a
Population	PD-L1+ (programmed death-ligand 1: Expression ≥1% on IC) n = 362			ITT (intent-to-treat) n = 915
PFS	Secondary			Secondary
mPFS (95% CI)	7.2 months (6.1, 11.1)	8.9 months (6.9, 12.5)		8.3 months (7.0, 9.7)	9.6 months (8.3, 11.5)
Stratified HR (95% CI)	0.93 (0.72, 1.21)			0.88 (0.74, 1.04)
Initial observations from the co-primary endpoint of overall survival: Descriptive Only
Treatment	TECENTRIQ & Avastin		Sunitinib	TECENTRIQ & Avastin	Sunitinib
Population	PD-L1+ (programmed death-ligand 1: Expression ≥1% on IC) n = 362			ITT (intent-to-treat) n = 915
Median OS	Not reached		23.3 (21.3, NR)	Not reached
HR (95% CI)	0.68 (0.46, 1.00)			0.81 (0.63, 1.03)
Event/patient ratio: PD-L1+, TECENTRIQ and Avastin, 25% and sunitinib, 35%; ITT, TECENTRIQ and Avastin, 27% and sunitinib, 31%. Assessed by investigator; minimum follow-up, 12 mo. Median of follow-up, 15 months.

NE, not estimable ^aData assessed by independent review facility

^✳ Difference in IRF-assessed PFS HR driven by IC1/2/3 population (IRF-assessed PFS HR in IC0 was 0.84 compared to 0.93 for Investigator-assessed PFS in IC0) despite study participants being blinded to PD-L1 status. Totality of data support the Investigator assessment of PFS. Preparations for further analyses of IRF-assessed PFS are ongoing.

About renal cell carcinoma

According to the American Cancer Society, more than 63,300 people will be diagnosed with kidney cancer in 2018. Renal cell carcinoma (RCC) accounts for approximately 90 percent of all cases. RCC occurs when abnormal cells develop in the tissue of the kidneys, specifically in the small tubes (also known as tubules) where the blood is filtered. Typically, RCC is a single tumor in one kidney but, in rare cases, there can be multiple tumors, which can occur in one or both kidneys. Despite recent progress in the field of kidney cancer, treatment options for people with the disease remains limited.

About the TECENTRIQ (atezolizumab) and Avastin (bevacizumab) combination

There is a strong scientific rationale to support further investigation of TECENTRIQ plus Avastin in combination. We are investigating this combination in a broad range of cancers, including advanced RCC. Avastin, in addition to its anti-angiogenic effects, may further enhance TECENTRIQ’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumor infiltration and enabling priming and activation of T-cell responses against tumor antigens.

About TECENTRIQ^® (atezolizumab)

TECENTRIQ is a monoclonal antibody designed to bind with a protein called PD-L1. TECENTRIQ is designed to bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, TECENTRIQ may enable the re-activation of T cells. TECENTRIQ may also affect normal cells.

About Avastin^® (bevacizumab)

Avastin is a prescription-only medicine that is a solution for intravenous infusion. It is a biologic antibody designed to specifically bind to a protein called vascular endothelial growth factor (VEGF) that plays an important role throughout the lifecycle of the tumor to develop and maintain blood vessels, a process known as angiogenesis. Avastin is designed to interfere with the tumor blood supply by directly binding to the VEGF protein to prevent interactions with receptors on blood vessel cells. The tumor blood supply is thought to be critical to a tumor's ability to grow and spread in the body (metastasize). Avastin is the only currently available treatment for people with mRCC that directly inhibits VEGF.

TECENTRIQ U.S. Indication (pronounced ‘tē-SEN-trik’)

TECENTRIQ is a prescription medicine used to treat:

a type of bladder and urinary tract cancer called urothelial carcinoma.

• TECENTRIQ may be used when your bladder cancer:
  • has spread or cannot be removed by surgery (advanced urothelial carcinoma), and
  • you are not able to take chemotherapy that contains a medicine called cisplatin, or
  • you have tried chemotherapy that contains platinum, and it did not work or is no longer working.

The approval of TECENTRIQ in these patients is based on a study that measured response rate and duration of response. There is an ongoing study to confirm clinical benefit.

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

• TECENTRIQ may be used 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.

It is not known if TECENTRIQ is safe and effective in children.

Important Safety Information

Important Information About TECENTRIQ

TECENTRIQ can cause the immune system to attack normal organs and tissues in many areas of the body and can affect the way they work. These problems can sometimes become serious or life-threatening and can lead to death.

Getting medical treatment right away may help keep these problems from becoming more serious. A healthcare provider may treat a patient with corticosteroid or hormone replacement medicines. A healthcare provider may delay or completely stop treatment with TECENTRIQ if a patient has severe side effects.

Patients should call or see their healthcare provider right away if they get any symptoms of the following problems or these symptoms get worse.

TECENTRIQ can cause serious side effects, including:

• Lung Problems (pneumonitis) – Signs and symptoms of pneumonitis may include: new or worsening cough, shortness of breath, or chest pain
• Liver Problems (hepatitis) – Signs and symptoms of hepatitis may include: yellowing of the skin or the whites of the eyes, severe nausea or vomiting, pain on the right side of the stomach area (abdomen), drowsiness, dark urine (tea colored), bleeding or bruising more easily than normal, feeling less hungry than usual
• Intestinal Problems (colitis) – Signs and symptoms of colitis may include: diarrhea (loose stools) or more bowel movements than usual, blood in the stools or dark, tarry, sticky stools, severe stomach area (abdomen) pain or tenderness
• Hormone Gland Problems (especially the pituitary, thyroid, adrenal glands and pancreas) – Signs and symptoms that the hormone glands are not working properly may include: headaches that will not go away or unusual headaches, extreme tiredness, weight gain or weight loss, dizziness or fainting, feeling more hungry or thirsty than usual, hair loss, changes in mood or behavior (such as decreased sex drive, irritability, or forgetfulness), feeling cold, constipation, voice gets deeper, urinating more often than usual, nausea or vomiting, stomach area (abdomen) pain
• Nervous System Problems (neuropathy, meningitis, encephalitis) – Signs and symptoms of nervous system problems may include: severe muscle weakness, numbness or tingling in hands and feet, fever, confusion, changes in mood or behavior, extreme sensitivity to light, neck stiffness
• Inflammation of the Eyes – Signs and symptoms may include blurry vision, double vision, other vision problems, eye pain or redness
• Severe Infections – Signs and symptoms of infection may include: fever, cough, frequent urination, flu-like symptoms, pain when urinating
• Severe Infusion Reactions – Signs and symptoms of infusion reactions may include: chills or shaking, itching or rash, flushing, shortness of breath or wheezing, dizziness, fever, feeling like passing out, back or neck pain, and swelling of the face or lips

Before receiving TECENTRIQ, patients should tell their healthcare provider about all of their medical conditions, including if they:

• Have immune system problems (such as Crohn’s disease, ulcerative colitis, or lupus); have had an organ transplant; have lung or breathing problems; have liver problems; have a condition that affects their nervous system (such as myasthenia gravis, or Guillain-Barre syndrome); or are being treated for an infection
• Are pregnant or plan to become pregnant
  • TECENTRIQ can harm an unborn baby
  • If patients are able to become pregnant, they should use an effective method of birth control during 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 the breast milk
  • Do not breastfeed during treatment and for at least 5 months after the last dose of TECENTRIQ

Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

The most common side effects of TECENTRIQ in people with urothelial carcinoma include:

• feeling tired
• decreased appetite
• nausea
• constipation
• urinary tract infection
• diarrhea
• fever

The most common side effects of TECENTRIQ in people with non-small cell lung cancer include:

• feeling tired
• decreased appetite
• shortness of breath
• cough
• nausea
• muscle or bone pain
• constipation

These are not all the possible side effects of TECENTRIQ. Patients should ask their healthcare provider or pharmacist for more information.
TECENTRIQ may cause fertility problems in females, which may affect the ability to have children. Patients should talk to their healthcare provider if they have concerns about fertility.

Report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch . Report side effects to Genentech at 1-888-835-2555.

Please visit http://www.Tecentriq.com for the TECENTRIQ full Prescribing Information for additional Important Safety Information.

Avastin Indications:

• Metastatic colorectal cancer (mCRC) for first- or second-line treatment in combination with intravenous 5-fluorouracil–based chemotherapy. It is also approved to treat mCRC for second-line treatment when used with fluoropyrimidine-based (combined with irinotecan or oxaliplatin) chemotherapy after cancer progresses following a first-line treatment that includes Avastin.
• Avastin is not approved for use after the primary treatment of colon cancer that has not spread to other parts of the body.
• Advanced nonsquamous non–small cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel in people who have not received chemotherapy for their advanced disease.
• Metastatic kidney cancer (mRCC) when used with interferon alfa.
• Glioblastoma (GBM) in adult patients whose cancer has progressed after prior treatment (recurrent or rGBM).
• Advanced cervical cancer (CC) in combination with paclitaxel and cisplatin or paclitaxel and topotecan is approved to treat persistent, recurrent, or metastatic cancer of the cervix.
• Recurrent ovarian cancer (rOC) . Avastin in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan, is approved to treat platinum-resistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer (prOC) in women who received no more than two prior chemotherapy treatments. Avastin, either in combination with carboplatin and paclitaxel or with carboplatin and gemcitabine, followed by Avastin alone, is approved for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer (psOC).

Possible serious side effects

Everyone reacts differently to Avastin therapy. So it’s important to know what the side effects are. Although some people may have a life-threatening side effect, most do not. Their doctor will stop treatment if any serious side effects occur. Patients should talk to their doctor if there are any signs of these side effects.

Most serious side effects (not common, but sometimes fatal):

• GI perforation . A hole that develops in the stomach or intestine. Symptoms include pain in the abdomen, nausea, vomiting, constipation, or fever

• Wounds that don’t heal . A cut made during surgery can be slow to heal or may not fully heal. Avastin should not be used for at least 28 days before or after surgery and until surgical wounds are fully healed

• Serious bleeding . This includes vomiting or coughing up blood; bleeding in the stomach, brain, or spinal cord; nosebleeds; and vaginal bleeding. If a patient has recently coughed up blood or had serious bleeding, they should be sure to tell their doctor

Other possible serious side effects

• Abnormal passage in the body . This type of passage—known as a fistula—is an irregular connection from one part of the body to another and can sometimes be fatal
• Severe high blood pressure . Blood pressure that severely spikes or shows signs of affecting the brain. Blood pressure should be monitored every 2 to 3 weeks while on Avastin and after stopping treatment
• Kidney problems . These may be caused by too much protein in the urine and can sometimes be fatal
• Infusion reactions . These were uncommon with the first dose (less than 3 percent of patients). 0.2 percent of patients had severe reactions. Infusion reactions include high blood pressure or severe high blood pressure that may lead to stroke, trouble breathing, decreased oxygen in red blood cells, a serious allergic reaction, chest pain, headache, tremors, and excessive sweating. The patient’s doctor or nurse will monitor for signs of infusion reactions
• Severe stroke or heart problems . These may include blood clots, mini-stroke, heart attack, chest pain, and the heart may become too weak to pump blood to other parts of the body (congestive heart failure). These can sometimes be fatal
• Nervous system and vision problems . Signs include headache, seizure, high blood pressure, sluggishness, confusion, and blindness

Side effects seen most often

In clinical studies across different types of cancer, some patients experienced the following side effects:

• High blood pressure
• Too much protein in the urine
• Nosebleeds
• Rectal bleeding
• Back pain
• Headache
• Taste change
• Dry skin
• Inflammation of the skin
• Inflammation of the nose
• Watery eyes

Avastin is not for everyone

Patients should talk to their doctor if they are:

• Undergoing surgery . Avastin should not be used for 28 days before or after surgery and until surgical wounds are fully healed
• Pregnant or think they are pregnant . Data have shown that Avastin may harm a woman’s unborn baby. Birth control should be used while patients are on Avastin. If Avastin is stopped, patients should keep using birth control for 6 months before trying to become pregnant

• Planning to become pregnant . Taking Avastin could cause a woman’s ovaries to stop working and may impair her ability to have children.
• Breastfeeding . Breastfeeding while on Avastin may harm the baby and is therefore not recommended

Patients should talk with their doctor if they have any questions about their condition or treatment.

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

For full Prescribing Information on Avastin please visit http://www.avastin.com .

About Genentech in Personalized Cancer Immunotherapy

For more than 30 years, Genentech has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever to bring personalized cancer immunotherapy (PCI) to people with cancer. The goal of PCI is to provide each person with a treatment tailored to harness his or her own immune system to fight cancer. Genentech is studying more than 20 investigational medicines, 10 of which are in clinical trials. In every study we are evaluating biomarkers to identify which people may be appropriate candidates for our medicines. For more information visit http://www.gene.com/cancer-immunotherapy .

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious or life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

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