January 2017 Edition Vol.11, Issue 1

Phase 3 Hits and Misses of 2016

With the help of our OBR news archives, we’ve assembled a list of some of the more memorable phase 3 trials from 2016 that either shone or flopped for your reading pleasure.  And again this year we’ll advise that you may not find your favorite late-stage winner or loser in the summary below since the list isn’t necessarily meant to be all-inclusive.

HITS:

1) The PI3K inhibitor buparlisib (Novartis) in combination with endocrine therapy, improved outcomes for patients with hormone (HR)-positive advanced breast cancer that had progressed after treatment with everolimus plus exemestane, according to data from the BELLE-3 phase 3 trial presented at SABCS.

The primary endpoint of the trial was progression-free survival (PFS)—median PFS for patients in the buparlisib arm was 3.9 months, versus 1.8 months for those in the placebo arm. (Dec. 8, 2016)

2) AstraZeneca’s Tagrisso® (osimertinib) reduced the risk of disease progression by 70% and improved progression-free survival (PFS) by almost six months in a phase 3 trial.  AURA3 evaluated Tagrisso as a 2nd-line therapy for patients with EGFR T790M mutation-positive advanced non-small cell lung cancer (NSCLC) against standard chemotherapy. (Dec. 6, 2016)

3) Novartis said its cancer drug Zykadia® (ceritinib) was twice as effective as chemotherapy in slowing the progression of a rare form of lung cancer in the ASCEND-4 study. Patients with anaplastic lymphoma kinase-positive (ALK+) advanced non-small cell lung cancer treated with first-line Zykadia had a median progression-free survival of 16.6 months, compared to 8.1 months for those on chemotherapy. (Dec. 6, 2016)

4) A phase 3 trial at ASCO of Celator Pharmaceuticals’ Vyxeos™ (cytarabine:daunorubicin; also known as CPX-351) demonstrated significantly improved overall survival, event-free survival, and response rates compared to a standard regimen of cytarabine and daunorubicin (7+3) in older patients with high-risk or secondary acute myeloid leukemia  (AML).  Median overall survival for patients treated with Vyxeos was 9.56 months compared to 5.95 months for patients receiving 7+3, or a 3.61 month improvement in favor of Vyxeos. Data was also presented at ASH. (Jun. 6, 2016; Dec. 5, 2016)

5) Pfizer’s cancer drug, Bosulif® (bosutinib) was found to be superior to Novartis’ Gleevec® (imatinib mesylate) in a late-stage study on untreated patients with a form of blood and bone marrow cancer characterized by abnormal white blood cells production. (Dec. 5, 2016)

6) In the head-to-head phase 3 GALLIUM study of patients with previously untreated follicular lymphoma presented at ASH, Roche’s Gazyva® (obinutuzumab) plus chemotherapy followed by Gazyva alone compared to Rituxan® (rituximab) plus chemotherapy followed by Rituxan alone reduced the risk of disease worsening or death by 34% compared to Rituxan-based treatment. (Dec. 4, 2016)

7) Bristol-Myers Squibb’s Opdivo helped patients with advanced stomach cancer live longer in the phase 3 ONO-4538-12, becoming the first drug of its kind to show a survival benefit in patients who failed to respond to or are intolerant of standard chemotherapy for the disease. The trial was conducted by partner Ono Pharmaceutical Co. (Nov. 10, 2016)

8) In the phase 3 SOLO trial of AstraZeneca’s PARP inhibitor Lynparza® (olaparib) alone as maintenance treatment for women with BRCA-mutated metastatic ovarian cancer, top-line results showed a significant progression-free survival benefit for patients compared to placebo.  More detailed data is forthcoming. (Oct. 26, 2017)

9) In results from the pivotal phase 3 Keynote-024 trial, Merck’s flagship immunotherapy Keytruda® (pembrolizumab) demonstrated superior progression-free and overall survival compared to platinum-based chemotherapy as a first-line treatment in patients with advanced non-small cell lung cancer (NSCLC) whose tumors expressed high levels of the protein PD-L1.  The Merck trial restricted enrollment to previously untreated patients with at least 50% of lung tumors cells expressing PD-L1.  At ESMO, data presented from the trial showed that patients treated with Keytruda had a significant progression-free survival benefit of 10.3 months versus 6 months for chemotherapy.  The one year overall survival (OS) rate was 70% and 54% for chemo patients that crossed over to Keytruda.  (Jun. 16, 2016; Oct. 21, 2016)

10) In new data from the phase 3 OAK study reported at ESMO, Roche’s immunotherapy Tecentriq® (atezolizumab) outperformed chemotherapy in the second-line treatment of non–small cell lung cancer (NSCLC).  The trial demonstrated a 27% improvement in overall survival (OS) for patients on the immunotherapy  (median OS was 13.8 months versus 9.6 months on docetaxel), and median OS was significantly better with the immunotherapy in all subgroups of patients, regardless of their PD-L1 expression levels. (Sept. 1, 2016; Oct. 9, 2016)

11) Data from the phase 3 ENGOT-OV16/NOVA trial presented at ESMO demonstrated that adding Tesaro’s PARP inhibitor niraparib to standard platinum-based chemotherapy significantly delayed tumor recurrence in patients with ovarian cancer compared to chemo alone. Patients with the BRCA mutation benefited from niraparib given as second-line maintenance therapy, in addition to patients with another tumor biomarker known as HRD. The company had announced top-line results from the trial, whose primary endpoint was progression-free survival earlier in July.  The FDA is expected to make a decision on the niraparib New Drug Application by June 30, 2017.  (Jul. 8, 2016; Oct. 8, 2016)

12) Novartis’ ribociclib, a CDK4/6 inhibitor, added to letrozole, in postmenopausal women with hormone-receptor positive (HR+) metastatic breast cancer showed significant improvement in progression-free survival (PFS) compared with letrozole alone, new results from the MONALEESA-2 study at ESMO showed. Adding ribociclib to letrozole improved progression-free survival (PFS) by 44% and significantly improved overall response to therapy, the interim results showed. (Oct. 8, 2016)

13) In the POLLUX trial, adding Janssen Biotech’s monoclonal antibody Darzalex® (daratumumab) to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. The rate of progression-free survival at 12 months was 83.2% for patients who received daratumumab, compared with 60.1% in the control group.  (Jun. 11, 2016)

14) Median overall survival was 7.7 months for Amgen’s Blincyto® (blinatumomab) versus 4 months for standard of care in the phase 3 TOWER study of adult patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL). (June 10, 2016)

15) In the pivotal phase 3 CASTOR study presented at ASCO, the three-drug regimen of Darzalex plus bortezomib and dexamethasone significantly improved progression-free survival and the overall response rate in patients with relapsed or refractory multiple myeloma. Experts called the triplet combination, which achieved about a 60% reduction in death or progression compared with bortezomib and dexamethasone alone a “new standard of care” for relapsed myeloma. (June 5, 2016)

16) Mylan’s trastuzumab biosimilar, MYL-1401O, was comparable in efficacy and safety to Roche’s targeted breast cancer drug Herceptin® in women with HER2-positive advanced breast cancer, based on a phase 3 study presented at ASCO.  Response rates were comparable for women on Herceptin and for those who received MYL-1401O with no significant differences in safety between the two groups.  (Jun. 3, 2016)

MISSES:

1) Pfizer and Astellas announced top-line results from the phase 4 Plato study and said that continuing treatment with Xtandi® (enzalutamide) in addition to a regimen of Johnson & Johnson’s Zytiga® (abiraterone acetate) and a steroid worked no better than the two other drugs alone in patients with advanced prostate cancer whose disease had worsened. (Dec. 14, 2016)

2) Compared with standard therapy, CTI BioPharma’s pacritinib significantly reduced spleen size among people with myelofibrosis with very low levels of platelets, and also significantly improved symptoms when a twice-daily dose was taken, based on results of the phase 3 PERSIST-2 study presented at ASH.  The analysis was based on study data before a full FDA clinical hold was imposed in February 2016 due to safety concerns about increases in risk of bleeding and cardiac events; the hold was lifted on January 5, 2017.  (Aug. 29, 2016; Dec. 6, 2016)

3) Amgen announced top-line results from the phase 3 head-to-head Clarion study, evaluating an investigational regimen of Kyprolis® (carfilzomib), melphalan and prednisone (KMP) versus Velcade® (bortezomib), melphalan and prednisone (VMP) in transplant-ineligible patients with newly diagnosed multiple myeloma. The trial did not meet its primary endpoint of superiority in progression-free survival (PFS) (median PFS 22.3 months for KMP versus 22.1 months for VMP).  (Sept. 27, 2016)

4) OncoGenex Pharmaceuticals’ experimental drug custirsen failed to show a survival benefit in the phase 3 AFFINITY trial in patients with advanced prostate cancer in combination with cabazitaxel/prednisone compared to cabazitaxel/prednisone alone. (Aug. 16, 2016)

5) Bristol-Myers Squibb’s immunotherapy Opdivo® (nivolumab) failed to meet the primary endpoint of progression-free survival in the phase 3 CheckMate-026 trial in patients with previously untreated advanced non-small cell lung cancer (NSCLC) when tested as a monotherapy against investigator’s-choice of chemotherapy.  The data showed median PFS favored chemotherapy instead of Opdivo. The company gambled and enrolled more patients (5%) whose tumors expressed lower levels of the protein PD-L1 in the trial, hoping to expand the potential patient population for nivo as a first-line treatment. (Aug. 5, 2016)

6) After an interim analysis failed to show any survival benefit for Revlimid® (lenalidomide) over placebo in the phase 3 REMARC trial, Celgene said it would not seek approval for the treatment as a maintenance therapy for patients with diffuse large B-cell lymphoma (DLBCL).  It was the company’s first try at expanding the blood cancer drug into non-Hodgkin lymphoma (NHL).  (Jul. 25, 2017)

7) In the GOYA phase 3 trial of patients with previously untreated diffuse large B-cell lymphoma, there was no improvement in progression-free survival when the newer agent Roche’s Gazyva® (obinutuzumab) was compared to Rituxan® (rituximab) when both drugs were added to standard chemotherapy (cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone or CHOP). (Jul. 18, 2016)

8) Galena BioPharma shut down a phase 3 study of its experimental breast cancer vaccine NeuVax™ (nelipepimut-S) after independent data monitors examining interim data concluded that NeuVax was ineffective at preventing tumor recurrence in breast cancer patients compared to placebo.  After a phase 2 study of the vaccine failed in patients with HER2-positive breast cancer, the company tested the vaccine in the late-stage trial in a subgroup of breast cancer patients with low levels of HER2 protein expression in their tumors. (Jun. 29, 2016)

9) AstraZeneca said that Lynparza® (olaparib) plus chemotherapy versus chemotherapy alone,did not meet the primary endpoint of overall survival (OS) in the phase 3 GOLD trial in advanced gastric cancer patients, in either the overall population or patients whose tumour tested negative for Ataxia-Telangectasia Mutated (ATM) protein. (May 18, 2016)

10) After bypassing a futility analysis by independent data monitors for its algenpantucel-L phase 3 study, NewLink Genetics’ experimental cancer vaccine later failed to prolong survival in patients with pancreatic cancer compared to a standard therapy in the lmpress trial. Patients treated with algenpantucel-L lived for a median of 27.3 months compared to median survival of 30.4 months for patients on standard therapy. (May 9, 2016)

11) Celldex Therapeutics discontinued the clinical development of its experimental brain cancer vaccine, Rintega® (rindopepimut) after the pivotal phase 3 ACT IV trial in patients with newly diagnosed EGFRvIII-positive glioblastoma was stopped for futility.  At the interim analysis, Rintega was found to reduce the risk of death by only 1% compared to the control arm. (Mar. 7, 2016)

12) Incyte discontinued the phase 3 study (JANUS 1) of Jakafi® (ruxolitinib) in combination with capecitabine for the second-line treatment of patients with advanced pancreatic cancer after a planned interim analysis showed that the trial failed to show efficacy. Incyte halted several trials testing its top drug in solid tumor cancers, saying the data couldn’t justify moving forward. (Feb. 11, 2016)

Compiled from various online media sources and corporate press releases.

New FDA approvals were down overall in 2016 from the previous year and oncology was no exception.  But we can find comfort in the fact that some very important new cancer therapies were approved for patients in 2016—including the first PD-L1 inhibitor for bladder cancer, Genentech’s Tecentriq (atezolizumab), which was also approved later in 2016 for non-small cell lung cancer; and Clovis Oncology’s PARP inhibitor, Rubraca (rucaparib) for BRCA-positive patients with ovarian cancer. Two first-in-class cancer therapies were also green lighted:  AbbVie/Genentech’s Venclexta (venetoclax) for specific patients with chronic lymphocytic leukemia (CLL) and Jazz Pharmaceuticals’ Defitelio, for veno-occlusive disease (VOD) after stem cell transplant. And let’s not forget that Merck’s Keytruda (pembrolizumab) became the first checkpoint inhibitor to win approval as a first-line lung cancer treatment.

See our table below for a recap of oncology drug and device approvals for 2016.

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