Phase 3 Hits and Misses of 2015

Based on OBR’s news archives, we’ve put together a recap of some of the more high profile phase 3 clinical trial results – both winners and losers – that were announced in 2015. Be advised that our list is by no means all inclusive, and is only meant to jog your memory as to what some of the highlighted late-stage trials were from the past year.  So read on.

HITS:

1) In the pivotal KEYNOTE-010 phase 2/3 study, Merck’s anti-PD-1 (programmed death receptor-1) therapy Keytruda® (pembrolizumab) significantly improved overall survival (OS) compared with chemotherapy in patients with any level of PD-L1 expression, as defined by a tumor proportion score of 1% or more.  It was the first study of its kind to evaluate the potential of an immunotherapy compared with chemotherapy, based on prospective measurement of PD-L1 expression in patients with advanced non-small cell lung cancer (NSCLC). (Dec. 19, 2015)

2) In top-line results reported from the NEMO trial, patients with advanced NRAS-mutant melanoma treated with binimetinib (Array BioPharma) lived for a median of 2.8 months before their disease worsened, compared with 1.5 months for patients treated with dacarbazine. The trial met its primary endpoint of improving progression-free survival (PFS). (Dec. 16, 2015)

3) In the BELLE-2 trial, women with metastatic hormone receptor-positive breast cancer resistant to hormone therapy who had mutated PIK3CA detected in their blood benefited from a combination of the PI3K inhibitor buparlisib and fulvestrant. Women had 7 months of PFS in the combination arm compared with only 3.2 months for those receiving fulvestrant plus a placebo. (SABCS, Dec. 11, 2015)

4) In the RAY trial of mantle cell lymphoma (MCL), Imbruvica significantly improved PFS versus Pfizer’s Torisel® (temsirolimus).  Janssen’s therapy was associated with a 57% reduction in the risk of disease progression or death with a median follow-up of 20 months. (ASH, Dec. 8, 2015)

5) In STUDY 115, conducted with patients with previously treated chronic lymphocytic leukemia (CLL), a triplet of Gilead’s Zydelig® (idelalisib) in combination with bendamustine and rituximab (BR) proved superior to bendamustine/rituximab alone, increasing both PFS and OS, with a 67% reduction in the risk of progression or death and a 45% reduction in death.  The trial was stopped early due to “overwhelming efficacy.” (ASH, Dec. 8, 2015)

6) Results from the TOURMALINE-MM1 trial in relapsed and/or refractory multiple myeloma showed that an oral triplet combination of Takeda’s Ninlaro® (ixazomib), lenalidomide, and dexamethasone significantly improved PFS, compared with the doublet of lenalidomide and dexamethasone. Median PFS was 20.6 months with the triplet versus 14.7 months in the control group. Ninlaro, the first available oral proteasome inhibitor, offered patients with multiple myeloma the option of taking an all-oral treatment regimen. (ASH, Dec. 7, 2015)

7) The PROTECT 2 study of Novartis’s pegfilgrastim, a biosimilar of Amgen’s Neulasta® (pegfilgrastim)‎, met the trial’s primary endpoints and demonstrated similar safety and efficacy to the original product for the prevention of neutropenia in patients with breast cancer. (Dec. 7, 2015)

8) The RESONATE study showed that some elderly patients with treatment-naive chronic lymphocytic leukemia (CLL) fared much better on Janssen’s Imbruvica® (ibrutinib) compared with those who were given standard chemotherapy (chlorambucil). At 24 months, patients taking ibrutinib achieved a 98% OS rate, a key secondary endpoint of the trial, versus 85% for chlorambucil. Ibrutinib also significantly prolonged PFS, reducing the risk of progression or death by 84%, the primary endpoint of the trial, versus chlorambucil. (ASH, Dec. 6, 2015)

9) In the RATIFY (CALGB 10603) study, Novartis’s experimental drug PKC412 (midostaurin), added to standard chemotherapy, became the first targeted treatment to improve survival for a high-risk, genetically defined subgroup of patients – OS improved by 23% for patients with FLT3-mutated acute myeloid leukemia (AML). (ASH, Dec. 6, 2015)

10) In the coBRIM trial, Roche/Exelixis’s Cotellic (cobimetinib) used in combination with vemurafenib helped people with previously untreated BRAF V600 mutation-positive advanced melanoma live significantly longer compared with vemurafenib alone. The median OS was 22.3 months for the combination versus 17.4 months for vemurafenib alone, or a 30% reduction in the rate of death for the combination compared with vemurafenib alone. (Nov. 21, 2015)

11) Novartis announced results of the RADIANT-4 study showing that Afinitor® (everolimus) reduced the risk of disease progression by 52% versus placebo in patients with advanced, progressive, nonfunctional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin. (ECC, Sept. 27, 2015)

12) Treatment with Exelixis’s Cometriq® (cabozantinib) reduced the rate of disease progression or death (progression free survival) by 42% compared with Afinitor in the METEOR trial, which compared cabozantinib with everolimus in patients with advanced clear-cell renal cell carcinoma (RCC) previously treated with at least one VEGF-targeted drug.  (ECC, Sept. 26, 2015; Jul. 20, 2015)

13) The results from the CHECKMATE -025 trial marked the first time that an immuno-oncology drug, in this case Bristol-Myers Squibb's Opdivo® (nivolumab), demonstrated the ability to help patients live longer. Patients with previously treated advanced renal cell carcinoma (RCC) taking Opdivo had a median OS of 25 months, or more than two years, as compared with 19.6 months for those on everolimus, a current standard of care for kidney cancer. The trial was stopped early since it met its endpoint.  (ECC, Sept. 25, 2015; Jul. 20, 2015)

14) Amgen’s investigational virus-based immunotherapy, Imlygic (talimogene laherparepvec), significantly increased the durable response rate in patients with metastatic melanoma compared with granulocyte-macrophage colony-stimulating factor (GM-CSF) in the OPTiM trial.  The trial was the first for an oncolytic virus to show a benefit in patients with cancer. (Jul. 21, 2015)

15) Data from the COMPLEMENT 2 study in relapsed chronic lymphocytic leukemia showed that a combination of Novartis’s Arzerra® (ofatumumab), fludarabine, and cyclophosphamide boosted PFS by 54% compared with therapy with the latter two drugs alone (28.9 months versus 18.8 months, respectively). (EHA, Jun. 18, 2015) 

Phase 3 Hits and Misses of 2015 (continued)

16) In the first head-to-head study of two proteasome inhibitors named the ENDEAVOR trial, patients with relapsed multiple myeloma treated with Amgen’s Kyprolis® (carfilzomib) and low-dose dexamethasone lived twice as long without their disease worsening, demonstrating statistically and clinically significant superiority over bortezomib and low-dose dexamethasone (median PFS 18.7 months versus 9.4 months). (EHA, Jun. 15, 2015)

17) In the ELOQUENT-2 study of 646 patients with recurrent multiple myeloma, those who received a three-drug combination of elotuzumab (Bristol-Myers Squibb / AbbVie) with Celgene’s Revlimid® (lenalidomide) and the corticosteroid dexamethasone on average went 19.4 months before the cancer began to worsen, compared with 14.9 months for those who received the standard therapy only of Revlimid and dexamethasone.  After 2 years, elotuzumab reduced the risk of cancer progression and death by 30%. (ASCO, Jun. 2, 2015)

18) For the first time, a drug was shown to improve survival in patients with liposarcoma (LPS) or leiomyosarcoma (LMS) in a phase 3 trial of Eisai’s breast cancer drug Halaven® (eribulin).  The therapy improved OS by 2 months compared with standard therapy, dacarbazine (13.5 months with eribulin versus 11.5 months with dacarbazine). (ASCO, Jun. 1, 2015)

19) In the PALOMA-3 trial, Pfizer’s Ibrance® (palbociclib) in combination with hormone therapy more than doubled the duration of disease control for women with estrogen receptor (ER)–positive/HER2-negative endocrine-resistant breast cancer. Patients given Ibrance and fulvestrant lived an average of 9.2 months before their cancer worsened compared with 3.8 months for patients in the fulvestrant-placebo group. The trial was stopped earlier after an interim analysis showed that the drug more than doubled the duration of disease control and delayed progression by more than 5 months. (ASCO, Jun. 1, 2015; Apr. 15, 2015)

20) In CHECKMATE 067, two cancer immunotherapies proved significantly better than one alone in slowing the progression of advanced melanoma. First-line Opdivo combined with Bristol-Myers Squibb’s Yervoy® (ipilimumab) or used alone produced a longer PFS than ipilimumab alone.  After at least 9 months of follow-up, median PFS was 2.9 months for ipilimumab alone, 6.9 months for nivolumab alone, and 11.5 months for the combination. In contrast to other studies’ results, the benefit seen in delaying disease progression with the combination therapy was mostly in patients with PD-L1-negative tumors, rather than those with PD-L1-positive tumors. (ASCO, May 31, 2015)

21) In the first results from HELIOS, Pharmacyclics’s Imbruvica® (ibrutinib) in combination with standard therapy (bendamustine/rituximab) in relapsed/refractory chronic lymphocytic leukemia (CLL) reduced the risk for disease progression by 80%, compared with placebo plus bendamustine/rituximab. (ASCO, May 30, 2015)

22) In the GADOLIN study, Genentech’s Gazyva® (obinutuzumab) showed significant benefit for patients with indolent non-Hodgkin’s lymphoma (iNHL) refractory to rituximab treatment. Gazyva plus bendamustine followed by Gazyva alone reduced the risk of disease worsening or death (PFS) by 45% compared with bendamustine alone. The study was stopped prior to its protocol-specified final analysis due to the high level of benefit seen in the Gazyva arm. (ASCO, May 30, 2015)

23) In the PERSIST-3 trial, CTI BioPharma’s experimental JAK2 and FLT3 inhibitor, pacritinib, was shown to be superior to best available therapy for patients with myelofibrosis.  After 24 weeks of taking pacritinib, 19.1% of patients showed a reduction in spleen volume by 35% or more compared with 4.7% of patients receiving best available therapy.  The only FDA-approved treatment for myelofibrosis, Incyte’s Jakafi® (ruxolitinib), was intentionally excluded from the trial due to safety issues for those patients enrolled in the study with extremely low platelet counts. (ASCO, May 30, 2015)

24) A second phase 3 trial (CHECKMATE 057) in lung cancer showed an improvement in OS over chemotherapy when Opdivo was used in certain patients.  The study was conducted in 582 patients with advanced non-squamous non-small cell lung cancer (nsNSCLC) who had progressed on platinum-doublet chemotherapy.  The overall results show that treatment with nivolumab extended median OS by 3 months versus docetaxel (12.2 vs 9.4 months). A subset of patients with high levels of expression of programmed death ligand 1 (PD-L1) showed even great benefit (median OS was 17.2 to 19.4 months). (ASCO, May 29, 2015)

25) Results from the KEYNOTE-006 trial of Merck’s Keytruda in front-line advanced melanoma demonstrated that the immunotherapy was statistically superior to ipilimumab for PFS and OS, the trial’s co-primary endpoints, in addition to overall response rate (ORR), a secondary endpoint.  The trial was stopped early based on its results. Based on the study’s data, Keytruda became the first anti-PD-1 therapy to demonstrate a survival advantage compared with the standard of care for the first-line treatment of advanced melanoma. (AACR, Apr. 19, 2015; Mar. 24, 2015)

 

MISSES:

1) Merck and Threshold Pharmaceuticals said that their investigational hypoxia-activated prodrug, evofosfamide, missed the main goal in 2 late-stage studies and failed to improve OS in patients suffering from both advanced pancreatic cancer (MAESTRO) and advanced soft tissue sarcoma (TH-CR-406/SARC021) when combined with chemotherapy.  Both companies said they would drop the development of evofosfamide in those tumor types. (Dec. 7, 2015)

2) A phase 3 study of Genmab A/S’s single agent Arzerra® (ofatumumab) compared with single agent rituximab in patients with relapsed follicular non-Hodgkin's lymphoma (NHL) was stopped early. A planned interim analysis by an Independent Data Monitoring Committee (IDMC) showed it was unlikely that ofatumumab would show superiority if the trial were to be completed as planned. (Nov. 23, 2015)

3) ImmunoGen and partner Roche said that a late-stage study of the breast cancer drug Kadcyla® (ado-trastuzumab emtansine) failed to meet its primary endpoint of OS as a second-line treatment for gastric cancer. (Oct. 22, 2015) 

4) Synta Pharmaceuticals terminated the GALAXY-2 study evaluating ganetespib in combination with docetaxel as a second-line treatment in advanced NSCLC after an IDMC said the trial was unlikely to show a statistically significant improvement in OS compared with docetaxel alone. (Oct. 20, 2015)

5) AstraZeneca said it was temporarily halting 2 combination cancer trials due to reports of an increase in lung disease in some patients.  The trials, one an early-stage study (TATTON), the other a late-stage study (CAURAL), combined its AZD9291 compound, which targets a specific genetic mutation, with the anti-PD-L1 therapy durvalumab, in patients with advanced NSCLC. (Oct. 9, 2015)

6) Northwest Biotherapeutics temporarily stopped enrolling new patients in its late-stage trial of DCVax-L, an experimental brain cancer drug. The company later issued a statement saying that screening had only been "temporarily suspended while the company submits certain information from the trial for regulatory review.”  Investors expressed doubt that the positive results from much smaller, informal studies, which showed that DCVax-L plus standard treatment helped patients live 2.5 times as long as those receiving standard care alone, could be repeated in the larger ongoing trial, which is scheduled to be completed in 2016. (Aug. 21, 2015)

7) AstraZeneca’s experiment MEK inhibitor selumetinib in combination with dacarbazine failed to meet its primary endpoint of PFS in the SUMIT trial of metastatic uveal melanoma. The company said that the negative outcome wouldn’t affect other studies of the drug, which is being investigated primarily in KRAS-mutant advanced NSCLC.  (Jul. 22, 2015)

8) Nektar Therapeutics’ experimental drug NKTR-102 failed to meet the main goal in previously treated patients with advanced breast cancer in a late-stage study. The drug provided a 2.1 month improvement in median OS over patients on chemotherapy in the trial, but the effect was not statistically significant. (Mar. 17, 2015)

9) Bayer closed a phase 3 study of Stivarga® (regorafenib) in colorectal cancer saying the trial would not get any relevant results since it failed to recruit a sufficient number of participants. Due to slow patient accrual, the company said, the study would be closed to further enrollment before the trial’s endpoints could be assessed.  The study was to evaluate regorafenib as an additional treatment in colorectal cancer following surgical removal of liver metastases with curative intent. (Mar. 5, 2015)

10) GW Pharmaceuticals’s experimental cannabis drug Sativex® failed to meet its primary endpoint and alleviate pain in cancer patients in a phase 3 study compared with those on placebo. Sativex also failed to meet the primary endpoint in top-line data reported from two remaining phase 3 cancer pain trials announced later on. (Jan. 8, 2015; Oct. 27, 2015)

Compiled from various online media sources and corporate press releases.

Phase 3 Hits and Misses of 2015 (continued)

2015 was a banner year for FDA approvals, and there was no shortage of cancer therapies included in the list — oncology was at the top of the leader board as the therapeutic category winning the most new drug approvals this past year. 

Among the cancer therapies that U.S. regulators greenlighted were the first approved U.S. biosimilar, the first oncolytic virus therapy, several new multiple myeloma drugs, and new indications for the immunotherapies Opdivo and Keytruda in lung (both drugs) and kidney cancer (Opdivo only). 

See our table below:

© Caribou Publishing. All rights reserved. Reproduction in whole or in part is prohibited.