June 2014 Edition Vol.8, Issue 6

Hits And Misses at ASCO 2014

Hits and Misses at ASCO 2014

By Nancy Ciancaglini

This year at ASCO the spotlight was on a small group of high-profile immunotherapies: PD-1 and PD-L1 checkpoint inhibitors. In some cases, these investigational agents provided meaningful clinical benefit and seemed to work in a broader range of cancers. Some studies were small though and the side effect profiles in trials were less than desirable.  We’ve selected some of the ‘hits and misses’ that either shone or disappointed clinicians, investors and analysts, with a particular emphasis on newer agents, at this year’s meeting and have listed them below as a recap:


Pharmacyclics’ Imbruvica (ibrutinib):  “Game-changing” and “transformative” were the words clinicians used to describe the early findings from the phase 3 RESONATE study.  The trial compared ibrutinib with the standard treatment, ofatumumab (Arzerra), in elderly patients with resistant or relapsed chronic lymphocytic leukemia (CLL).  It was the first time an oral drug demonstrated a survival improvement over standard therapy in relapsed CLL.  Ibrutinib was associated with an 80% lower risk of disease progression and a 57% lower risk of dying compared with ofatumumab. Eighty percent of patients were still in remission at one year, twice as many as expected with standard therapy. The study’s lead author thought that all patients, with few exceptions, should be offered ibrutinib in the relapse setting.

Ibrutinib was recently granted accelerated approval as a treatment for CLL patients who’ve tried at least one previous therapy.  On Oct. 7, the FDA will decide whether to grant the once-daily oral drug a full approval based on the RESONATE data.    

AbbVie's ABT-199/GDC-0199:  Another experimental CLL therapy that’s being closely watched is ABT-199/GDC-0199. In a phase 1b study, results showed an overall response rate (ORR) of 84% in patients with relapsed/refractory CLL treated with ABT-199/GDC-0199 plus rituximab (Rituxan).  One analyst said that while ABT-199/GDC-0199 appears to be very effective, its side effects may limit how long patients will take it, and doctors may opt to use it after patients have tried other therapies including Imbruvica.

Novartis’ Panobinostat (LBH589):  In the phase 3 PANORAMA-1 trial, adding LBH589 to bortezomib (Velcade) and dexamethasone significantly improved progression-free survival (PFS) by 37% for patients with relapsed/refractory multiple myeloma who had failed on at least one prior treatment. Patients in the LBH589-bortezomib-dexamethasone arm showed an increase of 4 month prolongation of median PFS compared with patients in the control arm (12 months vs. 8 months, respectively).  Most patients with multiple myeloma relapse or become refractory; if LBH589 is granted FDA approval, it will be first in its class of available treatments in this patient population.  Based on this data, LBH589 was granted priority review in May. 

Bristol-Myer Squibb’s nivolumab and Yervoy: Updated results from a small phase 1 study of advanced melanoma combining two of BMS’s immunotherapies, nivolumab and ipilimumab (Yervoy), showed that the combination treatment resulted in a 2-year survival rate of 79% for patients. Nivolumab and ipilimumab are two distinct immune checkpoint inhibitors: nivolumab targets PD-1; ipilimumab targets CTLA-4. Tumor reduction of ≥80% was seen in 42% of patients (n=53). The combination therapy increased toxicity compared with single-agent treatment, but adverse events were considered manageable and reversible. Researchers cautioned that the “amazing” results would need to be tested in a much larger, randomized phase 3 trial.

Merck’s Pembrolizumab (MK-3475): In a phase 1 trial of patients with advanced melanoma (n=411), pembrolizumab, a PD-1 targeting agent, produced tumor shrinkage in 34% of patients; including 28% of those who progressed on prior treatment with ipilimumab (Yervoy). Among patients whose tumors responded to pembrolizumab, 88% had ongoing responses at 1-year follow up.  Merck is seeking approval for pembro as a treatment for patients with melanoma who no longer respond to Yervoy.  Merck’s BLA is under priority review by the FDA with a PDUFA date of Oct. 28. 

Lilly’s Cyramza™ (ramucirumab) in NSCLC: Although the 1.4 month survival benefit shown in the large phase III REVEL trial is small, it is the first study in a decade to improve outcomes and extend survival for patients with advanced non-small cell lung cancer (NSCLC) in the second-line setting. The trial tested Cyramza in combination with standard chemotherapy (docetaxel) in patients with advanced NSCLC who had relapsed after initial, or first-line, treatment. Some doctors questioned if the marginal benefit seen would be worth the drug’s high cost (currently approved for gastric cancer, Cyramza costs $6,000 per infusion).  Cyramza’s survival benefit was also consistent for a subset of patients in the study with squamous lung cancer where little else works.   

AstraZeneca’s AZD9291: In the phase 1 AURA trial (n=205), 94% of patients with advanced non-small cell lung cancer (NSCLC) whose tumors were T790M mutation positive (T790M+) had their tumors shrink or become stable after treatment with AZD9291. In addition, 64% of T790M+ patients achieved tumor shrinkage of 30% or more.  Patients in the trial had failed treatment on established epidermal growth factor receptor mutation positive (EGFR+) tyrosine kinase inhibitors (TKIs).  There are currently no approved treatments for patients with T790M+ NSCLC.  Grade 3 and 4 side effects were reported in 24% of patients.

AstraZeneca’s olaparib and cediranib: In an NCI-sponsored phase 2 trial of women with platinum-sensitive high-grade serous ovarian cancer, the combination of two targeted oral drugs, the PARP inhibitor olaparib and the anti-angiogenesis drug cediranib, extended progression-free survival by 17.7 months vs. 9 months with olaparib alone and also improved objective response rate (ORR).  The significant activity of the combination, used in an ovarian cancer study for the first time, suggested it might be an effective alternative to standard chemotherapy.

Roche’s MPDL3280A: In a small, single-arm, multi-center, open-label phase 1 study (n=68), patients previously treated for metastatic urothelial bladder cancer whose tumors were characterized as PD-L1 positive showed an overall response rate of 43% (tumor shrinkage) after being treated with Roche’s anti–PD-L1 immunotherapy.  Patients were identified as being PD-L1+ with a Roche diagnostic test. Nicholas Vogelzang, MD, of US Oncology, who was involved in the trial, called MPDL3280A “the most promising new agent…in at least 25 years.”  MPDL3280A has been granted a Breakthrough Therapy Designation by the FDA.   

Eisai’s Lenvatinib:  Based on the SELECT study’s results, Eisai’s investigational tyrosine kinase inhibitor (TKI) could become another approved treatment option for patients with differentiated thyroid cancer that’s become resistant to standard radio-iodine therapy. In the trial, almost two-thirds of patients showed tumor shrinkage. The median progression-free survival with lenvatinib was 18.3 months compared with 3.6 months on placebo (disease progression was delayed by 14.7 months).

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