Biologics in Development

Cancer Immunotherapies--and Their Cost--Take Center Stage at ASCO's 2015 Annual Meeting


Katherine T. Adams

Affirmation of the efficacy of new and not-so-new cancer therapies was a running theme at the 2015 ASCO Annual Meeting. But a fiery talk by Memorial Sloan Kettering Cancer Center’s Leonard Saltz, MD, about the costs of many oncology therapies (see box below) has given greater momentum to the opinion that their affordability should be addressed. Here are some highlights of ASCO presentations.

Melanoma

Amgen’s OPTiM study showed that talimogene laherparepvec (T-vec), its investigational immunotherapy, provided therapeutic benefit to patients with metastatic melanoma. T-Vec is injected directly into tumors, where it replicates, causing tumor cells to rupture and die. The rupture releases tumor-derived antigens, along with granulocyte macrophage colony-stimulating factor, to stimulate a systemwide immune response. The FDA’s advisory committees have supported approval of the drug—the first oncolytic immunotherapy to demonstrate therapeutic benefit in a phase 3 trial.

Long-term data from the KEYNOTE-001 study showed that the anti–programmed death receptor-1 (PD-1) therapy pembrolizumab (Keytruda) produces durable responses in metastatic melanoma patients. Pembrolizumab has a second-line indication for metastatic melanoma following treatment with either ipilimumab or, for patients with BRAF-mutated tumors, an oral BRAF inhibitor. More than 2,000 melanoma patients have been evaluated in clinical trials.

A nivolumab (Opdivo)–ipilimumab (Yervoy) combination and nivolumab monotherapy both were superior to ipilimumab alone, the current standard of care for patients with previously untreated advanced melanoma, according to results from the CheckMate-067 trial. The combination increased average progression-free survival (PFS) by 6.9 months over ipilimumab alone, while nivolumab monotherapy showed a 4-month PFS advantage versus ipilimumab. Survival time was even greater for patients if their tumors expressed more of the PD-L1 target protein. CheckMate-067 is the first phase 3 trial to demonstrate that a PD-1 immune checkpoint inhibitor as monotherapy and in combination with another immuno-oncology agent improves outcomes versus the standard of care. Both nivolumab and ipilimumab are marketed by Bristol-Myers Squibb.

Lung, breast, and prostate

Nivolumab cut risk of death from non–small-cell lung cancer (NSCLC) by 27% compared with docetaxel in the CheckMate-017 study, while CheckMate-057 found that nivolumab boosted 1-year survival for patients with non–squamous-cell NSCLC and with fewer side effects. In Check-Mate 017, 42% who got nivolumab were still alive 1 year later compared with 24% of those who got docetaxel; in CheckMate-057, 1-year survival was superior in the nivolumab group.

Palbociclib (Ibrance) plus fulvestrant (Faslodex) was superior to treatment with fulvestrant alone, significantly extending PFS in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer whose disease has progressed during or after endocrine therapy. The global PALOMA-3 study was stopped in April when it met its primary endpoint of statistically improving PFS.

Custirsen (OGX-011), combined with first-line docetaxel, provided a 27% lower risk of death in men versus docetaxel alone in men with metastatic castrate-resistant prostate cancer and at least 2 of 5 risk factors for a poor prognosis, according to a post-hoc analysis of the SYNERGY trial.

Hematology

Idelalisib (Zydelig), Gilead Sciences’ investigational drug, combined with ofatumumab (Arzerra) in previously treated patients with chronic lymphocytic leukemia (CLL) showed a 73% reduction in the risk of disease progression or death compared with ofatumumab alone, according to Study 119.

A subanalysis of the RESONATE trial found that previously treated patients with CLL who adhered to the recommended 420 mg dose of ibrutinib (Imbruvica) achieved PFS compared with patients who took lower doses or missed doses, regardless of high-risk genetic factors.

In the HELIOS trial, the addition of ibrutinib to a combination regimen of bendamustine (Treanda) and rituximab (Rituxan) reduced the risk of progression or death in patients with previously treated CLL or small lymphocytic lymphoma by 80%, compared with patients who were given placebo with the combined regimen. Patients in the ibrutinib arm also had a higher overall response rate after a median follow-up of 17 months.

Obinutuzumab (Gazyva), Genentech’s anticipated successor to rituximab, plus bendamustine followed by obinutuzumab alone significantly improved PFS in 413 patients with indolent, refractory non-Hodgkin lymphoma compared with bendamustine alone, according to the GADOLIN trial results. The trial was stopped in February because it met its PFS endpoint. Obinutuzumab is approved in combination with chlorambucil for patients with CLL.

Adding the investigational SLAMF7 monoclonal antibody elotuzumab to lenalidomide (Revlimid) plus dexamethasone could be a new treatment option for patients with relapsed or refractory multiple myeloma (MM), based on ELOQUENT-2 trial results. In an open-label study, adding elotuzumab to a Rev-Dex regimen delayed remission by 4.5 months. If FDA approved, elotuzumab would become the first monoclonal antibody to treat MM.

Brain

Celldex’s experimental targeted immunotherapy rindopepimut delays tumor growth and extends survival in patients with EGFRvIII-positive glioblastoma, according to an update of a phase 2 study results. When combined with bevacizumab (Avastin), the immunotherapy reduced the risk of death by 43% compared with bevacizumab plus a control agent.

Supportive care

The MAGIC study demonstrated efficacy and safety of Heron’s 5-HT3 receptor antagonist product candidate granisetron (Sustol) as part of a three-drug regimen with fosaprepitant, a neurokinin-1 receptor antagonist, plus dexamethasone to prevent chemotherapy-induced nausea and vomiting in patients given highly emetogenic chemotherapy agents.

Non-ASCO clinical studies

Regeneron’s IL-6 receptor antibody, sarilumab, significantly beat placebo in reducing rheumatoid arthritis symptoms and improving physical function in patients who can’t tolerate TNF-a inhibitors, based on 24-week data. In a 546-patient efficacy trial, the sarilumab 200 mg and 150 mg groups showed ACR20 improvements of 61% and 56% respectively, compared with 34% in the placebo group.

Novartis’s study of everolimus (Afinitor) plus best supportive care in patients with advanced nonfunctional neuroendocrine tumors (NET) of gastrointestinal or lung origin significantly extended PFS compared to placebo plus best supportive care. NET is a rare type of cancer most often found in the GI tract, lungs, or pancreas.

Denosumab (Prolia), administered 60 mg once every 6 months in postmenopausal women with early HR+ breast cancer receiving aromatase inhibitor therapy, reduced the incidence of new vertebral or worsening of existing fractures, based on Amgen’s multicenter study.

Have you heard?

The FDA has released new guidance on the use of alternative endpoints, in addition to OS, for clinical trials of non–small-cell lung cancer therapies. Pharmaceutical companies will be allowed to use several types of endpoints to show efficacy. The FDA also included guidance on gathering patient-reported outcome measures to further substantiate treatment efficacy.

The House Energy and Commerce committee has unanimously approved a version of the bipartisan 21st Century Cures Act. The initiative, spearheaded by Reps. Fred Upton, of Michigan, and Diana DeGette, of Colorado, is an effort to streamline the drug development and testing process. The version reported out by committee omitted 340B reforms in the original legislation. DeGette claims there’s support for the bill from pharmaceutical investors, researchers, and patient-advocacy groups.

All clinical studies mentioned in this article are phase 3 unless otherwise stated.

Increasing scrutiny of high-cost cancer therapies

The high—some would say exorbitant—cost of oncology therapies is attracting greater and much-needed attention among leaders in the treatment community. Leonard Saltz, MD, chief of the gastrointestinal oncology service at Memorial Sloan Kettering Cancer Center, gave an impassioned speech at ASCO’s 2015 annual meeting, where he insisted that the new oncology therapies are simply too expensive and their cost unsustainable.

“Cancer drug prices are not related to the value of the drug,” Saltz told the group. Rather, he said, drug pricing is based on the cost of existing therapies and what the manufacturer believes the market will bear. Saltz warned that a proliferation of indications for promising but costly therapies would yield an unsustainable cost burden—perhaps as much as $1 million per patient per year, citing a hypothetical example.

Saltz is not a newcomer to the subject of drug prices; in 2012, he cowrote a New York Times op-ed piece with Peter Bach, MD, in which they announced that Sloan Kettering would not give its patients ziv-aflibercept (Zaltrap), a Sanofi drug for advanced colorectal cancer, when bevacizumab (Avastin) worked just as well at half the price. Soon after, Sanofi cut the cost of ziv-aflibercept. Bach has recently developed an online tool for measuring the value of cancer drugs that takes into account price and efficacy (see “Tools for Taking the Measure of Cancer Drugs”).

Saltz is not a lone voice. Express Scripts has been notably vocal about oncology drug costs, and even Novartis CEO Joseph Jimenez has said that oncology pricing needs to be revised. AARP is running articles in its publication about the unsustainability of specialty drug costs. Because AARP sponsors a Medicare Part D plan, AARP’s foray into the cost issue bears watching. IMS Health says that U.S. spending on therapeutic oncology drugs and oncology supportive care drugs reached $42.4 billion in 2014.

Selected FDA approvals of biologics and other specialty drugs, April 1–May 31, 2015
New marketing approvals
Date (type) Manufacturer Drug (trade) name; administration Indication Notes
April 15 (NDA) Amgen ivabradine (Corlanor); oral Reduce risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with LVEF ≤35%, who are in sinus rhythm with resting heart rate ≥70 beats per minute and either are on highest tolerated doses of beta blockers or have a contraindication to beta blockers Dose is adjusted after 2 weeks, depending on heart rate. For clinicians, heart rate is a new treatment target, and uptake in Europe (where ivabradine has been approved since 2012) has been slow as a result. FDA approved ivabradine without convening an advisory committee, so clinicians will have to learn the significance of the target. A 1-month course wholesales at $375.
April 16 (BLA) Sandoz glatiramer acetate (Glatopa); subcutaneous injection Treatment of patients with relapsing forms of multiple sclerosis First approved generic for Copaxone. Teva is responding my moving patients over to a long-acting form of Copaxone.
April 29 (NDA) Kythera Biopharma deoxycholic acid (Kybella); subcutaneous injection Adults with moderate to severe submental (below the chin) fat Deoxycholic acid has a history of off-label use for unwanted subcutaneous fat; Kybella is not indicated for other areas of the body. “Double chin” drug is strictly cosmetic.
April 30 (BLA) Emergent Biosolutions coagulation factor IX (recombinant) (Ixinity) Control and prevention of bleeding episodes and perioperative management in patients age ≥12 years with Hemophilia B Approval based on phase 1/3 open-label, uncontrolled, multicenter, global study in previously treated patients with severe to moderately severe (factor IX level <2%) Hemophilia B (N=68). 84% of bleeds were resolved by 1 or 2 infusions.
New indications of previously approved treatments
April 24 (sBLA) Eli Lilly ramucirumab (Cyramza); IV injection In combination with FOLFIRI chemotherapy for metastatic colorectal cancer with disease progression on or after prior therapy with bevacizumab (Avastin), oxaliplatin, and a fluoropyrimidine Previously approved for gastric and NSCLC. New indication based on phase 3 RAISE trial of the indication population. OS in patients receiving ramucirumab+FOLFIRI was 13.3 months compared with 11.7 months for placebo+FOLFIRI group.
ASCO=American Society of Clinical Oncology, BLA=biologics license application, IV=intravenous, LVEF=left ventricular ejection fraction, NDA=new drug approval, NSCLC=non–small-cell lung cancer, sBLA=supplemental biologics license application.
Sources: ASCO, FDA, Fierce Biotech, Fierce Pharma, Medscape, New York Times, and manufacturers’ news releases and package inserts.
Career Opportunities

Manager of Government Enrollment and Physician Credentialing

Fantastic opportunity to grow with Alliance HealthCare Services in this unique role

Location: Irvine, CA - RELOCATION ASSISTANCE AVAILABLE

Click here to learn more