A new regulatory pathway established last year allows drugs with dramatic early clinical promise to be expedited to the market quicker than ever before. To date, most of these ‘breakthrough’ designations have gone to cancer agents, raising the prospect of faster access to the latest lifesaving therapies for the estimated 4,500 people newly diagnosed with cancer each day in the US. Elie Dolgin looks at what sets these breakthrough medicines apart.
In March 2012, a congressional briefing was held on Capitol Hill to discuss the prospects of a new development pathway for the US Food and Drug Administration (FDA). The facilitator, a local advocacy organization called Friends of Cancer Research (FOCR), trotted out an oncology expert, a healthcare investor and current and former FDA officials, all to make the case that experimental drugs that produce large and unprecedented treatment effects in early-phase clinical trials were not reaching the market fast enough.
The existing regulatory mechanisms for expediting drug development and regulatory review—fast track, accelerated approval and priority review—were still too slow. Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, called for an ‘all hands on deck’ approach.
Four months later, FOCR got its wish. As part of the July 2012 FDA Safety and Innovation Act, Congress created a new ‘breakthrough therapy designation’ for drugs intended to treat a serious or life-threatening disease and for which preliminary clinical evidence pointed to a substantial improvement over existing therapies. No longer might such trailblazing therapies have to go through the rigid three-phase drug development paradigm. No longer might dying patients have to wait as long to receive the latest cancer drugs that medicine has to offer.
“The breakthrough therapy designation is really exciting,” says Mikkael Sekeres, a leukemia specialist at the Cleveland Clinic Taussig Cancer Institute in Ohio who chairs the FDA’s Oncologic Drugs Advisory Committee, the panel that recommends whether the agency should approve cancer drugs or not. “We have patients who are desperate with cancers that we’re not doing a good enough job at conquering. So we need new drugs to be available to patients, and getting highly effective drugs with good toxicity profiles out to patients quickly is a wonderful thing.”
It’s still somewhat uncertain how quickly the regulatory wheels will turn for these drugs, though. At press time, the FDA had yet to issue guidance into how the breakthrough pathway would be implemented. According to agency spokesperson Stephen King, this document, along with further guidance for industry on the accelerated approval pathway and the use of surrogate clinical endpoints, should be released by mid-July.
Yet, eager to offer advice, FOCR released its own recommendations late last year outlining a vision for the new designation. That white paper, published in November 2012, highlighted four already approved drugs that the authors felt would have merited designations as breakthrough therapies had such a regulatory pathway been in place at the time. One such case study looked at Kalydeco (ivacaftor), a cystic fibrosis therapy approved in January 2012 for the 4% of patients with the disease who carry a particular mutation known as G551D. As it turns out, Kalydeco, along with a sister drug known as VX-809, ended up receiving the first breakthrough designations from the FDA in January 2013 for a wider number of patient populations (see Nat. Med. 19, 116–117, 2013).
The FOCR panel’s choices were also calculated in that the other three case studies presented involved anticancer agents. That’s no coincidence. The cancer field has long been the hotbed of so-called ‘genomic medicine’, in which healthcare decisions are tailored to the individual patient in response to his or her unique genetic profile—often with dramatic and unparalleled benefits. Think Gleevec (imatinib), the ‘miracle’ pill for people with chronic myeloid leukemia who harbor a specific genetic alteration found only in their tumor cells. Or, more recently, Zelboraf (vemurafenib), a targeted inhibitor approved in 2011 of a mutated protein found in the skin cancer lesions of more than half of all people with melanoma.
So, it’s perhaps not surprising that more than half of the experimental therapies known to be stamped by the FDA with the breakthrough badge since the designation went into effect have been in the oncology space. These drugs, from a who’s who of big pharma, include antibody therapies and small-molecule drugs designed to treat various forms of cancer affecting the skin, breast, lungs and other organs.
Given these drugs’ unprecedented early clinical effects, “it begs the question about the old rules,” says Sandra Horning, global head on clinical development in hematology/oncology at Genentech in South San Francisco and one of the authors of FOCR’s November white paper. “The enthusiasm now is having these new agents at hand and refining the clinical research process and the interactions with regulatory authorities so that we can bring really important new medicines to patients much earlier.”
Here, Nature Medicine looks at the five cancer drugs that, by mid-May, drug companies had disclosed as receiving breakthrough endorsements from the FDA. (The agency itself does not reveal information about investigational new drug applications or any associated designations.) As Jeff Allen, executive director of FOCR, puts it: “These stuck out as obvious drugs that have the potential to change how each of these diseases is managed.”
Oncologist Amita Patnaik has led dozens of first-in-human studies during her time as associate director of clinical research at South Texas Accelerated Research Therapeutics, a San Antonio–based research center with one of the largest phase 1 programs in the world for novel anticancer agents. But few, if any, investigational trials she has been involved with over the past 15 years have given way to such dramatic clinical responses as the phase 1 study she started two years ago involving patients with advanced solid tumors who were treated with the experimental antibody drug lambrolizumab (MK-3475).
Although the study was designed to assess safety, several of the participants, all of whom had cancers that withstood standard therapies, experienced complete and lasting responses. “It was very clear that this was an emerging molecule that had the potential for significant benefit,” Patnaik says.
One study participant entered the trial because of an advanced case of melanoma that had spread throughout his body—to multiple lymph node sites, the adrenal gland and the lungs. The patient, a man in his 80s, received lambrolizumab for around six months, during which time the cancerous lesions completely vanished. After suffering a heart attack that doctors think was unrelated to the drug therapy, he become too weak to continue with further treatment. Nonetheless, “to this day, which is more than a year after receiving his last dose, he has no evidence of disease,” Patnaik says. “There are very few anticancer therapies that have this degree of dramatic and sustained response that one sees so early in the course of development,” she adds.
The therapy is an antibody drug from New Jersey–based Merck that promotes T cell function. It works by blocking a surface protein on T cells called programmed death-1 (PD-1) that usually dampens immune function. In a larger phase 1 trial involving 85 patients with metastatic and inoperable melanoma, all of whom received lambrolizumab at varying doses, 43 people showed at least a partial antitumor response, including eight who, like Patnaik’s patient, experienced a complete regression of all their cancerous lesions.
The average duration of response was 7.6 months, with mostly only minor side effects. By comparison, approved drugs for melanoma have either lower response rates or less durability. Lambrolizumab “seems to have the best of both worlds,” says trial investigator Omid Hamid, director of the Melanoma Center at the Angeles Clinic and Research Institute in Los Angeles, who presented the data last November at the 2012 International Congress of the Society for Melanoma Research in Hollywood, California. “This is something that’s fairly paradigm shifting.”
Notably, of 27 participants who had previously tried and not responded to Yervoy (ipilimumab), an FDA-approved immunotherapy drug from New York–based Bristol-Myers Squibb (BMS) that, like lambrolizumab, enhances the ability of T cells to kill melanoma cells (although by a different mechanism), 11 demonstrated a partial response. A handful of companies besides Merck, including BMS, also have drugs in clinical development directed at either PD-1 or its ligand (see Nat. Med. 18, 993, 2012). But, according to Hamid, “this is the first data presented with this type of therapy in people who have failed Yervoy.” Merck announced lambrolizumab’s breakthrough status for treating advanced melanoma on 24 April.
Hank Stupi was diagnosed with a rare form of non-Hodgkin’s lymphoma in 2005. He had experienced months of traveling joint pain that would affect his wrists one day and his shoulders the next. When Stupi finally went to see his physician, a bone marrow biopsy showed that his B cells were growing out of control. Blood tests revealed that levels of the antibody immunoglobulin M (IgM) had spiked—a sure indication of Waldenström’s macroglobulinemia, a disease with only around 1,500 new cases in the US each year.
Stupi, now 66 and a retired accounting instructor living in southeastern Virginia, had tried a number of therapies over the years, including the chemotherapy drug cyclophosphamide and a now-discontinued experimental Akt inhibitor called perifosine. From 2008 to 2012, he seemed to respond well to a combination of the proteasome inhibitor Velcade (bortezomib) and the CD20-specific antibody rituximab. But in May of last year, Stupi’s IgM levels began to rise, and he had to undergo plasma exchange therapy every three weeks to remove the excess antibodies from his bloodstream.
Fortunately, the need for plasmapheresis didn’t last long. Stupi soon found space in a clinical trial that was testing ibrutinib (PCI-32765), a first-in-class inhibitor of Bruton’s tyrosine kinase, a key signaling enzyme in the B cell receptor pathway, which becomes highly active in many lymphomas. Stupi started the two-year therapy in August 2012—popping three pills each day at 8:00 a.m. and then waiting a half-hour before eating breakfast—and quickly his IgM levels plummeted by half. Although those levels have not dropped further, his once-low hemoglobin and neutrophil counts continue to climb with each quarterly blood test. Best of all: he hasn’t felt a single side effect. Ibrutinib “is the kindest and gentlest of any [drug therapy] that I’ve had,” Stupi says. “I’m getting close to normal and I can feel that,” he adds. “I have more energy now than I have had for a long time.”
In February, ibrutinib chalked up two breakthrough designations: one for Waldenström’s macroglobulinemia and another for a second rare type of B cell malignancy known as mantle cell lymphoma (MCL) for people who have failed on other therapies. On 8 April, Janssen Pharmaceuticals, the New Jersey–based firm that is developing ibrutinib together with Pharmacyclics of Sunnyvale, California, announced that the FDA had also extended breakthrough status for the drug for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in people for whom the short arm of chromosome 17 has been deleted in tumor cells—a mutation associated with a particularly aggressive form of disease and subsequent poor prognosis. It’s not that ibrutinib works in only the subgroup with the deletion, it’s just that “these high-risk patients have no good alternative,” explains Jan Burger, a leukemia specialist at the University of Texas MD Anderson Cancer Center in Houston who has run studies with ibrutinib, “and therefore it’s a population where these new treatments are particularly valuable.”
To date, five phase 3 trials have been initiated with ibrutinib for patients with either MCL, CLL or SLL. Yet, because of the breakthrough designation for MCL, the drug sponsors plan to apply for regulatory approval of the drug for this indication no later than September 2013—much sooner than originally anticipated. “Breakthrough, for us, really expands the potential of using phase 2 data for initial approval,” says Urte Gayko, head of regulatory affairs at Pharmacyclics. Meanwhile, phase 2 trials involving people with Waldenström’s macroglobulinemia, as well as patients with SLL or CLL with the 17p deletion, are now active. Filing discussions for these indications are still ongoing with the FDA.
“People call it the Gleevec of CLL, but it’s really so much more,” says Richard Furman, a lymphoma specialist at the Weill Cornell Medical College in New York. “It’s a remarkable agent that really does afford to make all low-grade lymphomas truly chronic diseases.”
Stop the Vicious Cycle
For more than two decades, various companies have tried their hand at developing cyclin-dependent kinase (CDK) inhibitors, with dozens of such agents evaluated over the years. Yet, despite their potential to selectively disrupt cell cycle progression in cancer cells, none of these drugs has yet reached the market. Either toxicity problems or underwhelming antitumor activities in clinical trials have sunk nearly each and every candidate agent.
Palbociclib (PD-0332991), a compound from New York–based Pfizer that blocks both CDK4 and CDK6, could be different. In a 10 April press release announcing the drug’s breakthrough designation for treating all kinds of breast cancer, Pfizer highlighted phase 2 data from a trial involving 165 post-menopausal women with a type of metastatic breast cancer in which estrogen receptors are overexpressed but the HER2 (human epidermal growth factor receptor 2) protein is not. Participants in this study who received palbociclib in addition to the standard antihormonal agent letrozole had a median progression-free survival time of 26.1 months, compared with only 7.5 months in those who received letrozole alone.
“That’s not just unprecedented for breast cancer, where we have some successes, but that’s unprecedented for most of solid tumor oncology to see this magnitude of increase,” says Richard Finn, an oncologist at the University of California–Los Angeles Jonsson Comprehensive Cancer Center who led the trial and presented the preliminary data in December at last year’s San Antonio Breast Cancer Symposium in Texas.
Among the study participants, palbociclib was generally well tolerated, with some reports of low platelet or white blood cell counts, but none that required hospitalization. A 450-person, phase 3 trial evaluating the palbociclib-letrozole combination in patients with the same type of advanced breast cancer is currently open and enrolling. Meanwhile, earlier-phase trials are now ongoing to test palbociclib in women with breast cancer with different biomarker profiles, in different drug combinations and at earlier stages in the disease.
“It’s important that we find a place for this drug in our armamentarium, because it’s clearly active, it’s extremely well tolerated and it could be that it works differently in different types of breast cancer,” says trial investigator Angela DeMichele, a breast cancer specialist at the University of Pennsylvania Perelman School of Medicine in Philadelphia. “There could be several different types of biomarkers that would predict who is going to respond, and the key here is really just trying to figure that out.”
Target Zone Rearrangement
One of the drugs singled out in FOCR’s November 2012 white paper as a ‘breakthrough in hindsight’ was Xalkori (crizotinib). The FDA approved the Pfizer drug, along with a companion diagnostic test from Illinois-based Abbott Laboratories, in 2011. Xalkori is an inhibitor of anaplastic lymphoma kinase (ALK), a cancer-causing enzyme that, owing to a gene rearrangement, gets constitutively activated in approximately 5% of cases of non–small-cell lung cancer (NSCLC), the most common form of lung cancer. Phase 1 and 2 trials demonstrated a response rate of 50–60% in people with ALK-positive NSCLC, a level far exceeding response rates of 10% in patients given other treatments available at the time.
However, even with Xalkori on the market, up to half of all people with ALK-positive NSCLC still don’t have a suitable drug option today. Fortunately, a more potent and selective ALK inhibitor—the experimental agent LDK378, which was granted breakthrough status in March—could help. In phase 1 trial data presented on 3 June at the American Society for Clinical Oncology meeting in Chicago, 47 of 64 people with ALK-positive NSCLC who had experienced disease progression after failing on Xalkori and were subsequently given LDK378 once daily for three weeks experienced significant tumor shrinkage. “To see such a high response rate and dramatic clinical responses among patients who have received a lot of prior therapies, and also other ALK inhibitors, I think definitely stands out,” says Ranee Mehra, an oncologist at the Fox Chase Cancer Center in Philadelphia who co-led the trial.
David Spigel, who heads the lung cancer research program at the Sarah Cannon Research Institute in Nashville, Tennessee, agrees. “To me, that was a very strong statement that this drug is active,” he says, “and of course it begs the question: ‘Well, what if you gave it to patients who were less heavily pretreated? Could you see even better results?’”
LDK378’s sponsor, the Swiss drug giant Novartis, now has two phase 2 clinical trials ongoing at multiple sites (including Mehra’s and Spigel’s) to further evaluate the compound both in people who have received prior Xalkori treatment and those who haven’t. The company also plans to initiate several phase 3 trials later this year, although it won’t wait for those studies to yield data before seeking market approval. Off the back of interim phase 2 results—and thanks to the breakthrough therapy designation—Novartis expects to file for market approval sometime in early 2014, just three years after initiating the first phase 1 trial with the compound.
Hematologist Torben Plesner was extremely nervous as he dosed his first patients. Five years ago, Plesner launched a first-in-human trial at Vejle Hospital in Denmark investigating an experimental monoclonal antibody called daratumumab (HuMax-CD38) in people with multiple myeloma who had exhausted all other treatment options. The drug targets the CD38 molecule, which is present on the surface of many immune cells and is especially highly expressed on malignant blood cells. The hope was that daratumumab would kill only the aberrant myeloma cells, but Plesner was worried about off-target effects.
He started with doses of just 0.005 milligrams of drug per kilogram of body weight. “It was almost pure water we used in the beginning,” Plesner says. Slowly, he upped the drug concentration, and, to his great surprise and delight, daratumumab showed no dose-related toxicities, with most of the adverse reactions stemming from the infusion process, a side effect commonly seen with antibody treatments. What’s more, among the first 12 study subjects who received at least 4 milligrams per kilogram of daratumumab, 7 saw their cancerous plasma cell levels drop by 50% or more. Plesner presented the data in December at the American Society for Hematology meeting in Atlanta. Janssen, which is co-developing daratumumab with the Danish company Genmab, announced the drug’s breakthrough status on 1 May.
Of note, Plesner’s trial results came about with daratumumab administered as a single-agent therapy. In contrast, elotuzumab, another antibody that BMS is currently developing for multiple myeloma treatment, must be combined with other drugs to reverse the effects of the disease. “This is the first time we’ve had a monoclonal antibody on its own generating such an encouraging response rate,” says Paul Richardson, a myeloma specialist at the Dana-Farber Cancer Institute in Boston who is also involved in daratumumab’s clinical tests.
Laurens Schotman can attest to this benefit firsthand. Schotman was diagnosed with myeloma close to six years ago, right around the time of his forty-eighth birthday. After undergoing two transplants involving blood-forming stem cells and multiple drug therapies, only to have his cancer bounce back time and again, he signed up for Plesner’s and Richardson’s ongoing trial earlier this year. In February, he weaned off all of his drugs, and every Wednesday this spring he traveled three hours from his home in the northern Netherlands to the University Medical Center Utrecht in the middle of the country for weekly antibody infusions. His blood concentrations of the free light chains derived from immunoglobin antibodies—a measure of myeloma disease progression—quickly halved and have since stabilized. More important to Schotman, who continues to receive biweekly treatments, is that his energy levels have improved. “I feel a lot better than I did a few months ago,” he says. “That’s for sure.”
Now physicians want to know what effect daratumumab will have when given together with other therapies. A 50-person study in which patients with myeloma will be given the experimental antibody in combination with Revlimid (lenalidomide) and dexamethasone is expected to start enrolling soon. “We are very hopeful that daratumumab will be a great dance partner with our other drugs,” Richardson says.