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In the early days of cancer chemotherapy, doctors quickly realized that the single agents they were testing were not only highly toxic, they were simply ineffective at curing their patients. Initial discussions about combining some of these drugs were met with heated opposition by the medical community. As former NCI Director Vincent DeVita Jr. stated in his recent memoir The Death of Cancer (2015), “Using more than one drug at a time to treat something was, as a general rule, considered sloppy medicine.” The first effective cancer treatments evolved to include combinations of four chemotherapeutic drugs. This pattern is now repeating itself in the field of cancer immunotherapy.
While some of the current drugs are working as single agents, the push is on big time to develop more effective combination treatments. Even Vice President Biden is extolling the virtues of this approach, promising that the government will work hard to speed up the approval of auspicious drug combinations.
Immunotherapy treatments for cancer represent the hottest trend in the drug business, with many companies making an effort to recast their pipelines in terms of their effects on the immune system. Hot fads, as we know, attract both the glamorous and the desperate because everyone wants a piece of the action. So what happens if you have a failed or marginally effective immuno-regulatory drug buried deep within your development pipeline, but you don’t want to give up on it? All is not lost: your drug may rise from the biopharma graveyard and find salvation in the arms of a strong partner. Set up a clinical study combining your favorite underperforming molecule with somebody else’s blockbuster drug, and pray to the pharma gods that there’s some additive or synergistic effect against some particular cancer. Your company’s chance to climb aboard the immuno-oncology gravy train may be just a small clinical trial away.
Several years ago I fretted over the sad fates of a large number of interesting, biologically active, immuno-modulatory proteins that had been set aside by the biotech companies that had developed them. There were good reasons why many of these older drugs were moved to the clinical back burner. Some had patents that had expired. Others couldn’t be manufactured in a cost-effective manner, or their clinical trials were either poorly designed or couldn’t recruit enough patients. Many companies put all of their eggs in a one clinical trial basket and then ran out of money. Toxicity in the clinic doomed others prospects at an early stage. There are, however, some compelling reasons to resurrect some of the more promising molecules that just didn’t work on their own. I’m betting that at least a few of these interleukins, cytokines, growth factors, and other immuno-modulatory proteins would boost the efficacy of one of the current immunotherapy stars: pembrolizumab (Keytruda), nivolumab (Opdivo), or ipilimumab (Yervoy). Even manipulating a patient’s microbiome may be a good way to boost the efficacy of some immunotherapy drugs. One oldie-but-goodie that's already been targeted for resurrection in combination with a checkpoint inhibitor is IL-10, which was first identified more than 25 years ago.
I’m deliberately not naming specific candidate molecules here because I don’t want to introduce any overt patentability problems for companies that are actually thinking about testing some of these combinations, but haven’t filed their IP yet. Agonistic or neutralizing antibodies that are biologically equivalent to these older molecules might also be effective as combination agents. It all depends on their biological activities. A great deal has been learned about the underlying biology of these proteins over the last ten to twenty years. This info will enable their champions to better choose an appropriate setting to return them to the clinic. If thalidomide, which causes severe birth defects and is widely considered to be the greatest drug disaster of all time, could be resurrected and turned into a blockbuster medication, then anything is possible if the biology is right. A repeat trip down the clinical trial aisle may, like many second marriages, lead to a more successful outcome.
The “molecular resurrection” approach is likely to curry favor from those who invest in virtual biotech companies or have an aversion to funding early stage biotech research. The work plan is pretty straightforward. First, file the necessary intellectual property to cover the combination of molecules and the disease(s) to be treated. While I’m not an intellectual property expert, I believe that defining specific combinations of drugs that would be used to treat specific diseases would be patentable. After patent applications have been filed and a new supply of the old drug has been manufactured, it will be time to set the clinical trial plans in motion. Try to partner with one of the companies that are already selling (or at least running clinical trials) with one of the hot new immunotherapy compounds, and keep your fingers crossed.
A new group, the National Immunotherapy Coalition, has been formed to facilitate this combinatorial approach. It will be led by industry heavyweight Dr. Patrick Soon-Shiong, who faces the challenge of moving forward without some of the industries highest profile immunotherapy companies, including Bristol-Myers Squibb, Juno Therapeutics, and Kite Pharma. To facilitate this combinatorial process, the government should encourage the development of drugs whose patents have expired by offering a longer period of market exclusivity to attract new investments. Drugs in the U.S. currently average only about 12.4 years of market exclusivity, and running clinical trials is an expensive proposition.
Why Do We Even Need Combination Therapies?
The simple answer is that while some of the newest immunotherapy agents have achieved remarkable response rates in several difficult-to-treat cancers, there is plenty of room for improvement. Let’s look at some of the new checkpoint inhibitors. Opdivo, as a single agent in melanoma, had an objective response rate of only 32 percent, the vast majority of which were partial responses. It costs about $150,000 per year. In contrast, a combination trial of Opdivo plus ipilmumab (Yervoy) in melanoma boosted the response rate to 60 percent. The overall response rate in a clinical trial of Keytruda in melanoma was 24 percent, and once again almost all of these patients were classified as having only partial responses. Keytruda for use in melanoma also costs about $150,000 per year, essentially the same as Opdivo.
Other checkpoint inhibitors are flowing down the pipelines of Roche, AstraZeneca, and Merck KGa/Pfizer. It’s clear that these will also be partnered with a variety of other molecules from a broad spectrum of biopharma companies, and will be tested in numerous sub-types of cancer. One drug combo was just approved for treating a subset of melanoma patients with specific mutations in the BRAF gene. Genentech’s vemurafenib (Zelboraf), in combination with cobimetinib from Exelixis, extended progression free survival about 5 months compared to Zelboraf alone. The combination of the two drugs will be sold under the name Cotellic.
Combine the New Stars with Something Old, or Something New?
The short answer is: it really doesn’t matter. The two key drivers here are efficacy and patentability. Whatever combination works to satisfy both of these criteria is the one to move forward with. A potential advantage of combining a new immunotherapy drug with an older lymphokine or cytokine is that the older molecule may have already been to the clinic, and as such may have an existing patient safety dataset. The same cannot be said for new molecules that have never been tested in people. Safety trials will need to be done on the combination, but the odds of getting over this hurdle will be enhanced with a drug that has already been shown to have a good safely record as a single agent.
Another expense is the cost of developing and manufacturing the individual components. If the two drugs are from different companies, it is immensely helpful if they are working together to fund the clinical trials. That way the company that makes drug B doesn’t have to buy (already on the market) drug A for the clinical trials, which could be quite expensive. Testing any given clinical protocol on just a few patients to look for signs of enhanced efficacy is likely to be readily affordable for these partners.
Combination Drug Therapies Are A Well Accepted Concept
A number of “drugs” on the market today are actually combinations of agents that have been shown to be effective together. Let me share a few examples. Many of the highly active anti-retroviral therapy (HAART) drugs taken by AIDS patients contain a mixture of three or four medications from different classes. ASAQ, a malaria drug developed by the Drugs for Neglected Diseases Initiative (DNDI), contains two active ingredients (artesunate and amodiaquine) that have previously been given as separate pills. Finally, Omeros’s Omidria is used during cataract and lens replacement surgery. The drug is a proprietary combination of two well-known medicines, phenylephrine (an alpha1-adrenergic receptor agonist) and ketorolac (an anti-inflammatory drug that blocks the cyclooxygenase enzyme). Being able to follow strategies that have already been shown to be successful in the clinic should help to attract investors to back this approach. The FDA even has a separate page on its website to deal with the issue of combination products.
Who Leads the Combo Race?
Immunotherapy drugs are competing both as single agents (looking to expand into more disease settings) as well as in combination therapies. A search of nivolumab (Opdivo) on Clinicaltrials.gov website on Oct. 14th showed some 97 studies either underway or planned for this antibody. A similar search with the term pembrolizumab (Keytruda) identified 138 open studies. Finally, a search with the term ipilimumab (Yervoy) revealed 121 open studies. Both Keytruda and Opdivo are expanding from their early successes against solid tumors to work on hematological malignancies, and both have demonstrated some efficacy against Hodgkin lymphoma.
Here’s a sampling of molecules to be combined with Merck’s Keytruda: Immune Design’s G100 or LV305; Dynavax’s SD-101; Amgen’s Talimogene Laherlparepvec; Blincyto, and AMG820 (anti-CSF-1R mAb); Advasis’ ADXS-PSA; Tesaro’s niraparib; Eli Lilly’s Alimta (pemetrexed); OncoSec’s intratumoral IL-12; MD Anderson to test a variety of anti-cancer therapies; GlaxoSmithKline’s anti-OX40 monoclonal antibody GSK3174998; Incyte’s epacadostat. Merck has plans for some 80 ongoing and combination studies with Keytruda.
Some companies are hedging their bets and are working with Merck’s competitors as well. For example, Amgen is going to test its Talimogene Laherlparepvec in combination with Roche’s PD-L1 checkpoint inhibitor atezolizumab, which on its own showed good efficacy against lung cancer as well as bladder cancer.
Here’s a sampling of molecules to be combined with BMS’s Opdivo:
Eli Lilly’s galunisertib (LY2157299); Celgene’s Abraxane; Kyowa Hakko Kirin’s mogamulizumab (Poteligeo); Novartis’s Zykadia, INC280, and EGF816; Five Prime’s antibody FPA008 against the colony stimulating factor 1 receptor; Janssen and Pharmacyclics’ ibrutinib (Imbruvica); Seattle Genetics Brentuximab Vedotin (Adcetris), and Neon Therapeutics NEO-PV-01 personalized neoantigen.
Here are a few other planned or ongoing drug combo studies: Eli Lilly is combining an anti-CSF-1R monoclonal antibody with AstraZeneca's anti-CTLA-4 monoclonal antibody tremelimumab. Celgene and AstraZeneca are working together to combine PD-L1 checkpoint inhibitor durvalumab (MEDI4736) with a variety of different agents (pomalidomide; CC-486; azacitidine) against a spectrum of hematologic malignancies. Roche’s monoclonal antibody atezolizumab (which blocks the protein checkpoint PD-L1), when combined with Zelboraf, shrank tumors in 76 percent of volunteers in a phase Ib trial.
A Good Result: Combined Efficacy
A clinical trial in this category would show additive effects. The positive effects of the combination could be manifested as a greater amount of tumor shrinkage, or a higher percentage of patients show a complete or partial response. Ideally, one would hit on both of these parameters (more patients are helped, and individually they show a greater response).
A Better Result: Synergy
A clinical trial in this category would show responses that are greater than the sum of either of the individual components tested alone. For example, if 25 percent of patients responded to drug A alone, and none responded to drug B (the resurrected medicine) as a single agent, than a synergistic response might show 40 to 70 percent of patients responding. Alternatively, maybe only 10 percent of the patients or fewer have a complete response to approved drug A, but given in combination, the percent of people showing a complete response to the combination of drugs might be 30 percent. Synergistic responses are difficult to predict, but they are often seen in biological assays.
A Bad Result: Toxicity
While it’s certainly possible, and even likely, that some combinations will be more efficacious than either treatment alone, the opposite effect also holds true. A combination of drugs that cause no serious side effects when administered on their own might turn out to induce significant clinical problems. For example, AstraZeneca is running combination clinical trials of two of its drugs, AZD9291 and durvalumab (a PD-L1 checkpoint inhibitor; formerly MEDI4736) on patients with non-small lung cancer. Trials have been halted, at least for the time being, due to reports of patients developing interstitial lung disease (that can lead to scarring and decreased pulmonary function). Neither drug on its own seemed to have this side effect.
Combination Approaches In Cancer Are Not Limited To Immunotherapy
We know that most cancers have a significant number of driver mutations i.e. those changes in the DNA that contribute most significantly to the out-of-control growth of the cells. Three drug combinations have become the standard of care in the treatment of relapsed multiple myeloma. Neutralizing the effects of as many of these driver mutations as possible should, in theory, contribute to inhibiting tumor growth. The trade-off will likely be increases in patient side effects as the number of drugs is increased.
If They Work, Combo Treatments Are Going to Be Expensive
Combining certain medicines may allow for better clinical efficacy, which translates into creating greater economic “value” than single drugs that only extend lifespan by a few months at best (this describes many of those on the market). Since drug pricing is not directly tied to drug development costs, it’s possible that combo agents will not simply be priced as multiples of what a single agent alone costs. Strong results, however, will encourage drug companies to tag these drug combinations with very high prices. They will be able to make a much more convincing case for a $300,000 drug combo that extended a patients lifespan by a 22 months instead of a single $150,000 drug with 3 months of benefit. Given the large number of cancer patients, this will likely set off yet another battle royal between drug makers and insurers (i.e. the payers). With all of the controversy surrounding drug pricing, it’s clear that discussions about the affordability of these “end of life” medicinal combos are bound to come up in the U.S. Many of the newer oncology drugs are not available in the UK because their National Institute for Health and Care Excellence does not consider them to be cost effective (i.e. providing much bang for the buck).
Back To The Past
Let’s return to Vincent de Vita’s The Death of Cancer memoir. It was striking to read how strident the opposition was to his efforts to develop new cancer treatments, even after he and his colleagues obtained clinical data proving efficacy. Much of this resistance was derived from real concerns about the substantial toxicity associated with these drugs and treatments. Many patients were brought nearly to the brink of death before their tumors began to shrink, and in the early days a large percentage of them died. Over time, though, more efficient protocols and newer drugs led to a series of increasingly effective treatments. Today, many childhood cancers are considered to be highly curable as a result of this work done decades ago. I think this pattern will be repeated in the next few years, as new combinations of immunotherapy agents will result in better outcomes for a wide spectrum of cancers. The road ahead won’t always be smooth, and there will be setbacks along the way, but a deeper understanding of how these molecules work together will enlighten the path to progress in the war on cancer.
Update 3-3-16 - A combo trial was just announced using Pfizer/Merck KGaA checkpoint inhibitor avelumab and Verastem's failed mesothelioma drug defactinib