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Following the identification of the JAK kinase family in the late 1980s, the novel enzyme group was colloquially known as “just another kinase.”

Since then, these tyrosine kinases have defied that reputation amid abundant evidence showing that they transmit a variety of signals into the cell with many biological consequences.

Dysregulation of the JAK pathway plays a role in the development of numerous tumor types; it is particularly central to the pathophysiology of myelofibrosis (MF) and has long been recognized as a potentially valuable therapeutic target in that malignancy. Ruxolitinib (Jakafi), the first JAK inhibitor to gain FDA approval, has become a centerpiece in the treatment of patients with MF. JAK inhibition has not proved effective in other tumor types, and thus far, no other JAK-targeting therapies have become available.

Table. Clinical Trials Targeted the JAK Pathway

That picture, however, may be changing. A better understanding of the complexities of JAK signaling in normal and cancerous cells and the design of rational drug combinations, are poised to expand the use of JAK inhibitors in anticancer therapy for hematologic, and possibly solid, tumors. Ruxolitinib continues to be explored in multiple malignancies, and several promising novel agents are being evaluated in clinical trials (TABLE).

JAKs are now known as the Janus kinases, after the 2-faced Roman god of the same name, in recognition of their most striking feature: the presence of 2 near-identical kinase domains. There are 4 known members of the JAK family: JAK1, JAK2, JAK3, and TYK2, all sharing 7 conserved JAK homology (JH) domains within their protein structures.

At one end of the protein are JH1 and JH2, which comprise the 2 kinase domains. The first has tyrosine kinase activity, while the second is a pseudokinase domain with no catalytic activity that is thought to negatively regulate the first.3,4 At the other end, 3 of the JH domains collectively make up a larger FERM domain through which the JAKs are recruited to and bound by the cell-surface receptors that activate JAK signaling. A third domain, SH2, facilitates signal transducer and activator of transcription (STAT) signaling (FIGURE 1).

Figure 2. Broad Outlines of the JAK Signaling Pathway 

Cytokines and their receptors are among the most significant activators of the JAK pathway. Unlike tyrosine kinase receptors, cytokine receptors have no catalytic activity and are reliant upon the JAKs to perform kinase functions for them. JAKs bind to the part of the cytokine receptor that protrudes into the cell via their FERM domain. When the cytokine receptor is activated, it pairs up with another receptor molecule and this brings 2 JAKs close enough that they are able to phosphorylate and activate one another.

Activated JAKs then phosphorylate other target proteins, including the cytokine receptor to which they are bound, forming a binding platform for proteins containing an SH2 domain, primarily STAT proteins. Once they dock to the cytokine receptor, the STATs themselves are phosphorylated by the JAK proteins and become activated (FIGURE 2).

Figure 1. Domain structure of JAK Kinases

Activated STATs subsequently disengage from the cytokine receptor, pair up with one another and move into the nucleus, where they attach to specific sequences within the DNA to either activate or, less commonly, repress the transcription of a host of target genes. In this way, the interaction between JAKs and STATs transmits a signal from outside of the cell into the nucleus to coordinate a response to the signal.

Although this at first appears to be a relatively simple signaling cascade, the activity is complicated by the fact that there are 7 STATs. The diversity of possible JAK-STAT pairings, in addition to the range of different ligands and receptors that can activate JAKs upstream, allows for the multiplicity of biological effects coordinated by this pathway.

In addition, the pathway is negatively regulated in several ways. One involves protein tyrosine phosphatases (PTPs), which are enzymes that can deactivate JAK by reversing its phosphorylation. The suppressors of cytokine signaling (SOCS) are a family of proteins that are activated by STATs, and turn off the JAKSTAT pathway, thereby forming a negative feedback mechanism. They do this in several ways: directly inhibiting JAK kinase activity; blocking recruitment of downstream effector proteins; or mediating proteasomal degradation of JAKs. Finally, protein inhibitors of activated STATs (PIAS) block the activity of STATs in the nucleus through mechanisms that remain somewhat unclear.

Further adding to the complexity is the significant cross-talk with other signaling pathways, of which we currently have a relatively poor understanding. The best characterized interaction is with the mitogen-activated protein kinase pathway, which crosses paths with JAKSTAT signaling at multiple points.

As a result of its myriad roles in essential cellular processes such as growth, proliferation, survival, inflammation, and immunity, JAK pathway signaling is tightly regulated in normal cells by a delicate balance between activators and inhibitors.

Disruption of this balance and aberrant activation of the JAK pathway contributes to the development and progression of numerous cancer types by promoting many of the hallmark abilities of cancer cells, such as unchecked cell growth and proliferation. Because of its important role in regulating cytokine signaling, dysregulation of the JAK pathway can also contribute to inflammation and immunosuppression in the tumor microenvironment.

The mechanisms by which the JAK pathway becomes dysregulated include mutations in the receptors that sit upstream of JAK, which drive persistent activation of JAK, or in downstream effectors, which would bypass the need for JAK activation. Alternatively, the function of molecules involved in deactivation of the pathway, such as PTPs and SOCS, may be lost.

Fusions, mutations, deletions, and insertions in the 

 genes have been noted in intestinal, skin, stomach, and endometrial cancers, among others, whereas mutations in 

 have been identified in various hematologic malignancies.

In particular, the JAK pathway is central to the pathogenesis of myeloproliferative neoplasms (MPNs), including MF. These are cancers of the blood stem cells that cause an overproduction of white or red blood cells or platelets. Three mutually exclusive activating mutations in 

 are found in approximately 90% of patients with MF. The most commonly observed mutation is JAK2 V617F, which drives ligand-independent activation of the 

 pathway, and is observed in 40% to 60% of patients.

Activation of STATs is also commonly reported in several cancer types, including prostate cancer, non—small cell lung cancer (NSCLC), glioblastoma, and thyroid cancer, but is particularly prevalent in breast cancer. Upstream of JAK, increased expression of the cytokine interleukin-6 (IL-6) is observed almost universally across tumor types.

Ruxolitinib, a small-molecule inhibitor of JAK1 and JAK2, received FDA approval in 2011 for the treatment of patients with intermediateor high-risk MF, including primary MF, or MF that follows polycythemia vera (PV) or essential thrombocythemia.

Approval in this indication was based on data from 2 randomized phase III trials, COMFORT-I and COMFORT-II, which collectively involved more than 500 patients. Ruxolitinib more effectively reduced spleen size and MF symptom burden compared with placebo (COMFORT-I) and best available therapy (BAT; COMFORT-II). These studies also demonstrated an improvement in overall survival (OS) with ruxolitinib treatment. Ruxolitinib was well tolerated; grade 3/4 adverse events (AEs) included thrombocytopenia and anemia but these were manageable and did not often lead to treatment discontinuation.

The survival benefit was confirmed in recently published 5-year follow-up data for both trials, which also showed that long-term treatment with ruxolitinib was safe, with no significant cumulative toxicity. Long-term data from COMFORT-I also suggested that ruxolitinib improved patient quality of life.

 Various clinical trials of ruxolitinib are ongoing, including in other MPNs, hematologic malignancies, and solid tumors.

Although there are no other FDA-approved JAK inhibitors, other drugs have generated positive data in phase III clinical trials. Momelotinib, also a JAK1/2 inhibitor, has been evaluated in the phase III SIMPLIFY trials in patients with MF.

In SIMPLIFY-1, momelotinib was compared with ruxolitinib in patients with JAK inhibitor—naïve MF. The noninferiority of momelotinib was established in terms of the primary endpoint of a ≥35% reduction in spleen volume at 24 weeks. However, ruxolitinib was superior to momelotinib in the key secondary endpoint of a ≥50% reduction in total symptom score (42.2% vs 28.4%, respectively). There was also a higher rate of infections and treatment-emergent peripheral neuropathy with momelotinib.

Conversely, in the SIMPLIFY-2 trial in patients previously treated with ruxolitinib, participants who received momelotinib for 24 weeks did not experience superior outcomes for splenic response (≥35% reduction in spleen volume) compared with BAT (6.7% vs 5.8%, respectively). Nevertheless, momelotinib was significantly better than BAT at improving disease-related symptoms, defined as a ≥50% reduction in total symptom score (26.2% vs 5.9%) and in the transfusion independence rate (43.3% vs 21.2%). Given these mixed results, momelotinib’s future is uncertain as researchers attempt to determine the best next steps in its evaluation.

Pacritinib is a small-molecule inhibitor of JAK2 and the cytokine receptor FLT3. This drug has shown significant efficacy in a phase III clinical program in MF. In the PERSIST-1 trial, 327 patients were randomized to receive pacritinib or BAT as first-line treatment. At 24-weeks, spleen volume was reduced by ≥35% in 19.1% of patients treated with pacritinib compared with just 5% of those treated with BAT.

In the PERSIST-2 trial, pacritinib (at 2 different dosages—400 mg once daily or 200 mg twice daily) was also compared with BAT in 311 patients with MF and thrombocytopenia. The primary endpoint of a ≥35% reduction in spleen volume at 24 weeks was achieved in a significantly greater number of patients treated with either dosage of pacritinib than in those who received BAT (18.1% vs 2%, respectively).

In terms of this primary endpoint, the twice-daily dose was more effective than the once-daily regimen (21.6% vs 14.7%, respectively). Pacritinib was also superior in terms of total symptom score, with 25% of patients demonstrating a ≥50% reduction compared with 14% for BAT. Additionally, pacritinib reduced transfusion dependence.

Despite this display of substantial efficacy, higher death rates from intracranial hemorrhage, heart failure, and cardiac arrest in the PERSIST-2 trial prompted the FDA to place a clinical hold on pacritinib in February 2016. However, less than a year later, CTI BioPharma, the company developing the drug, reported that the clinical hold had been lifted after submission of final data from the PERSIST trials.

 A new clinical trial examining the safety of pacritinib in patients with primary MF who have previously received ruxolitinib also has been initiated (PAC203; NCT03165734).

The development of several other promising JAK inhibitors has been discontinued due to severe toxicities. AZD1480 caused neurological AEs, and lestaurtinib (CEP-701) resulted in frequent gastrointestinal toxicity. Fedratinib (SAR302503), a selective JAK2 inhibitor that showed significant efficacy in patients with MF in the phase III JAKARTA-1 trial, was put on a clinical hold by the FDA in 2013 after reports of potential cases of Wernicke encephalopathy. Sanofi subsequently discontinued its development.

However, fedratinib may be making a comeback. The rights for global development have been acquired by Impact Biomedicines. The company recently announced that the clinical hold was lifted based on a review of additional data from 18 studies in more than 800 patients, including JAKARTA-1 and the follow-up JAKARTA-2 study, which recruited patients who were resistant to all available therapies including ruxolitinib.

In JAKARTA-2, 55% of patients treated with fedratinib experienced a ≥35% reduction in spleen size. The most common AEs were anemia, nausea, diarrhea, and vomiting, and there were no cases of encephalopathy. No clinical trials of fedratinib are ongoing, but Impact Biomedicines plans to commercialize the drug for patients with MF and PV.

The complexity of the JAK pathway, the pleiotropic nature of its biological effects, and substantial amount of cross-talk between it and other important signaling pathways presents a significant challenge to the effectiveness of JAK inhibitors. The development of rational combinations of drugs could help to improve outcomes and these are starting to be studied in clinical trials.

Preclinical study results have suggested synergy between JAK inhibitors and epigenetic modifiers such as histone deacetylase and DNA methyltransferase inhibitors (DNMTs); agents targeting the Hedgehog (Hh) pathway, which plays a critical role in hematopoietic cell development and stem cell survival; inhibitors of PI3K, a key downstream effector of JAK signaling; and immune checkpoint inhibitors targeting PD-1 and its ligands.

The results of an ongoing phase II trial of ruxolitinib plus azacitidine, a DNMT inhibitor, in patients with MF, MPNs, and myelodysplastic syndrome (MDS) were recently presented at the 2017 American Society of Clinical Oncology Annual Meeting. Among the 39 patients evaluable for response, the objective response rate was 72%, and 79% of patients had >50% reduction in spleen size. Results from an ongoing phase I/II study of ruxolitinib plus decitabine, also a DNMT inhibitor, in accelerated phase MPN or post-MPN acute myeloid leukemia demonstrated a complete response (CR) or CR with incomplete blood count recovery in 33% of patients.

A phase I/II study of ruxolitinib in combination with the Hh inhibitor sonidegib in patients with MF is ongoing, but not actively recruiting participants. The regimen has demonstrated a ≥35% reduction in spleen size at 24 weeks in 44% of patients and was well tolerated.

 Meanwhile, the combination of JAK and PI3K inhibition has also been investigated in early-stage clinical trials. The phase Ib HARMONY trial showed promise for the combination of ruxolitinib plus buparlisib, and although studies of that combination are no longer ongoing, ruxolitinib is being evaluated in combinations with TGR-1202 and INCB050465, which are inhibitors of the delta isoform of PI3K. Preliminary data from the TGR-1202 study showed that the combination was well tolerated, with a clinical benefit rate of 89%.

Despite initial promise, JAK inhibitors have suffered several high-profile failures in clinical trials in patients with solid tumors. Incyte has halted its development of ruxolitinib in solid malignancies, following lack of efficacy in patients with pancreatic and colon cancers. However, combination therapy also could help to boost efficacy in this instance and several trials involving other JAK inhibitors are underway.

For example, there is evidence that activation of the JAK pathway could be a contributing factor to EGFR inhibitor resistance in 

-mutant NSCLC. A phase I study of ruxolitinib in combination with afatinib in patients with acquired resistance to EGFR inhibitors is ongoing, and preliminary data were recently presented. The combination demonstrated promising antitumor activity and was well tolerated.

 Also in this setting, itacitinib, a JAK1 inhibitor, is being evaluated in combination with osimertinib.

There is also some interest in targeting other components of the JAK pathway, with the cytokine IL-6 emerging as the most promising target thus far. Monoclonal antibodies have been developed against IL-6, primarily for the treatment of inflammatory diseases such as rheumatoid arthritis. Siltuximab (Sylvant), an IL-6 inhibitor, is being evaluated in multiple myeloma. As the principal downstream target of JAK signaling, the STAT proteins also make rational targets, but have proved to be a therapeutic challenge thus far. Several types of STAT inhibitors, predominantly aimed at STAT3 and STAT5, have been developed, including small-molecule inhibitors and, more recently, antisense oligonucleotides. The latter are short stretches of DNA or RNA that can bind to specific stretches of messenger RNA, and prevent its translation into a protein. AZD1950 is one example of this technology that has demonstrated single-agent antitumor activity in patients with treatment-refractory lymphoma or NSCLC.

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Articles

Dysregulation of the JAK pathway plays a role in the development of numerous tumor types; it is particularly central to the pathophysiology of myelofibrosis and has long been recognized as a potentially valuable therapeutic target in that malignancy.

Novel Approaches Show Promise in Targeting JAK Pathway

Right-to-try (RTT) legislation, which allows dying patients to take investigational medications without approval from the FDA, is on a roll. Legislatures in 39 states have approved such laws in recent years, as has the US Senate, and bills are pending in all other states

 and the US House of Representatives (FIGURE).

Figure. Status of Right to Try Legislation on State Level

The concept is far less popular, however, among academic researchers, learned societies, professional regulators, and other members of the medical establishment. Some objectors believe that RTT laws endanger patients. Others think the laws could hinder the FDA’s ability to weigh the harms and benefits of experimental drugs. Still others think that RTT laws are pointless bromides that leave the real obstacles to patient access fully intact.

There is, however, one aspect of RTT that generally wins the establishment’s support: the underlying goal. Organizations such as the American Society of Clinical Oncology (ASCO) and the American Cancer Society want to make it easier for people who have run out of approved treatments to receive promising new drugs that just might deliver a miracle.

 They don’t say, however, that RTT laws provide the best means of maximizing patient participation, benefit, and safety.

“The question isn’t whether patients should have better access to investigational agents. It’s whether right-to-try laws are the best way to improve access— and we don’t think that they are,” said Bruce E. Johnson, MD, president of ASCO, who also heads clinical research efforts at Dana-Farber Cancer Institute in Boston, Massachusetts.

Researchers outside the FDA have no real way to evaluate the efficacy of the current system for granting terminal patients access to investigational medicines. The agency has procedures in place through its expanded access program, sometimes called “compassionate use,” for 3 categories

: individual patients; intermediate-size populations, defined as smaller than the typical cohort for an investigational new drug (IND) of 20 to 80 patients

 or for a treatment protocol; and widespread use through a treatment IND or protocol. The FDA does not disclose exactly how many patients participate in the program each year, and it does not publicize any information about disease response or adverse events.

The FDA reports that it receives about 1400 requests a year, about half of them for individual patients and half for groups. The agency also has reported that it approves more than 99% of all applications.

 Unfortunately, the FDA does not disclose the size of each group, so there’s no way to know if it grants expanded access to 4500 patients a year or several times that number.

Either way, the total number is certainly tiny compared with the number of Americans who die as a result of diseases each year. Cancer, the second most common cause of death in the United States after heart disease, is expected to kill more than 600,000 people in 2017, accounting for nearly 1 of every 4 deaths.

 Although the expanded access program is open to patients with any serious medical condition, the oncology field is particularly affected.

It is, of course, impossible to compare experimental drug usage across nations when there are no concrete American figures, but compassionate use programs in several other countries seem to have far higher participation rates. France, for example, has just over a fifth as many residents as the United States, but it provided 6000 dying patients with access to investigational medications in 2013.

 This suggests to some that the number of Americans who would want experimental treatments may greatly exceed the number who get them under the current system. Others explain the discrepancy, in part at least, by asserting that the United States now approves breakthrough treatments faster than many nations and thus has less need of compassionate use.

“It’s pretty hard to argue that the FDA is a major obstacle to access right now—let alone the major obstacle&mdash;because they approve more than 99% of the requests,” Johnson said. “It is, therefore, difficult to see how patients would benefit from laws that take the FDA out of the loop, but it’s pretty easy to see how such laws might end up depriving regulators and the research community of valuable information about therapeutic effects and potential adverse events.”

The use of experimental medications by ordinary patients is a relatively modern phenomenon. Patients didn’t have to wait very long for new drugs to reach the market until 1962, when Congress mandated that the FDA use clinical trials to evaluate the safety and efficacy of would-be medications—and the average drug development time shot up from 2.5 to 8 years.

 Demand for investigational treatments began rising shortly thereafter and spiked in the 1980s, when the AIDS crisis reached its highest point. The FDA responded in 1987 by creating the first version of the basic compassionate use system that exists today.

Under current federal law, dying patients who have stopped responding to everything approved for the treatment of their condition have 2 main ways to access experimental medications: (1) enroll in a clinical trial or (2) apply for expanded access, which allows a doctor to administer an investigational drug to all patients in a similar therapeutic setting or to a single patient. The FDA has outlined 8 basic conditions that must be met to gain access (TABLE).

Table. FDA Requirements for Expanded Access Uses

Patients who wish to go the second route must work with a physician to find a promising experimental drug, convince that doctor to support a compassionate use application, petition the drug’s manufacturer for a supply, submit a formal application to the FDA, and— finally&mdash;ask an institutional review board (IRB) at the doctor’s practice or hospital for permission to use the therapy at that practice or hospital. Drugmakers typically give their products away, but patients who cannot independently finance the associated treatment costs must also secure monetary assistance from their insurer, which is not required to cover such costs, or some form of charity.

Applications can fail at every step, but anecdotes from both publications and interviews suggest that nearly all failures occur early, when the patients are trying to secure cooperation from doctors and drugmakers. The FDA, again, approves the overwhelming majority of applications, and IRBs appear to do likewise.

Alison Bateman-House, PhD, MPH, MA, an assistant professor in the Department of Medical Ethics at New York University Langone Health in New York City, has spent several years studying this topic and said in an interview with 

that she never heard of a rejection. Some doctors, on the other hand, clearly refuse to support at least some compassionate use applications, while some drug companies seem to decline them most of the time and the rest, at least some of the time. However, data are very sparse. Published papers don’t even try to estimate approval rates.

Even when patients gain approval at each step, the process takes time that some people do not have. Researchers have yet to quantify the number of patients who die before final approvals grant them access to a potentially useful drug, but there are published accounts of patients who died before their applications succeeded or before a drug had a chance to help them.

RTT laws take a very simple approach to making the process faster and easier: Remove the FDA from it entirely. Opponents object to this idea on 2 grounds. First, they say, the FDA is not much of a barrier. It not only approves 99% of all applications but also does so quickly once paperwork is received. Urgent applications, sometimes made by phone, are reviewed in just a few hours, and nonurgent applications typically are reviewed in 4 days or less. The FDA does not charge anyone for a review.

Second, RTT opponents say, the FDA review does provide concrete and significant benefits to patients. The FDA has less information about any particular drug than the company that makes it, but it has far more information than any single company about the range of drugs in a particular class, because it sees data from every trial, including data that drug companies do not share publicly. Therefore the FDA sometimes knows that a drug is likely to be toxic above a particular dose before its manufacturer realizes it.

Additionally, the FDA applies this information when considering compassionate use applications. The agency may not reject more than a tiny fraction of applications, but it does suggest changes in the prospective dose size or timing or in the wording of patient consent forms in about 11% of all cases.

“There’s an understandable tendency among patients, politicians, and the general public alike to think there’s no point in taking extra time and effort to reduce side effects when you’re dealing with people who don’t have long to live,” said Bateman-House.

“Everyone thinks, ‘It can’t get worse. They’re already dying of cancer.’ But, in reality, it can get worse—it can get much worse. Dying of cancer is terrible, but it’s far worse to lose your last days, weeks, or months to a medication that hastens your death or to exchange the manageable pain of cancer with the agony of having your cells decompose while you’re still alive, as has happened. These are real risks, which is why even dying patients should think carefully about trying unproven medications and why the FDA should have a role in reviewing these cases.”

Libertarians have sought to roll back the FDA’s ability to regulate the purchase and sale of medications since the modern agency began operations in 1930, but the movement that has made RTT the law in 38 states (in Hawaii, a bill passed but was vetoed by the governor) is quite recent. The movement began less than 4 years ago in the Phoenix offices of a Libertarian nonprofit organization called the Goldwater Institute, which drafted the sample legislation that is the basis for most RTT laws and remains a major force behind the movement. The model legislation, which is less than 4 pages long, allows patients with advanced, progressive, life-threatening disease who have run out of other therapeutic options to directly ask a drug manufacturer for an experimental medicine based on a physician’s recommendation and their own consent.

Goldwater officials concede that the FDA’s tweaks may sometimes improve treatment regimens for some patients, but they think the agency has no business standing between dying patients and potential cures. Their first objection is philosophical: Terminally ill patients, working in conjunction with medical specialists in good standing, should be free to make their own decisions without asking permission from regulators in Washington. Their second objection is practical: The FDA might approve the overwhelming number of applications in just a few days, but the onerous amount of paperwork required greatly reduces the number of applications.

“The application process, which can amount to 100 hours of paperwork and administration for a single patient, makes it virtually impossible for a physician to apply,” said Naomi Lopez Bauman, Goldwater’s director of healthcare policy.

“If it were possible to fill out the paperwork in 45 minutes, which is what the FDA currently estimates, many more doctors would be willing to use compassionate use, but the current system is so burdensome that scant few are able to devote that amount of time to a single patient.

“The process is similar to filling out your taxes,” she said. “While it may take a couple of hours to complete the written application, many more hours are spent gathering and analyzing documents, requesting employer records, and retrieving bank statements.”

Such arguments have resonated with elected officials across the country. RTT laws have typically passed through legislative chambers with overwhelming bipartisan support. The most recent state to pass such a law, Pennsylvania, did so with unanimous votes in both the state’s House of Representatives and its Senate.

 The US Senate also passed its RTT bill with unanimous consent.

The strength of this support may stem in part from the fact that state RTT laws are largely symbolic gestures supporting patient rights. No researcher or journalist has ever found a significant number of doctors and drug makers working to provide investigational drugs to dying patients without first getting the FDA’s approval. Just 1 doctor, Ebrahim Delpassand, MD, has used Texas’ RTT law to give an investigational treatment to about 100 patients with terminal cancer even though the FDA denied his request.

 If other doctors and patients are using state RTT laws, they are either very rare or very discreet.

Nevertheless, even if hardly anyone uses them, state RTT laws have already had a profound effect on compassionate use policy in the United States. The Goldwater Institute’s efforts got the entire medical establishment to think about a relatively obscure corner of medicine and find a need for change. That growing consensus has spurred the FDA to streamline the compassionate use process several times in the past several years.

The most heralded change may have come in February 2015, when the agency unveiled the “45-minute” compassionate use application culled from a far longer application that took—even in the FDA’s estimation&mdash;100 hours to fill out. Doctors who want expanded access for a class of patients must use the old form, but they don’t have to complete all sections.

 This year, the FDA tried to further ease the application process by streamlining institutional review. Commissioner Scott Gottlieb, MD, announced that, rather than requiring full IRB approval for compassionate use cases, doctors seeking permission to use investigational drugs at a given hospital simply needed approval from the IRB chair or “another appropriate person.”

These reforms do not mean the establishment is on board with RTT, however. The fact that RTT laws make truly discreet cases of compassionate use a genuine possibility ranks among opponents’ top concerns.

Compassionate use cases generate information about both the safety and efficacy of investigational medications, vital information that could be lost if drugmakers are not required to report responses to the FDA. Such concerns led to the revision of the Senate’s RTT bill, which originally forbade the FDA from penalizing candidate drugs because of adverse events among compassionate use patients but ended up mandating that the receive and use evidence of both benefits and harm.

Drugmakers, moreover, have not seemed enthusiastic about cutting the FDA out of loop. To the contrary, the Pharmaceutical Research and Manufacturers of America, an industry organization that represents most large drug makers, has been distinctly cool to the entire RTT movement. The organization has said state legislation is “unlikely to add any meaningful new approaches that can optimize the federal expanded access program”

 and expressed concern about any federal RTT legislation that would jeopardize the current trial process.

Why might RTT jeopardize the trial process? In theory, making it very easy for dying patients to access investigational medications on grounds of compassionate use could discourage them from participating in clinical trials. Why take a 50% chance of receiving either placebo or the existing standard of care when you can apply for compassionate use and guarantee yourself access to the newer medication?

That’s not the only plausible way that a massive expansion in compassionate use could reduce trial participation. “The current trial process is predicated on the fact that trials are about the only way to gain access to experimental medications. It’s pretty easy to imagine how a massive expansion in compassionate use could undermine that system,” said Y. Tony Yang, ScD, LLM, MPH, an associate professor in the Department of Health Administration and Policy at George Mason University in Fairfax, Virginia.

“For example, very sick patients often suffer serious adverse events from medications that are well tolerated by healthier patients, so if you have a dramatic increase in compassionate use, you’re going to have many reports of serious adverse events. Will those reports dissuade patients from participating in trials of seemingly dangerous medications? It certainly seems possible.”

It surprises many observers that drugmakers agree to supply their medications to patients who request compassionate use. Current regulations forbid them from selling investigational medications for a profit, so there’s no money to be made. What’s more, because compassionate use patients tend to be sicker than trial patients, they are more likely to suffer adverse events and less likely to respond to a drug, so compassionate use seems more likely to generate negative safety and efficacy data than standard trials.

The other surprise in the RTT debate is that nearly everyone, regardless of whether they support or oppose RTT, believes that dying patients should have easier access to investigational drugs than they do now.

“We simply have no idea whether compassionate use tends to help or hurt patients. The overwhelming majority of medications that begin phase II trials never win approval, so it’s almost certain the overwhelming majority of compassionate users get no benefit. But it could be worse than that. It may be that 90% of them are significantly harmed. We just don’t know, and yet nearly everyone, myself included, think we should make it easier for patients to access these medications,” said Bateman-House.

“It’s just an area where moral intuition trumps all else,” she said. “Most of us believe that dying people should be given wide latitude to try anything that may help them survive, even if it’s risky. But that doesn’t mean we have to throw out an FDA program that has helped, not harmed, patients, and make compassionate use anything goes.”

Right to try in your state. Right to Try website. righttotry.org/in-your-state/. Updated 2017. Accessed December 19, 2017.

ASCO releases position statement on access to investigational drugs [press release]. Alexandria, VA: ASCO; April 4, 2017. asco.org/about-asco/press-center/news-releases/asco-releases-position-statement-access-investigational-drugs. Accessed December 19, 2017.

Rawson K. Pink sheet—“right to try” and PDUFA VI: patient advocates, industry fight senate add-on. Friends of Cancer Research website. focr.org/news/pink-sheet-right-try-and-pdufa-vi-patient-advocates-industry-fight-senate-add. Published May 2, 2017. Accessed December 19, 2017.

FDA. Expanded access: information for physicians. FDA website. www.fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/ucm429624.htm#Expanded_Access_Categories. Updated October 3, 2017. Accessed December 21, 2017.

Investigational New Drug Application, 21eCFR, §312.20-312.48 (2017).

Exploring a Right to Try for Terminally Ill Patients: Hearing Before the U.S. Senate Committee on Homeland Security and Government Affairs, 114th Cong, 2nd Sess (2016) (statement of Peter Lurie, associate commissioner for public health strategy and analysis, FDA).

Cancer facts & figures 2017. American Cancer Society website. cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html. Published 2017. Accessed December 19, 2017.

Martinalbo J, Bowen D, Camarero J, et al. Early market access of cancer drugs in the EU. Ann Oncol. 2016;27(1):96-105. doi: 10.1093/annonc/mdv506.

Darrow JJ, Sarpatwari A, Avorn J, Kesselheim AS. Practical, legal, and ethical issues in expanded access to investigational drugs.

2015;372(3):279-286. doi: 10.1056/NEJMhle1409465.

FDA. Expanded access (compassionate use). FDA website. fda.gov/NewsEvents/PublicHealthFocus/ExpandedAccessCompassionateUse/default.htm#Statutory_Background. Updated October 3, 2017. Accessed December 21, 2017.

Cohen E. Dying patients denied drugs. CNN website. cnn.com/2014/04/05/health/cohen-compassionate-use/index.html. Updated April 6, 2014. Accessed December 19, 2017.

Tirrell M. When unapproved drugs are the only hope. CNBC website. cnbc.com/2014/08/05/a-case-for-compassionate-use-when-unapproved-drugs-are-the-only-hope.html. Published August 5, 2014. Accessed December 19, 2017.

Jarrow JP, Lurie P, Ikenberry SC, Lemery S. Overview of FDA’s expanded access program for investigational drugs. 

2017;51(2):177-179. doi: 10.1177/2168479017694850.

Right to try model legislation. Goldwater Institute website. goldwaterinstitute.org/wp-content/uploads/cms_page_media/2016/1/5/GoldwaterInstituteRighttoTryModel.pdf. Published October 5, 2014. Updated January 5, 2016. Accessed December 21, 2017.

Signing B. Governor Wolf signs legislation authorizing “right to try,” allows terminally ill patients to seek experimental treatments. Commonwealth of Pennsylvania website. governor.pa.gov/governor-wolf-signs-legislation-authorizing-right-try-allows-terminally-ill-patients-seek-experimental-treatments/. Published October 11, 2017. Accessed December 19, 2017.

Karlin-Smith S, Kim SM. Senate approves “right-to-try” drug bill. Politico website. politico.com/story/2017/08/03/senate-right-to-try-drug-bill-241293. Updated August 3, 2017. Accessed December 19, 2017.

Brennan Z. Who’s actually using “right to try” laws? A Texas oncologist explains his experience. Regulatory Affairs Professional Society website. raps.org/Regulatory-Focus/News/2017/08/04/28177/Whos-Actually-Using-Right-To-Try-Laws-A-Texas-Oncologist-Explains-his-Experience/. Published August 4, 2017. Accessed December 19, 2017.

Lurie P. A big step to help the patients most in need. FDA website. blogs.fda.gov/fdavoice/index.php/2015/02/a-big-step-to-help-the-patients-most-in-need/. Published February 4, 2015. Accessed December 19, 2017.

Gottlieb S. Expanded access: FDA describes efforts to ease application process. FDA website. blogs.fda.gov/fdavoice/index.php/2017/10/expanded-access-fda-describes-efforts-to-ease-application-process/. Published October 3, 2017. Accessed December 19, 2017.

Johnson SR. House lawmakers introduce federal “right to try” bill. Modern Healthcare website. modernhealthcare.com/article/20150715/NEWS/150719940. Published July 15, 2015. Updated July 16, 2015. Accessed December 19, 2017.

Right-to-try legislation, which allows dying patients to take investigational medications without approval from the FDA.

Demand Builds for Access to Experimental Drugs

There is a critically important subject associated with the clinical trial experience that has had inadequate discussion within the medical literature. That is, what is the role, or roles, of the patient beyond simply agreeing to serve as a research subject? This question is far from trivial or theoretical.

At the outset, let us consider that some clinical academic and bioethics experts as well as some governmental regulators have expressed the belief that clinical research and clinical care are fundamentally different endeavors. Such a belief apparently underlies decisions to conduct randomized placebo-controlled trials in order to observe an objectively measurable outcome in settings where others would strongly argue that available data clearly indicate the clinical value of an existing therapeutic strategy. However, the argument goes, if clinical research does not have to follow the ethical requirements of focusing on optimizing an individual patient’s chances for a favorable outcome—as would be the situation with clinical care&mdash;different rules would apply.

A most distressing example of how a rigid focus on determining an unequivocal measurable outcome to a research question may seriously negatively influence individual patient welfare is provided by the regulatory decision several years ago to mandate a randomized phase III trial that compared the utility of a novel BRAF inhibitor, vemurafenib, with a control arm of dacarbazine, a widely recognized, highly toxic, and ineffective cytotoxic agent in the management of metastatic melanoma.

 Remarkably, this study was undertaken at a time when overwhelming clinical data existed regarding the favorable impact of vemurafenib on the natural history of this devastating condition, but where socalled “gold-standard,” randomized phase III trial data proving an overall survival (OS) impact did not yet exist.

The decision to require this randomized trial to document statistically significant improvement in OS, as defined by a regulatory agency, was apparently justified, at least in part, by the morally problematic argument that clinical research need not overly concern itself with what the majority of the population would almost certainly consider to be in the best interest of the individual patient (in this case, the care of a patient with metastatic melanoma). The impact of what some might label an ethically objectionable decision by a regulatory body of the United States government was poignantly captured in a feature article that appeared in The New York Times.

Did the regulators ever consider asking individuals with melanoma or their families, or perhaps patients with cancer as a group, what they believed to be the appropriate clinical trial design, based on the existing data, to permit the approval of vemurafenib for noninvestigative use in metastatic melanoma? And if not, why was it considered appropriate that this critical determination be made in the absence of such input?

A more recent example of the complete absence of a patientfocused perspective regarding clinical research is evident in discussions of regulatory requirements for postapproval studies, following a decision by the FDA to permit commercial sale of a given antineoplastic agent. In a commentary that appeared in the New England Journal of Medicine, the authors criticized the FDA and pharmaceutical companies for their failure to complete such studies in a timely manner.

Although the editorial discussed a number of therapeutic areas, oncology was prominently highlighted. In commenting on delays in the completion of cancer-related postapproval studies, the authors noted: “Seven years later, one trial had missed deadlines for 2 milestones and had enrolled 30 patients; the other was still ongoing.” The drug in question (pralatrexate) had been shown in a nonrandomized trial involving 111 patients to produce an objective response (complete or partial) in one-quarter of patients with an uncommon lymphoma. These clinical data apparently were acceptable to the FDA to permit noninvestigative use.

Again, the question to be asked is why should patients who might be candidates to receive pralatrexate—or other agents where postregulatory studies have been mandated&mdash; be required to participate in these trials if they determine such participation is not in their best interest? In fact, it is relevant to suggest that perhaps one important issue for poor accrual is that the postapproval oncology studies designed by the companies, as required by regulators, are simply of very limited or no relevance to patients. To be clear, patients and their families are appropriately focused on the welfare of the individual, not on fulfilling bureaucratic requirements.

The authors of this commentary end their missive by declaring that with current efforts to speed up the FDA’s “’slow and burdensome’ approval process, drug approval is likely to become increasingly rapid and rely on looser evidence standards.” But who exactly determines what the evidence standards should be? Perhaps it is time for patients to play a much larger role in this regulatory realm and to help make these decisions.

Finally, it is important to acknowledge that many postregulatory studies have the potential to be very useful in defining optimal doses, schedules, drug combinations, and clinical indications. However, it is likely that such trials would be far more successful in meeting their accrual goals if relevant patient populations were included in the decision-making process regarding study designs, eligibility criteria, and defining meaningful endpoints.

Chapman PB, Hauswchild A, Robert C, et al; BRIM-3 Study Group. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507-2516. doi: 10.1056/NEJMoa1103782.

Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363(9):808-819. doi: 10.1056/NEHMoa1002011.

Harmon A. New drugs stir debate on rules of clinical trials. The New York Times. nytimes. com/2010/09/19/health/ research/19trial.html. Published September 18, 2010. Accessed December 15, 2017.

Woloshin S, Schwartz LM, White B. The fate of FDA postapproval studies. N Engl J Med. 2017;377(12):1114-1117. doi: 10.1056/NEJMoa1705800.

There is a critically important subject associated with the clinical trial experience that has had inadequate discussion within the medical literature, regarding the role of the patient beyond agreeing to serve as a research subject. 

Missing in Action: Patient Perspective on Cancer Trial Goal

Given that few options are available for intrahepatic cholangiocarcinoma (ICC), investigators are excited about a phase III trial of the multikinase inhibitor derazantinib (ARQ 087) as a second-line treatment for patients with inoperable or advanced disease. Current options are particularly limited for patients who experience disease progression after standard-of-care first-line chemotherapy. In the single-arm trial (NCT03230318), derazantinib is being tested in patients who have a genetic aberration in the fibroblast growth factor receptor 2 (

With this oral small-molecule inhibitor, investigators hope to treat what is currently considered an orphan disease. “Ten to 15% of patients with ICC may be effectively targeted with a specific FGFR inhibitor,” said Milind Javle, MD, a professor in the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. Javle is the principal investigator for the trial.

Among gastrointestinal cancers, FGFR2 fusions occur most commonly in ICC and are believed to be drivers in oncogenesis. Cancer triggered by 

-directed therapy, according to Javle. Also, mutations associated with a poor prognosis, such as 

 fusion, which makes it important to treat specifically for FGFR2-related cancer. “One interesting factor about 

 fusions is that the patients are often younger, often women, and have a relatively indolent, slow-growth cholangiocarcinoma compared with the 

 inhibitors have been very effective in ICC. A study of the FGFR inhibitor BGJ398 showed that patients with 

 genetic fusions responded well, achieving partial responses (PRs) or stable disease (SD).

 kinases. Fibroblast growth factors and their receptors tightly regulate cell proliferation, differentiation, migration, survival, and angiogenesis. In cancer, 

Given that few options are available for intrahepatic cholangiocarcinoma, investigators are excited about a phase III trial of the multikinase inhibitor derazantinib as a second-line treatment for patients with inoperable or advanced disease.

Vol. 19/No. 1 | Oncology Live®

Novel Approaches Show Promise in Targeting JAK Pathway

Demand Builds for Access to Experimental Drugs

Missing in Action: Patient Perspective on Cancer Trial Goal

FGFR Inhibitor Tested in Hard-to-Treat GI Cancer

Faster Care for Low-Income Patients: New Lung Cancer Treatment Models Emerge

Experts Discuss Optimal Timing of New Prostate Cancer Therapies