Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Cardiometabolic Medications That Inhibit mTOR Might Help Prevent or Treat Cancer

Curious Dr. George Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column

William H. Bestermann Jr, MD Senior Clinical Advisor at Congruity Health

Many people believe that cancer is a metabolic disease. A biological process known as the mTOR pathway controls cellular metabolism by way of central signaling, and it is involved in tumor growth. Here, our Curious Dr. George asks William H. Bestermann Jr, MD, an internal medicine doctor, how medications that target the protein mTOR and its associated pathway could prevent or treat cancer. Dr. Bestermann is Senior Clinical Advisor at Congruity Health.

Curious Dr. George: What drugs that are currently approved for use by the U.S. Food and Drug Administration (FDA) inhibit mTOR and might be worthy of testing for potential off-label use for cancer prevention or therapy?

William H. Bestermann Jr, MD: A search including the terms mTOR and cancer in PubMed brings up 125,000 articles on the subject. Aberrant mTOR activation and signaling play a central role in many malignancies. Mutations that persistently activate mTOR are a basis of many familial cancer syndromes.

So, what is mTOR? It is an abbreviation for the mechanistic target of rapamycin, which is a natural compound produced by a fungus. Rapamycin is an antibiotic that is slowly released from the most modern heart artery stents to keep them from blocking with scar tissue and inflammation. It accomplishes that by inhibiting the protein mTOR, a master metabolic genetic switch. The mTOR pathway regulates many metabolic processes. In the fetus and child, it is essential to coordinate food availability with growth. Overeating, excess abdominal fat, and tobacco smoke cause increased oxidant production and growth factor signaling, which activate mTOR to increase arterial thicknessheart size, and the likelihood of cancer. mTOR has a reciprocal relationship with the protein AMPK, another genetic master metabolic switch. When mTOR is switched on, AMPK is switched off. mTOR and AMPK are a final common signaling pathway for genetic signaling that causes heart disease and malignancy. Medications that block oxidant production from that signaling or directly impact the mTOR/AMPK axis inhibit malignant transformation and tumor growth.

Several cardiometabolic medications decrease oxidant production and epidermal growth factor receptor (EGFR) activation to switch off mTOR and switch on AMPK. These include ACE inhibitors like lisinopril, ARBs like losartan, statins, and mineralocorticoid receptors (MR) like spironolactone. Smoking cessation has the same effect. Caloric restriction, intermittent fasting, rapamycin, exercise, and metformin directly inhibit mTOR and activate AMPK. SGLT2 inhibitors directly activate AMPK. These components of optimal medical therapy interfere with the core biology that causes cardiovascular disease and cancer. That is why they have a greater impact on major cardiovascular events and all-cause mortality than their impact on the target risk factor. These interventions don’t merely lower the target risk factor, they interfere with the molecular biology that causes cardiovascular diseases and cancer. They protect cells and organs.

Medications with a structure and function similar to rapamycin are called rapalogs. These are used to treat cancer and prevent organ transplant rejection, and they have potential in several additional conditions. The cardiometabolic medications listed in the previous paragraph do the same thing by directly or indirectly switching off mTOR and activating AMPK. Rapalogs inhibit both mTORC1 and mTORC2. The effect on mTORC1 is beneficial, and inhibiting mTORC2 may have harmful side effects. Like rapalogs, metformin has a beneficial effect in cancer prevention and treatment, which it produces by directly and specifically inhibiting mTORC1 and activating AMPK. Statins and ACE inhibitors are also associated with decreased cancer incidence. Similarly, high aldosterone levels have been associated with increased cancer risk, and eplerenone blocks those effects in a highly specific manner.

Research to further evaluate cardiometabolic medications for cancer prevention and treatment benefit should be a priority.

Dr. Bestermann can be reached at whbester@gmail.com.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Using Virtual Trials to Screen for Potential Glioblastoma Therapies

Curious Dr. George
Cancer Commons Editor in Chief George Lundberg, MD, is the face and curator of this invitation-only column

Al Musella, DPM
President, Musella Foundation For Brain Tumor Research & Information, Inc.

The existing drug development system “has failed miserably” for people with glioblastoma brain tumors, according to Al Musella, DPM, President of the Musella Foundation for Brain Tumor Research & Information, Inc. In partnership with Cancer Commons, his organization’s Brain Tumor Virtual Trial aims to speed discovery of promising new glioblastoma treatments.

Curious Dr. George: How might your Virtual Trial approach speed the process toward either validating or invalidating potential therapies for glioblastoma?

Al Musella, DPM: I have watched how the current drug development system works since 1992, and think we could do much better. There are many problems but the top ones, as they relate to malignant brain tumors, are:

  1. The current system is set up to try to find one magic bullet that will successfully treat the disease. This concept has worked reasonably well for some diseases, but for brain tumors it has failed miserably. I feel that the ultimate cure for brain tumors will be a combination approach, and under the current system, it is very difficult to get the individual components of that ultimate cocktail approved by the U.S. Food and Drug administration (FDA).
  2. There are not enough patients for the number of trials needed. About 10% of adult glioblastoma patients—about 2,000 per year—enter clinical trials. There are currently 318 glioblastoma trials open for enrollment, which means only six patients are available per trial per year. And some trials require large numbers; it takes years to accrue enough patients, and many trials never do.
  3. Phase 3 trials are too long and inflexible. In the last 25 years, only one phase 3 glioblastoma study showed a statistically significant improvement in survival, adding only 3 months to median survival. As patients are treated, we learn how to use the treatments better, but the rigid structure of a phase 3 trial doesn’t allow for modifications midstream. Rather than stop a trial, discard the results and start over, researchers complete a trial anyway, knowing that there may be a better way to use the drug.

I propose an alternative approach:

  1. All patients must be watched in a regulatory-grade registry so we learn from every patient—not just the 10% who may not even represent the typical patient.
  2. A formal randomized trial is perfect to prove that a combination works, but we are not yet at the point where we have a combination worthy of a full-scale phase 3 trial. So, if a patient desires entry into a formal trial, I propose they be given access to the registry to pick the most promising trials.
  3. We need a system in which experimental treatments get fast conditional approvals when they are shown to be relatively safe, with early evidence that they have the intended effect—even if that effect doesn’t result by itself in prolonged life. This allows us to use them in combinations and figure out how best to use them.
  4. Paying for medical drugs is a problem. The only way this can work is if patients do not have to pay high costs for their treatments, and if drug companies get paid for the treatments. This will allow access to the drug. The Virtual Trial system should keep drug costs down, as it will take the vast majority of time and money out of the drug development process and break the monopolies currently preventing many new drugs from being developed. In fact, I have proposed a bill (see below) that basically requires Medicare and Medicaid to pay for them and encourages private insurance to pay. We are working out the exact wording and are considering a “pay for performance” model, or a compromise in which costs for non-standard treatments cannot exceed what the standard of care would have cost.
  5. Doctors, or teams of researchers, can then think up the best combinations for each individual patient, and test them in small, fast, inexpensive (or free) virtual trials. They can see the ongoing results in all patients and quickly determine if a conditionally approved drug is worthy of continued usage—perhaps tweaking how it is given or the combinations used, or if it should be dropped. Once the ultimate cocktail is found, it can then be tested in a formal phase 3 trial.

I have been working on the components of this plan. We already have “right-to-try” laws passed in the U.S., but these did not work out as intended, mainly because of cost issues and fear that the FDA would hold usage of this pathway against a drug company. So, I am now working on a much-improved version of early access called the “Promising Pathway Act,” which was recently introduced into Congress. It fixed most of the problems with right-to-try laws and the FDA’s Accelerated Approval Program. It provides for conditional approval of treatments and requires all patients who use any conditionally approved drug to participate in a registry.

My organization, in partnership with Cancer Commons and its for-profit spinoff xCures, has set up a patient-navigation program that should be the model for how we approach all serious diseases. Our team of neuro-oncologists, PhD researchers, and nurse navigators—aided by an artificial intelligence engine—can look at our rapidly growing patient registry (we now have over 1,250 patients) and evaluate medical research, the rationales presented in tumor board meetings, and patients’ medical histories in order to come up with a list of treatment plan options that may be best for any given patient. The patient and their own doctor can select a treatment from our list, or they can elect to try whatever other treatments they want. Whatever they choose, our team then follows up on every patient to see the outcome of their chosen treatment. This way we learn from every patient.

We try to help patients get access to their chosen treatments, but the most promising options are usually impossible to access because the components are not yet approved, and either they are unavailable under expanded access or the drug companies won’t allow us to combine the experimental drugs.

Nonetheless, any doctor or researcher who is using a new combination of FDA-approved drugs for a patient can submit that treatment plan option to our system to be run as a virtual trial, allowing the doctor or researcher to quickly test the theory in their patient and use our system as a screening tool. They can try many combinations quickly, and if a particular combination shows a lot of promise, it can then be promoted to a traditional phase 3 trial to validate the findings.

Any treatment plan options validated in this way would be made up of FDA-approved treatments, so any doctor could prescribe them, allowing every brain tumor patient to have access—not just those perfect patients that fit into existing clinical trials.

In summary, our Virtual Trials could be used as a screening tool to figure out the best combinations, and how best to use treatments, which then can be tested in formal trials. Conversely, this approach could be used to quickly eliminate bad combinations. Having all results available in a central registry would help doctors from around the country avoid trying the same ineffective combinations.

Dr. Musella can be reached at musella@virtualtrials.org.

WATCH the 11th Annual Lundberg Institute Lecture: The COVID Labyrinth: Where Are We In It and How Do We Escape?

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Manage His Wife’s Metastatic Breast Cancer

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Richard B. Schwab, MD

Professor of Medicine – Division of Hematology/Oncology; Medical Director, Koman Family Outpatient Pavilion Infusion Center – UC San Diego Moores Cancer Center

For most people with breast cancer, a lump is the first sign that leads to diagnosis. But some cases are not detected until after spread has already occurred. Here, our Curious Dr. George asks Richard B. Schwab, MD, how he would approach such a case if his own wife were the patient. Dr. Schwab is Professor of Medicine in the Division of Hematology/Oncology and Medical Director of the Koman Family Outpatient Pavilion Infusion Center at U.C. San Diego Moores Cancer Center.

Curious Dr. George: How would you, as a breast cancer expert, manage your wife’s cancer if it were to present as shortness of breath or back pain, with a breast mass only then detected?

Richard B. Schwab, MD: Doctors frequently take care of their family members for minor problems; cancer is not one of them. Even caring for patients, managing one’s own anxiety about the normal uncertainties of medicine is not easy. Managing of my wife’s cancer would not be possible, so I would have one of my excellent colleagues be her oncologist.

That said, I would be answering my wife’s questions about this frightening situation and trying to guide her. She gets her screening mammogram every year, so presenting with metastatic breast cancer would be very unusual. Only 5% of breast cancer is de novo metastatic, and many of these patients did not have recommended screening before diagnosis. However, screening mammograms are not perfect, so your hypothetical scenario is possible.

If she was short of breath, I think we would utilize the emergency department. Although cancer is usually a relatively slow process, there are rare times when patients can become very ill during the normal time required for diagnosis and treatment initiation. CT scans can be done quickly and could identify a pulmonary embolism, pleural effusion, or lymphangitic spread. Starting appropriate therapy quickly (anti-coagulation, thoracentesis, or chemotherapy respectively) could be critically important.

Making a pathologic diagnosis would be the next step, and would radically alter treatment (and life) plans. Breast cancer is not one disease. Oddly we would be hoping for an aggressive estrogen receptor-negative and HER2-positive cancer. These cancers are highly responsive to numerous treatments, and cures—even with metastatic disease—are becoming more and more common. A triple-negative cancer would be complicated. Some patients with triple-negative breast cancer, particularly limited to the lungs, do end up cured, but these cases are rare and overall this type of breast cancer has the fewest treatment options. Last but most common, particularly if her cancer had spread to the bones, would be estrogen receptor-positive disease. These cancers generally grow more slowly and on average patients survive longer with this type of disease. However, these cancers are never truly cured, although for older patients lifelong disease control can sometimes be obtained. For a patient as young as my wife new therapies would be needed to have any reasonable hope of lifelong disease control.

Which location to biopsy is a common challenge we would need to address. Biopsy of the breast is the easiest, but may not reflect the more dangerous disease that has spread to other organs. Lung biopsy has some additional risk, it is anxiety provoking, and sample quantity (or even successful sampling) can be challenging. Biopsy of the bone, while very safe, can give unreliable results due to the need to decalcify the sample prior to testing. The details of the patient’s case and the expertise of the doctor performing the biopsy matter. Having expert trusted colleagues in radiology and pulmonology would be a significant advantage for my wife.

I mentioned the idea of truly curing my wife. I define true cure as a lack of cancer progression for at least 5 years after stopping therapy. I have cared for many patients with metastatic disease that has been cured, and that knowledge would help my family get through what is fortunately only a hypothetical situation.

Dr. Schwab can be reached at rschwab@health.ucsd.edu.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Handle His Own Cancer of Unknown Origin Causing Severe Back Pain?

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Marc B. Garnick, MD

Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center

Treating cancer that has been fully diagnosed can be a complex challenge. But sometimes the process of diagnosis itself presents an urgent puzzle. Here, our Curious Dr. George asks Marc B. Garnick, MD, how he would approach his own case of an unknown form of cancer. Dr. Garnick is the Gorman Brothers Professor of Medicine at Harvard Medical School (HMS) and Beth Israel Deaconess Medical Center in Boston, MA. He is also Editor in Chief of the HMS Annual Report on Prostate Diseases.

Curious Dr. George: What would you do if you began to experience unrelenting back pain and visited your primary care physician, only to be informed that X-rays taken of your lower back demonstrated multiple lytic lesions of several lumbar vertebrae? In this hypothetical scenario, a prostate-specific antigen (PSA) blood test shows a level of 30 ng/ml, and you also recently lost 10 pounds unintentionally—but you have no significant urinary symptoms. How would you proceed?

Marc B. Garnick, MD: The findings of multiple lytic lesions of several lumbar vertebrae in the setting of unrelenting back pain constitute an oncologic emergency. If I, as a physician and oncologist in this case, were to face such a serious set of medical circumstances, there are things that need to be done immediately and hopefully within the next 24 hours.

The critical and most time-sensitive issue that I would want urgent input on is whether spinal cord compression with impending paralysis is present. Regardless of whether these lytic lesions are caused by an underlying plasma cell dyscrasia or prostate cancer—the two highest differentials on my list—a prompt evaluation of the spinal anatomy is urgently needed. My biggest concern is whether the findings represent a plasmacytoma in association with a plasma cell dyscrasia or prostate cancer. I know that the presence of spinal osteolytic lesions can also accompany metastatic lung cancer, renal cell carcinoma, or colorectal cancers as well, but given my overall history, this would be of less concern. I would not completely rule out prostate cancer, knowing that purely lytic osseous lesions are less common in prostate cancer, but that they do occur, often mixed in with osteoblastic lesions.

In anticipation of my emergent evaluation at the emergency ward (EW). I would expect that a full set of chemistries—especially looking at serum Ca++ level, and complete blood count—would be evaluated by EW staff. My concern is that the back pain, which has been really excruciating, is now accompanied by some leg weakness and some inklings of saddle anesthesia. I had not had a recent digital rectal exam (DRE) and would hope that the intern or resident in the EW knows how to perform this important examination (since DRE learning is completely de-emphasized in current-day medical training). The PSA of 30 is of obvious concern, but my history of benign prostatic hyperplasia (BPH) and prostatitis in the past, as well as multiple prostate evaluations, would place this as number two on my differential. I could also consider that there may be some underlying urinary retention ongoing as a possible result of some neurological dysfunction, giving rise to the elevation in PSA. A bladder scan check of post-void residual would be helpful here as well, and accomplished in less than 30 seconds with a bladder scanner.

On my way to the MRI scanning center, I would ask if my peripheral smear showed any evidence of rouleaux formation, a hint of an underlying blood dyscrasia, as well as my Ca++ levels. I would remember that hypercalcemia is distinctly unusual in widespread metastatic prostate cancer (as opposed to myeloma) and would recall an article that Dr. Rob F. Todd III and I wrote decades ago underscoring the rarity of this association, and when present, think of other etiologies such as sarcoidosis to account for the hypercalcemia.

As I am thinking about next steps, I would compartmentalize the two important scenarios. I first would assume that the scans will show no evidence of spinal cord compression: This is unlikely, especially given the widespread extent of the spinal lytic lesions and new subtle saddle anesthesia as well as continuing pain. Obtaining a tissue diagnosis will be dictated by the radiologic findings: if there is no evidence of spinal cord compression, and the cross sectional and other routine imaging do not suggest intra-abdominal or thoracic involvement, then consideration of the site to biopsy again would be dictated by the lab findings. Hematologic findings of plasma cell dyscrasia or plasmacytoma would be further evaluated by either a bone marrow biopsy and aspirate, or consideration of directly biopsying an accessible lytic lesion. If the DRE suggested prostate cancer, and a repeat PSA was confirmed to be elevated, a prostate needle biopsy could be performed.

I would then assume the most likely explanation—that there is evidence of spinal cord compression: Here the situation is different. I would urge the administration of dexamethasone, and consultation with radiation oncology and neurosurgery would be mandated to assess optimal approach management. If an operative intervention is recommended for decompression, tissue for pathologic analysis can be obtained at that juncture and then the therapy can be tailored according to the pathology. If surgical intervention is not recommended, then biopsy of lytic lesion and initiation of radiation therapy would be next. There would be some discussion as well at this juncture to determine the optimal sequencing of treating first and diagnosing later, or diagnosing first and and then treating—especially since the systemic therapies are so different. If neurosurgical decompression was mandated, then I would vote for the “treat first” option.

I would want the hierarchy of diagnostic and therapeutic decision making to address, first and foremost, the structural abnormalities induced the lytic lesion. It would be beneficial but not necessarily critical to know the specific pathologic diagnosis before the anatomic lesions were treated by surgery, since tissue would be obtained at that juncture. As stated above, tissue would be needed prior to initiating radiation. I would then select the most appropriate systemic therapies to be informed by the tissue of origin. These would include initial standard programs for a hematologic neoplasm or intensified androgen deprivation therapies with or without chemo if it turned out to be metastatic prostate cancer. Genomic profiling, of course, would be part of any diagnostic evaluation, using any one of a number of platforms such as Foundation Medicine.

Dr. Garnick can be reached at mgarnick@bidmc.harvard.edu.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How an Expert Would Treat Her Own Metastatic Melanoma

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Pauline Funchain, MD

Director of the Melanoma Medical Oncology and Genomics Programs at Taussig Cancer Institute, Cleveland Clinic

Cancer patients often ask their doctors, “What would you do if you were me?” Here, our Curious Dr. George asks Cleveland Clinic oncologist Pauline Funchain, MD, how she would handle her own diagnosis of advanced melanoma.

Curious Dr. George: What would you do if you personally were discovered on a routine exam to have abnormal liver function tests that led to scans and the finding of several liver masses? Remembering back some 15 years, you had surgery to remove a 7-mm-diameter, 2-mm-thick melanoma from the skin of your lower leg, treated by wide excision with clear margins. No spread detected at that time. No tumor testing then, aside from light microscopy. How would you proceed?

Pauline Funchain, MD:

Starting line: First, I would take a deep breath. I would remind myself that stage IV melanoma of the skin has become a disease state that can have durable remissions well over 5 years, and that such remissions are not rare. I would be heartened knowing that results approaching cure are possible for some stage IV melanomas.

Next, I would contact my nearest academic medical center. I would carefully research teams known to have good bedside manners, clear communication, and melanoma expertise. The field of melanoma is rapidly changing for the better, and I would want a team that is not only well aware of these developments, but also would be able to clearly explain the multiple therapy options available to me in the context of a briskly moving field. Lastly, I would prefer a medical center where medical subspecialists were readily available and accustomed to timely multidisciplinary communication, as immune-mediated adverse events (irAEs) are commonly elicited during the course of systemic therapy for melanoma.

Workup: At this center, I would first undergo a biopsy of a liver mass. I would ensure BRAF mutation screening was performed by immunohistochemistry (IHC), the most rapid of available BRAF testing modalities. If enough tissue was available, I would send for next generation sequencing (NGS) of the tumor specimen, to prepare for possible second- or third-line therapies. If I had a family history of cancer, personal history of multiple cancers, or was relatively young, I would see a genetic counselor to discuss germline genetic testing. For staging I would get either a CT chest/abdomen/pelvis or PET CT. MRI brain is absolutely essential, as brain metastases are common, often asymptomatic, and may influence first-line therapy choices.

First-line therapy: With staging complete, I would inquire about first-line immunotherapy-based trials. While the best outcomes for stage IV disease, particularly involving liver and/or brain, have been seen with combination ipilimumab/nivolumab, I would welcome the opportunity to try something new in a rapidly evolving melanoma treatment landscape. I would be reassured knowing that all gold standard therapies would still be available to me should a first-line clinical trial fail. If I was not eligible or did not like available clinical trials, I would proceed to first-line treatment with ipilimumab/nivolumab. If I had a personal history of autoimmune disease, I would request a consultation with the appropriate medical subspecialty prior to starting immunotherapy. Other medical conditions might influence me to prefer single-agent immunotherapy, and it is these situations that highlight the importance of having a medical team who is able to have a careful discussion with me to understand my individual needs.

While on therapy I would undergo systemic imaging every three months to assess response to therapy. If my original staging did not demonstrate brain metastases, I would undergo MRI brain every 6 months in the stage IV setting. If I had fast-growing disease, was rapidly losing weight, had a very large burden of disease, or some combination of these factors, I may prefer to invoke the rapid response typically seen with targeted BRAF/MEK therapy. On targeted therapy, I would consider imaging every 2 months, given a higher likelihood of developing therapeutic resistance with the combination of factors that led me to start targeted therapy. I would follow my status closely with serial LDH levels, which correlate well with BRAF-mutant disease burden.

Closing thoughts: In the landmark trial of first-line combination immunotherapy for stage IV melanoma, median melanoma-specific survival has not yet been reached after 6.5 years of follow-up. In plain English, more than half of those who underwent combination immunotherapy have survived stage IV melanoma at the 6.5-year mark. Because not everyone experiences prolonged survival, I would be realistic about having a stage IV cancer diagnosis that might be fatal, yet remain optimistic given the pace of new drug development that immunotherapy and targeted therapy have precipitated in the last decade.

Requests for Dr. Funchain’s email address can be sent to Curious Dr. George at gdlundberg@gmail.com.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Latest in Melanoma Treatment: A Guest Perspective

Ryan Sullivan, MD
Associate Director of the Melanoma Program at Massachusetts General Hospital Cancer Center, Associate Professor at Harvard Medical School

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

What’s new in melanoma treatment? Our chief scientist Emma Shtivelman, PhD, recently outlined the latest options. Here, our Curious Dr. George invites a response from Ryan Sullivan, MD, Associate Director of the Melanoma Program at Massachusetts General Hospital Cancer Center and Associate Professor at Harvard Medical School.

Curious Dr. George: As a melanoma expert, what are your thoughts on the treatments outlined in our recent article?

Ryan Sullivan, MD: It is a solid summary. The bottom line is that over the past decade, seven single-agents (in order, ipilimumab, vemurafenib, dabrafenib, trametinib, pembrolizumab, nivolumab, and talimogene laherparepvec) were approved by the U.S. Food and Drug Administration (FDA), as were five combinations (three BRAF/MEKi combinations—dabrafenib-trametinib, vemurafenib-cobimetinib, and encorafenib-binimetinib; one checkpoint inhibitor combo—ipilimumab-nivolumab; and one triplet regimen of a BRAFi, MEKi, and PD-L1i—vemurafenib-cobimetinib-atezolizumab) for metastatic melanoma as well as three new adjuvant therapies (dabrafenib-trametinib, pembrolizumab, nivolumab).

Thus, the past decade has been revolutionary in terms of treatments for patients with stage III and stage IV melanoma. With that said, a near majority of patients with stage III melanoma are likely to relapse (data gleaned from long-term stage III adjuvant trials), and a majority of patients with metastatic disease (extrapolated from long-term stage IV regimen data and the knowledge that only “well-enough” patients are enrolled onto trials) will die of their disease. So, there are a number of unmet needs, and emerging data is providing some idea of how to meet these needs.

The neoadjuvant data is very interesting. A number of my colleagues have shown that therapy with BRAF-targeted therapy (nearly all the published literature is with dabrafenib-trametinib) or immune checkpoint inhibition (either single-agent anti-PD1 or combined ipilimumab-nivolumab) is associated with significant rates of major pathologic or complete pathologic responses in patients with bulky, resectable stage III melanoma. Despite this data, there is yet to be an approved neoadjuvant therapy for this patient population. It seems logical that there will be either approved and/or guideline supported regimens over the next half-decade or so, but presently the neoadjuvant setting remains a very exciting opportunity for clinical trial enrollment and translational analysis.

The frontline metastatic setting remains a hotly debated situation regarding treatment selection. There are basically five generally accepted front-line therapies—BRAF/MEK combination therapy (there are three potential regimens, all noted above) in BRAF-mutated melanoma populations, BRAF/MEK/PD-L1 targeted triplet therapy in BRAF-mutant melanoma populations, single-agent anti-PD-1 antibody therapy (with either pembrolizumab or nivolumab), combined immune checkpoint inhibition, or even high-dose IL-2 for the BRAF-mutant or wild-type population.

As it stands, most specialists will offer immune checkpoint inhibition therapy over BRAF-targeted therapy (either the BRAF/MEK inhibitor doublets or the triplet regimen) in BRAF-mutant populations. When deciding between single-agent anti-PD-1 and combined checkpoint inhibitor therapy, the benefits of combination—superior response rates, prolonged progression-free survival, and numerically better overall survival—are juxtaposed with the dramatically increased risk of immune-related adverse events (irAEs) and the fact that combination therapy is effective in a significant percentage (~25-30%) of patients in the second-line setting after single-agent anti-PD-1 therapy. Thus, most patients will be offered single-agent anti-PD-1 therapy unless they have the following: brain metastasis, rapidly progressing disease such that the patient will not likely survive long-enough to receive second-line therapy, disease necessitating response as quickly as possible, or other potential factors that some specialists consider (including BRAF mutation status, hepatic metastasis, or bulking disease).

This, however, is likely to change with the recently presented data of a randomized study of the combination of nivolumab plus relatlimab, an anti-LAG3 monoclonal antibody, versus nivolumab on its own, which demonstrated superior progression-free survival without a substantial increase in toxicity/irAEs. Thus, it is anticipated that this regimen will receive regulatory approval for the frontline metastatic/unresectable melanoma setting and will replace single-agent anti-PD-1 as the go-to frontline therapy. Whether this regimen replaces ipilimumab/nivolumab is uncertain.

Finally, there are a number of regimens being tested in the second-line setting, but outside of ipilimumab/nivolumab or ipilimumab/pembrolizumab, the only agent that has demonstrated remarkable toxicity is therapy with lifileucel, a tumor-infiltrating lymphocyte product that is given via adoptive transfer. Otherwise, there are dozens of therapies, either single agents or combinations (typically with an anti-PD-1/anti-PD-L1) that have shown some responses in the immune checkpoint-resistant populations. It is expected that a number of these regimens will be tested in expanded cohorts or randomized trials, and our hope is that intensive biomarker analysis will help sort out which populations of patients benefit the most from these therapies.

Dr. Sullivan can be reached at rsullivan7@mgh.harvard.edu.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Helping Patients Access Investigational Treatments

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Lea Ann Browning-McNeeDirector of Communications & Stakeholder Engagement at the Reagan-Udall Foundation for the FDA

 

Susan C. Winckler, RPh, Esq. CEO at the Reagan-Udall Foundation for the FDA

 

For some advanced cancer patients, the best course of action may lie beyond standard treatment options. Some of these patients can enroll in clinical trials that investigate promising new treatments. But others may find their best option is to apply for individual “expanded access” to an investigational treatment.

Here, our Curious Dr. George asks two leaders from the Reagan-Udall Foundation for the Food and Drug Administration (FDA) how their organization supports the FDA by striving to facilitate patient access to investigational products:

Curious Dr. George: The goals and process of “Right to Try” legislation have blended with existing policies and practices of expanded access to investigational treatments for patients beyond standard of curative care—especially for those with cancer. How does the Reagan-Udall Foundation for the FDA help physicians better serve their patients’ needs by more easily navigating expanded access, including use of institutional review boards (IRBs) for Investigational New Drugs (IND) for individual patients?

Susan C. Winckler, RPh, Esq. and Lea Ann Browning-McNee, MS, of the Reagan-Udall Foundation for the FDA: Expanded access, sometimes called compassionate use, provides a pathway to investigational treatments not approved by the FDA for patients who have serious or life-threatening illnesses and cannot participate in clinical trials. Single-patient expanded access allows a treating physician to request an investigational product from a pharmaceutical company on behalf of an individual patient. Typically, FDA approves close to 99% of single-patient expanded access requests.

FDA and its Foundation, the Reagan-Udall Foundation for the FDA, are working to make it easier for physicians to navigate the process and better serve their patients by creating new tools to simplify and de-mystify the process.

One such tool is Project Facilitate, created by FDA’s Oncology Center of Excellence as a single point of contact for physicians (and their healthcare teams) who have questions or simply want help submitting a request for their patient. Project Facilitate staff answer questions via phone or email and walk the physician through every step of the process.

Another new tool, Expanded Access eRequest, launched last year by the FDA Foundation and experts at FDA, moves the request from paper or fax to an online app. eRequest takes physicians screen-by-screen through the expanded access application process — from determining if expanded access is appropriate for their patient to submitting the request to FDA. It even sends reminders to let physicians know when follow up reports should be submitted. And the app’s home on the FDA Foundation’s Expanded Access Navigator website means physicians can identify potential investigational therapies; access sponsor (pharmaceutical) information; complete, sign, and submit the request form (FDA form 3926); and upload supporting documentation all in one place.

There are important considerations to bear in mind before pursuing any investigational treatment—whether through a clinical trial or expanded access. In addition to practical considerations like travel and treatment costs, there are medical considerations, including potential risks and unknowns of the investigational treatment, the severity or stage of illness, comorbid conditions, and the likelihood that the treatment will be effective. That’s where the Institutional Review Board (IRB) Curious Dr. George references comes in. The IRB is a committee of medical and ethics experts along with community or legal representatives who review and approve biomedical research involving patients. Even though expanded access is considered a treatment and not formal research, the IRB wants to be sure all patient safeguards are adhered to because an investigational product is involved. One such safeguard is informed consent, which helps ensure patients have details about the treatment protocol that clearly defines expectations, foreseeable outcomes and risks, and patient rights.

The patient, physician, IRB, FDA, and sponsor all need to agree that expanded access to a particular product is right for the patient. Each of these voices and perspectives is important. The company, for example, may not approve a request for a variety of reasons, such as simply not having enough of the investigational product available. A patient might, after considering all the information, choose not to pursue it. The overall expanded access process is intended to help each party understand the situation, and then decide about going forward.

FDA continues to simplify the expanded access journey for physicians and, ultimately, their patients. You can learn more on the Expanded Access Navigator.

Ms. Winckler can be reached at swinckler@reaganudall.org and Ms. Browning-McNee at lmcnee@reaganudall.org.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

When is the Best Time to Seek a Clinical Trial for Glioblastoma?

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Eric T. Wong, MD
Cancer Commons Expert Physician Advisor, Associate Professor of Neurology at Harvard Medical School, and Co-Director of the Brain Tumor Center at Beth Israel Deaconess Medical Center

For some people with glioblastoma brain tumors, enrolling in a clinical trial enables access to cutting-edge treatment. Here, our Curious Dr. George talks clinical trials with Cancer Commons Expert Physician Advisor, Eric T. Wong, MD. Dr. Wong is also Associate Professor of Neurology at Harvard Medical School and Co-Director of the Brain Tumor Center at Beth Israel Deaconess Medical Center.

Curious Dr. George: Malignant brain tumors are often treated initially by surgery and follow-up radiation. However, many recur and progress. Glioblastoma patients have many treatment options from which to choose, including clinical trials. But when is the best time to look for a clinical trial? Prior to initial therapy, immediately after initial treatment, or upon recognized tumor progression? How should a patient and their physician seek the most appropriate clinical trials?

Dr. Wong: This is a very important question for adult patients with glioblastoma and for a clinical neuro-oncologist like me who cares for them. At the time of diagnosis, the tumor is unstable and it is often difficult to determine the extent of microscopic spread to the adjacent brain. This is because glioblastoma is an infiltrative disease. Although MRI scans allow us to visualize the tumor, there are still microscopic tumors that we cannot see on head MRI scans. I always have to watch out for microscopic tumors causing motor or language dysfunctions.

Radiation is the mainstay of glioblastoma treatment, and it takes 6 weeks to administer. The reason is that we can only give a small fraction of radiation daily because normal brain and nerve cells cannot handle large fractions of radiation. The total dose needed to control the tumor is also at the maximum of brain tolerance. It takes at least 4 to 5 weeks to accumulate enough radiation dosage to exert an effect on the glioblastoma to halt tumor growth. Therefore, it is often a misconception that once radiation is started, tumor growth is controlled. In fact, the tumor can still grow during the initial 4 to 5 weeks of radiation, and it is not until the last week of 1.5 weeks that the radiation exerts its full effect on halting tumor progression.

For these reasons, it is often difficult to find a trial that fits a newly diagnosed patient with glioblastoma without delaying radiation. This is a logistics problem—a patient needs to be at the right time and right place where a clinical trial is available for them, and radiation can still be initiated within 4 to 6 weeks after surgery. It is my opinion that if a clinical trial cannot be found in a timely fashion, the patient should take conventional treatment. The time to look for clinical trials is when the tumor is stabilized with radiation and temozolomide.

After radiation and temozolomide, the patient goes into the adjuvant phase of treatment with monthly adjuvant temozolomide and monitoring with periodic head MRI scans. It is during this period that the patient has more time to look for a clinical trial in the event of recurrence or disease progression.

If you are at this point and looking for a trial, ask a family member to help you navigate the clinicaltrials.gov website or contact Cancer Commons and work with our Scientists to find a promising trial. At this point, you will also have more time to think about traveling and lodging in a faraway city, while talking to your neuro-oncologist about options. You and your care team should look at the inclusion and exclusion criteria to see if you fit into a particular trial. If none fits, your treating neuro-oncologist can still develop a personalized treatment for you.

Dr. Wong can be reached at ewong@bidmc.harvard.edu.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How Can Detection of Tumor DNA in the Blood Aid Advanced Cancer Treatment?

Curious Dr. George
Cancer Commons Contributing Editor George Lundberg, MD, is the face and curator of this invitation-only column.

Paul Billings, MD, PhD
Chief Medical Officer at Natera

Alexey Aleshin, MD, MBA
VP Medical Affairs, Oncology, at Natera

 

As a tumor grows, it may shed fragments of its DNA into the patient’s bloodstream. After treatment, if part of the tumor remains or it begins to grow again, more of this circulating tumor DNA (ctDNA) may enter the blood. That raises the possibility that detecting ctDNA could help clinicians monitor molecular or minimal residual disease—cancer that remains after treatment and cannot be detected by traditional imaging methods.

Here, our Curious Dr. George talks ctDNA with two leaders at Natera, a company that develops ctDNA tests: Chief Medical Officer Paul Billings, MD, PhD, and VP Medical Affairs, Oncology, Alexey Aleshin, MD, MBA.

Curious Dr. George: When initially diagnosed, potentially lethal cancers found at advanced stages can pose quandaries for treatment and management. Many advanced technologies are now being applied to address these challenges. How might the detection of ctDNA be used to assess molecular residual disease and assist in cancer monitoring and management?

Drs. Billings and Aleshin: Treating advanced-stage cancer is challenging. While treatments are available, they have toxicities and can impact patients’ quality of life. Moreover, as tumors evolve over time, they may become treatment resistant. Determining treatment resistance early can have significant clinical implications.

With the advent of next-generation sequencing, it is now possible to sequence the tumor tissue and identify a set of mutations that are specific to the patient’s tumor. These mutations, which are linked to early tumor development and are not related to specific response to treatment, can be tracked later by analyzing free-floating fragments of tumor DNA—circulating tumor DNA (ctDNA)—in the patient’s blood, without the need for any additional biopsy.

Moreover, the short half-life of ctDNA provides a real-time snapshot of subtle changes in the tumor burden, and is far more effective than a radiological scan that relies on detecting a visible lesion. Such a personalized and tumor-informed approach has emerged as a sensitive, non-invasive, and cost-effective tool for identifying tumor molecules (molecular residual disease) down to a single molecule in a tube of blood.

Immunotherapy has fundamentally changed how cancer is managed. However, only a fraction of patients respond to immunotherapy, while all patients are at risk of developing side effects from this treatment. An example of how ctDNA could address this issue is a hypothetical patient who was treated with pembrolizumab (Keytruda) for her non-small cell lung cancer. Initial imaging showed a mixed result that was difficult to interpret. However, ctDNA showed a markedly elevated ctDNA level suggestive of progression. This allowed the oncologist to reconcile ambiguous findings on imaging and alter the patient’s clinical course by switching to an alternative therapy.

Our recently published study, in Nature Cancer, highlights the advantage of monitoring ctDNA dynamics in a cohort of patients with 25 different types of histologies. The study showed significantly better outcomes for patients who cleared their ctDNA posttreatment, indicating exceptional response. The study also illustrated molecular progression as early as 6 weeks in a percentage of patients who received, on average, two cycles (six weeks) of additional treatment, which could have been avoided. This shows a clear utility of ctDNA that could have enabled an earlier switch to alternative treatment with a higher degree of efficacy and a lower financial burden.

More recently, the U.S. Food and Drug Administration (FDA) approved pembrolizumab as a first-line treatment for patients with unresectable or metastatic mismatch repair deficient/microsatellite instability status (dMMR/MSI-H) colorectal cancer (CRC), which constitutes 15 percent of metastatic CRC (mCRC) patients. The remaining have a microsatellite-stable status. Both of these subtypes have shown poor expression of CEA, which is a commonly used protein biomarker. Many studies have alluded to its poor sensitivity, specificity, and unreliability in predicting treatment response or risk of relapse. We recently presented a few case examples at the Society for Immunotherapy of Cancer (SITC) conference that highlight a physician’s experience in treating patients with mCRC and the value of ctDNA over conventional methodologies.

In summary, there is strong scientific evidence showing that the incorporation of ctDNA analysis into routine clinical practice can help physicians make better-informed decisions for patients battling an aggressive disease.

Drs. Billings and Aleshin can be reached at pbillings@natera.com.

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Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.