Patients with relapsed or refractory CD30-positive lymphoma have demonstrated encouraging clinical activity following receipt of the allogeneic TT11X therapy, an off-the-shelf cellular therapy, according to results of a phase 1 trial (NCT04288726) presented at the 24th Annual Meeting of American Society of Gene and Cell Therapy (ASGCT 2021).

The ongoing trial is examining the CD30-targeting chimeric antigen receptor (CAR) T-cell therapy, which uses augmented Epstein Barr Virus–Specific T cells (EBVSTs) coupled with CD30-CAR technology to prevent graft rejection.

“This is early but significant data supporting development of Tessa’s ‘off-the-shelf,’ allogeneic cell therapy,” Jeffrey H. Buchalter, president and CEO of the company responsible for developing the treatment, Tessa Therapeutics, said in a press release. “We believe there is an enormous potential for our allogeneic CD30-CAR EBVST platform, and we remain committed to our longer-term plan to develop this platform to tackle both hematologic malignancies and solid tumors where there is significant patient need.”

The primary end point of the ongoing trial was the rate of dose-limiting toxicity with secondary measures of antitumor objective response rate, duration of response, rate and duration of stable disease, and progression-free survival.

At ASGCT, data from 6 treated patients were presented and showed a favorable safety profile and positive clinical activity at the lowest and second dose levels of 4 × 10

Of note, there were no serious adverse events or dose-limiting toxicities and no events of graft-versus-host disease, cytokine release syndrome, or neurotoxicity. Three out of 5 patients evaluated for response experienced disease control and there was 1 partial response.

The target enrollment for the study is 18 participants between the ages of 12 and 75 years. Inclusion criteria include patients with a diagnosis of Hodgkin lymphoma, aggressive non-Hodgkin lymphoma, ALK-negative anaplastic T-cell lymphoma or another peripheral T-cell lymphoma, or ALK-positive anaplastic T-cell lymphoma. CD30 positivity must be confirmed using a CLIA-certified pathologic assay. Patients must have recovered from all acute nonhematologic toxic effects from prior treatment lines and levels of bilirubin and aspartate aminotransferase must be within a certain criterion determined by the upper limits of normal.

Patients receiving other investigational agents or any tumor vaccines within the previous 6 weeks and those having CD30 antibody–based therapy within 4 weeks are excluded from participation. History of hypersensitivity reactions to murine protein-containing products; pregnancy or lactation; tumors that could cause airway obstruction; use of corticosteroids equivalent to prednisone at 10 mg/day; active, significant, and uncontrolled infections; and symptomatic cardiac disease are all excluding factors.

The trial will continue to enroll to 3 escalating dose levels, with the highest being 4 × 10

 CD30.CAR EBVSTs. Full results from the trial are expected to be presented by the end of 2021.

“We are encouraged by the early data generated on the study. The therapy has been well tolerated with no evidence of GVHD or any severe adverse events, with encouraging clinical activity,” Carlos Ramos, MD, lead principal investigator and professor at the Center for Cell and Gene Therapy and member of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, said in a press release. “While these are preliminary results, the data gleaned from the first 5 patients suggest that allogeneic CD30-CAR EBVSTs may be able to overcome the safety and tolerability challenges that are common to allogenic cell therapies. We look forward to completing enrollment on the trial and further developing our understanding of this potential new therapy platform for oncology.”

Tessa Therapeutics Announces Positive, Topline Data from Ongoing Phase 1 Trial of Allogeneic, “Off-the-Shelf” Cell Therapy, in Patients with Relapsed or Refractory CD30-Positive Lymphoma. News release. Tessa Therapeutics. May 14, 2021. Accessed May 17, 2021. https://bit.ly/3okITd6

Articles

An off-the-shelf cellular therapy that combines Epstein Barr Virus–Specific T cells and a CD30-targeting chimeric antigen receptor product demonstrated safety and early efficacy in a group of patients with CD30-positive lymphomas. 

Allogeneic CAR T-Cell Product Shows Early Promise for Patients With CD30+ Lymphomas

 is a Clinical Pharmacy Specialist of Multiple Myeloma at the Winship Cancer Institute of Emory Healthcare in Atlanta, GA.

Can you briefly describe the mechanism of action of belantamab mafodotin?

 Belantamab mafodotin [bela-maf] is a first-in-class, novel antibody-drug conjugate. It is an antibody targeting BCMA [B-cell maturation antigen], which is expressed on multiple myeloma cells. The antibody-drug conjugate has a payload of monomethyl auristatin F, which is more like our traditional cytotoxic chemotherapy [drugs]. The antibody component binds to the BCMA expressed on the myeloma cells. The whole antibody conjugate is taken into the cell, where the payload is then released to cause the cell death, so it helps deliver more of that cytotoxic chemotherapy into just those BCMA-targeted cells.

Q: What are some of the biggest concerns with the toxicity profile of bela-maf? Have any new safety concerns become more apparent with its use in the real-world treatment setting?

: The top 3 grade 3/4 adverse effects that we saw in the clinical trials were keratopathy (changes to the cornea), thrombocytopenia, and anemia. Those are the top 3 adverse effects that we’re seeing in clinical practice, as well. The most important thing to know, and especially [to discuss with] patients, is the [possibility of] keratopathy. Some patients will have symptomatic eye toxicity: blurry vision, dry eyes, or changes in their vision. Many patients will not have symptoms, but they’ll have those cornea changes on exam. That’s an important [distinction] to make to the patients, because they’re not used to having their treatment held. Patients [with myeloma], especially at this stage in the game, have been on therapy for many, many years and are used to it. With bela-maf, we’re having to dose, then hold, and dose, then hold, because of the keratopathy. [It’s important to] explain to them that they may not have any symptoms, but what the eye doctor is seeing on their eyes is resulting in the dose being held. What we’ve seen in clinical practice has been consistent with what we saw on the clinical trials, and we are seeing that [with the use of] dose holds and dose reductions, these symptoms are resolving. And most commonly, I would say we’re seeing them occur around cycle 2 or cycle 3.

Beyond the eye toxicity, we most commonly see thrombocytopenia and anemia, especially in these heavily pretreated patients, so [management involves] utilizing platelet transfusions and blood transfusions, as needed.

Do you recommend that all patients who are on this drug be monitored by an eye care professional?

: That’s actually a requirement for the REMS [Risk Evaluation and Mitigation Strategy] program. In the clinical trials, the eye care professional had to be an ophthalmologist, but with the FDA approval, it can be any eye care professional. The patient will see this eye care professional for a baseline exam, prior to starting [bela-maf], and then they will see them every 3 weeks, prior to every single dose. It’s a good thing to educate the patients on, because it’s going to be 1 more doctor visit that they will have to have every 3 weeks, to make sure that we’re following the REMS program and having their eyes checked. They will see those eye doctors very frequently, and we work very closely with them for any additional medications that they may need for their eye toxicity.

Should patients and providers know about any additional aspects of the REMS program, beyond the close eye monitoring?

: The REMS program has 3 key players. First, the providers have to enroll, and they will take an assessment quiz as part of their enrollment. But then they can assign delegates, so that could be their [physician assistant, nurse practitioner], or it could be their clinical pharmacists. I have been assigned as a delegate for my providers. Those are going to be the people who are assessing what the eye doctor tells us.

The eye doctor fills out a form that grades the patient’s vision changes as well as their keratopathy changes. We input these data into the REMS program [to determine] if the patient can continue therapy. The patient also has to enroll, so we do that initially as part of their patient education.

The third component, which is important for infusion pharmacists and nurses to be aware of, is the infusion center, which also has to be enrolled in the REMS program. They have the final component, called the REMS checklist; once the drug is given, they sign off on the exact milligram dose that was given, and the day that it was given.

The eye doctors are not enrolled, but they’re a key player. Making sure that you have all 3 of those things set up before you get your first patient going is very critical.

Are dosing modifications common with this agent?

: If the patient experiences a grade 2 toxicity—be it visual acuity changes or keratopathy—the recommendation is to hold [the dose] until they return to grade 1. At that point, you can resume at the 2.5-mg/kg dosing. However, if a patient experiences grade 3 toxicity, then the recommendation is to again hold until they return to grade 1. At that point, you would reduce down to a 1.9-mg/kg dose. Based on of the grade of the toxicity, we’re always going to be holding, but the difference between grade 2 and grade 3 is [that the latter] requires a dose reduction.

Should clinicians be aware of any major drug interactions?

: Luckily, with this medication, there are not many significant drug interactions. Of course, [we’d like] to avoid any other medications that cause eye toxicity. As this is an antibody-based medication, we don’t have many significant drug interactions to worry about.

Have any barriers to administration or receipt by the patient emerged since this agent’s approval, such as common reimbursement issues or logistical challenges to obtaining the medication?

: The biggest barrier is the REMS program. While it exists for a necessary reason and it’s very doable, it is a cumbersome thing to get started, just to make sure that everything is in alignment. Our biggest barrier was making sure that we had everything set up at the infusion center before we could even get the drug delivered. If your institution, like mine, has multiple infusion sites, they may each have to be registered individually, so only 1 of ours is currently registered. Something for patients to keep in mind is that even if they’re used to getting treatment at one place, they may have to get it somewhere else just based upon the requirements there.

In terms of reimbursement, the patients who we are putting on this medication have more than those 4 prior therapies, so just being mindful of the type of patient who you’re initiating on this therapy will reduce any issues with getting reimbursement.

[You should] think about getting the eye appointment scheduled [for the patient]. This is not a therapy that you can decide on today and start treatment tomorrow. It will take at least a week or so to get set up, so that’s something for the patient and the team to keep in mind. 

The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma. FDA. Updated August 6, 2020. Accessed April 19, 2021. https://bit.ly/3dyY2ns

Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. 

 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0

Kathryn Maples, PharmD, BCOP, discusses real-world implications of belantamab mafodotin in patients with pretreated multiple myeloma.

Expert Commentary on The Product Profile of Belantamab Mafodotin

 Dr Socinski, what have been the response rates with standard-of-care frontline therapies in patients with extensive-stage small cell lung cancer?

 The response rates to platinum-based doublets have typically been in the 60%-to-70% range. Most are partial responses. Maybe 10% might be a complete response. But that’s really been our expectation with standard-of-care platinum-based doublets, specifically platinum etoposide.

 What is the rationale for adding immunotherapy in this setting?

 One of the factors that seems to be predictive of a benefit from immunotherapy in lung cancer has been a history of smoking. As we’ve established, this is a smoking-related disease. When you look at tumor mutational burden, which we also think is potentially related to the effectiveness of immunotherapy, these patients have a very high tumor mutational burden. Like other tumors where immunotherapy has been successful—melanoma, bladder cancer, non–small cell lung cancer—small cell would fit into that category. That is the underlying rationale for thinking about adding I/O [immuno-oncology] in this setting.

 Which patients would be eligible for immunotherapy in the front line? Does PD-L1 status matter?

 The trials that have been done have been agnostic to PD-L1. PD-L1 is a bit difficult to measure in small cell lung cancer because of the nature of many specimens we get there. The eligibility for I/O up front in these patients has to do with whether they have comorbid illnesses that would exclude them from immunotherapy. Do they have any interstitial lung disease, autoimmune disease, or other things that would make I/O a contraindication? Most people don’t have those, so most are eligible for I/O in the first-line setting. But we don’t routinely do PD-L1 sustaining in this setting when we’re not sure if it makes a difference.

 Has the withdrawal of the pembrolizumab indication for metastatic small cell lung cancer affected treatment options for the extensive-stage small cell lung cancer population?

 That’s an interesting question. In both pembrolizumab and nivolumab, which were both indicated in third-line treatment of extensive-stage small cell lung cancer, those data were generated prior to the routine use of immunotherapy with first-line treatment. I don’t think the withdrawal of those indications really alters the treatment options, because I/O should be used first line, not third line. I don’t think that really has made a difference in any way, shape, or form.

 I know we just mentioned pembrolizumab and nivolumab. What other immunotherapies have been used or tried in this patient population?

 What I would call the big four—atezolizumab, durvalumab, pembrolizumab, and nivolumab—have all been tested, all in phase 3 except for nivolumab. Nivolumab was in a very large phase 2 there. It’s interesting that the results of all these trials have been very consistent, which is reassuring. Not all the trials have been statistically positive, but the impact of adding I/O has been pretty consistent across these trials. There’s actually a wealth of information about I/O therapy in the first-line setting.

Videos

The rationale for adding an immunotherapy agent to frontline therapy for extensive-stage small cell lung cancer and considerations for patient selection.

Immunotherapy as First-Line Treatment for Extensive-Stage SCLC

 How is extensive-stage small cell lung cancer defined? How does it differ from metastatic small cell lung cancer?

 It really doesn’t differ from metastatic small cell lung cancer. As I mentioned, we should be thinking of this in the context of the TNM staging system. Extensive-stage small cell lung cancer would essentially be stage IV disease, and that is equated to the term 

. Extensive-stage disease is disease that is beyond a reasonable radiation port. It can include a malignant pleural effusion, liver metastases, brain metastases, or bone metastases—these sorts of things. I look at the terms extensive-stage small cell, metastatic small cell, and stage IV small cell as all meaning the same thing.

 What percentage of patients first present with extensive-stage small cell lung cancer?

 Unfortunately, it’s about 70% or so. It’s the majority of patients. As I mentioned, this is an aggressive disease clinically. For many of these patients their first presentation is a hospitalization because they have some complication of their treatment: They’re sick, they get into the hospital, and they’re discovered to have extensive-stage small cell lung cancer. The majority of patients present with extensive-stage disease.

 What are some challenges specific to treating extensive-stage small cell lung cancer?

 As I mentioned, this is a smoking-related disease. The median age of this population is about 70 years. If you combine smoking and an old age, you get a bunch of comorbidities that are associated with this. People have COPD [chronic obstructive pulmonary disease], cardiac disease, atherosclerotic disease, sometimes cerebrovascular disease, diabetes. Other kind of diseases that go along with an older population. That really makes it difficult. Now that 70% of patients are presenting with extensive-stage disease, there are implications with regard to performance status. These patients get sick, and it’s difficult for them. Performance status is often an issue. The complexity of managing the comorbidities, a declining performance status, disease-related symptoms, complications of disease. Also, I haven’t pointed it out yet, but this is a disease in which there are high number of paraneoplastic syndromes. A syndrome of inappropriate ADH [antidiuretic hormone] is a common one. You can develop Cushing disease. There are a number of neurological paraneoplastic syndromes that can occur with extensive-stage small cell lung cancer. Those can be quite challenging. We see them in small cell lung cancer, but we typically don’t see them that often in non–small cell lung cancer.

 What’s the prognosis for patients at this stage of the disease?

 The expectation from our old standard of platinum-based therapies is a median survival of about 10 months. Response rates would typically be in the 60%-to-70% range. The median progression-free survival would typically be 4 to 5 months. And the 1 year survival in the phase 3 trials that have been done over the past decade is just above or just below 40%. Most people do unfortunately die of this disease in the first year after diagnosis. As I mentioned, with platinum-based doublets, the 2-year survival is typically less than 15%.

 To bring it all together, what are the unmet needs in this patient population?

 It’s developing more effective therapy. It’s been a challenge again because of the complex molecular nature of this disease and it being a very refractory disease. We’ve been stuck in the platinum doublet standard of care for a couple of decades and really nothing has changed that until we began incorporating immunotherapy into first line treatment.

A review of current options for management of SCLC and the challenges of treating this population.

Treatment Challenges in Extensive-Stage SCLC

The success of systemic therapies in the treatment of hematologic and solid tumors has revolutionized oncology treatment, with multiple immunotherapy and targeted agents supplanting prior standard-of-care disease management practices. Advances in lung cancer are unrivaled by research in many diseases, making reflection on the last generation of breakthroughs critical in understanding how far the field has come.

“[T]he fact that we could take scientific discoveries…and [translate that to] targeted therapy and immunotherapy is fantastic,” Roy S. Herbst, MD, PhD, of Yale Cancer Center and Smilow Cancer Hospital, in New Haven, Connecticut, and cochair of the 

 International Lung Cancer Congress®, hosted by Physicians’ Education Resource®, LLC (PER®), said in an interview with 

®. “It speaks to how we are bridging the gap and helping people live longer with this disease. That’s what gets me up every morning: seeing the science translated to the patient.”

In the interview, Herbst takes a deep dive into his career as a lung cancer physician and the research he has conducted. He details the timelines of significant clinical research studies, such as pivotal trials that led to approvals of targeted agents against EGFR and have revolutionized approaches to treating advanced non–small cell lung cancer.

® editors debuted the first installment of Product Profile, aimed at discovering real-world implications of systemic therapies with new indications. This month, we spoke with Kathryn Maples, PharmD, BCOP, clinical pharmacy specialist of multiple myeloma at Winship Cancer Institute of Emory Healthcare in Atlanta, Georgia, about belantamab mafodotin (Blenrep). In a disease state that saw multiple FDA approvals and designations throughout the preceding year, belantamab mafodotin stood out as being the first B-cell maturation antigen–targeted agent for use in patients with myeloma, offering a new therapeutic mechanism of action in a population of patients who are often treated with multiple lines of therapy throughout the course of their disease.

Aiko Nagayama, MD, PhD, of Keio University School of Medicine in Tokyo, Japan, and her colleagues presented a comprehensive review of novel therapies for triple-negative breast cancer, which has traditionally been associated with poor outcomes as compared with other tumor subtypes. At the forefront, the authors discuss antibody-drug conjugates and immunotherapy agents that have recently been approved.

As always, the articles within these pages and more on breakthroughs in oncology across multidisciplinary specialties can be found at CancerNetwork.com, home of the journal 

Exploring Novel Mechanisms of Action–Then and Now

CancerNetwork® sat down with Mehmet Sitki Copur, MD, Medical Director of Oncology, Medical Oncology/Hematology Mary Lanning Healthcare Morrison Cancer Center and Professor, University of Nebraska Medical Center, to discuss his article in the journal

Messenger RNA Vaccines-Beckoning of a New Era in Cancer Immunotherapy

Copur discussed how the approval of recent messenger RNA (mRNA) vaccines by the FDA to combat COVID-19 opens a door for the potential future of cancer immunotherapy and mRNA vaccines.

This segment comes from the CancerNetwork® portion of the MJH Life Sciences™ Medical World News®, airing daily on all MJH Life Sciences™ channels.

Copur spoke with CancerNetwork® about the potential for a new era of cancer treatment and immunotherapy with the recent approval of mRNA vaccines to treat COVID-19.

Medical World News® Deep Dive: Mehmet Sitki Copur, MD, on the Potential of mRNA Vaccines in Cancer Immunotherapy

A recent ‘Narratives in Oncology’ article written for 

 journal details the experience of physician and marathon runner Amy Comander, MD, with the 124th Boston Marathon. Like most events scheduled in 2020, the marathon was canceled due to the COVID-19 pandemic. In her narrative, Comander discusses gratitude and resilience in times of uncertainty, explaining how the running community has helped her remember to keep her head up.

In addition, Comander has helped organize fundraising races, like the 

, a virtual 5k to be held June 4 through 6, 2021.

CancerNetwork® sat down with Comander, of the Mass General Cancer Center in Waltham and Harvard Medical School, to talk about what marathon running means to her and her plans for participating in future races.

1. Comander A. Remember Your Why: An Oncologist's Reflections on Running During the COVID-19 Pandemic. 

. 2021;26(4):348-349. doi:10.1002/onco.13683

During an After Hours segment of Medical World News®, Amy Comander, MD, spoke about her passion for marathon running and how it helps keep her inspired in her work as an oncologist. 

Medical World News® After Hours: Oncologist Amy Comander, MD, Discusses Marathon Running and Motivation

 is Distinguished Professor of Medicine at Rutgers Robert Wood Johnson Medical School and Associate Director for Clinical Research at Rutgers Cancer Institute of New Jersey as well as Director of Oncology Research at RWJBarnabas Health.

®, Christine Y. Chung, DO, and colleagues 

report on the next-generation sequence (NGS) testing status of 77 patients referred to their practice for phase 1 study enrollment

. It seems in the case of both community and academic practices, in their Colorado area referral zone, about half the patients had previously received either tumor or circulating tumor (ct)DNA testing for actionable mutations. Although the authors point out the rate of sequencing is approximately equal in the 2 settings, my question is why physicians are even doing this expensive testing.

Through The Cancer Genome Atlas1 determination of molecular profile for 150 pancreatic cancers, we know that 93% of patients will have 

 mutations and another 10% other, usually concurrent 

 mutations occur 72% of the time, and only 4% to 5% have a 

 mutation. Other actionable mutations are really quite rare. For example, 3% will have 

mutations. Also, in the SWOG 1513 study (NCT02890355),2 E. Gabriela Chiorean, MD, and her colleagues showed, in a second-line chemotherapy setting, that perhaps 30% had some kind of DNA repair defective gene based on a defined “HDR” assay, yet the addition of a PARP inhibitor to FOLFIRI (folinic acid, 5-FU, oxaliplatin, and irinotecan) was not beneficial.

In the “Know Your Tumor” (KYT) study3 referenced by Chung, the patients who had sequencing-informed treatment seemed to do better. But let’s look further at these data. Nearly 1900 patients were enrolled and 1082 were sequenced. Only 667 had outcome data and 38% of these were considered “actionable,” yet many of these are mutations with no known molecular drugs effective for pancreatic cancer, including 

 mutations. The outcome data are heavily influenced by the very few with microsatellite instability–high tumors, diagnosable with immunohistochemistry—no NGS required—and 

fusions. The outcome of this so-called actionable group was indeed superior, yet what does it represent? This is a noncontrolled trial that perhaps tells us that patients with DNA repair deficits do better overall, perhaps due to sensitivity to our current chemotherapy drugs. It does tell us very little beyond the few actionable mutations we already know about.

Finally, we know that patients with germline mutations may be candidates for olaparib (Lynparza) following induction chemotherapy. However, the guidelines recommend that all patients receive germline testing. This is less expensive than tumor NGS or even ctDNA testing, and may be done even by generally available platforms such as 23andMe. If we perform tumor NGS to find 

 mutations and then later perform germline testing, this will lead to increased costs to the health care system. Additionally, the approval for use of this PARP inhibitor in pancreatic cancer does not include patients with somatic 

A new class of RAS inhibitor drugs, specifically targeting 

 G12C is now in the clinic. These drugs are showing activity in non–small cell lung cancer and potentially will be active in colon cancer. Once these drugs and others targeting more common 

 mutations have been shown effective for pancreatic cancer, there will be a good reason to perform NGS testing on all patients with pancreatic cancer. At the moment, NGS testing is an expensive test that would cost the health care system over $200 million annually, if all 60,000 cases of newly diagnosed pancreatic cancer were tested. Personally, I am looking forward to when this will be a cost-effective technology.

1. Cancer Genome Atlas Research Network. Integrated genomic characterization of pancreatic ductal adenocarcinoma. 

 2017;32(2):185-203.e13. doi: 10.1016/j.ccell.2017.07.007

2. Chiorean EG, Guthrie KA, Philip PA, et al. Randomized phase II study of second-line modified FOLFIRI with PARP inhibitor ABT-888 (Veliparib) (NSC-737664) versus FOLFIRI in metastatic pancreatic cancer (mPC): SWOG S1513. 

. 2019;37(suppl 15):4014. doi:10.1200/JCO.2019.37.15_suppl.4014

3. Pishvaian M, Blais E, Brody J, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. 

 2020;21(4):508-518. doi: 10.1016/S1470-2045(20)30074-7

In his "Letter to the Readers", co-editor-in-chief of the journal ONCOLOGY Howard S. Hochster, MD, reviews the utility of next-generation sequencing in pancreatic ductal adenocarcinoma.



Next-Generation Sequencing for Advanced Pancreatic Cancer: A Technology Whose Time Has NOT Come

 Hyperkeratotic Plaques. These plaques, on the undersurface of the great toes and heels of both feet, occur predominantly at sites of pressure and friction.

A man, age 45 years, was diagnosed with intermediate-risk stage IV clear cell renal carcinoma (lung and lymph node metastases). He was prescribed first-line systemic treatment with sunitinib (Sutent) 50 mg per day (each cycle: 4 weeks on, 2 weeks off). Upon day 22 of his second sunitinib cycle, he came to the oncology clinic complaining of difficulty walking due to bilateral sole pain. He described initial tingling sensations, which then became burning and painful, with symmetrical erythema and edema of the soles, without blisters. These turned into painful plaques with yellowish discoloration and hyperkeratosis on pressure-bearing areas. He denied fever or other symptoms. The pain limited his instrumental activities of daily living, but not his self-care activities of daily living. Total body skin examination disclosed hyperkeratotic plaques on the undersurface of the great toes and heels of both feet, predominantly at sites of pressure (

); no blisters, crusts, ulcers, or fissures were found. No relevant findings were found upon physical examination of his hands, mucosae, and scalp. A diagnosis of grade 2 hand-foot skin reaction (HFSR) was made.

A. Hot compresses and scrubbing the lesions

B. Low- or medium-potency topical steroid (ie, hydrocortisone 1% cream) plus a keratolytic agent (ie, urea 40% cream)

C. High-potency topical steroid (ie, clobetasol propionate 0.05% ointment) only

D. High-potency topical steroid (ie, clobetasol propionate 0.05% ointment) plus a keratolytic agent (ie, urea 40% cream).

Discontinue sunitinib until improvement to grade 1

 is a dermatologist in the Hematology/Oncology Department at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.

 is a clinical researcher at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.

is an associate professor and head of the Department of Dermatology and National Researcher at Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.

 is an associate professor and head of the Urologic Oncology Clinic, National Researcher. Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Mexico City, Mexico. She is also a member of the American Society of Clinical Oncology’s IDEA Working Group.

Hand-foot syndrome (HFS) is a well-described cutaneous adverse event (AE) of certain chemotherapeutic agents, like capecitabine, docetaxel, 5-fluorouracil, and pegylated liposomal doxorubicin. It was first described in 1974 by Zuelke; alternative names for this AE include acral erythema, palmar-plantar erythrodysesthesia, and Burgdorf reaction.

 Clinical dermatological manifestations may include erythema, edema, dryness, blisters, fissures, ulcers, and/or desquamation. Varying degrees of paresthesia, dysesthesia, and pain can accompany such changes.

 Although palms and soles are the most commonly affected areas, changes in the dorsal surfaces and nails can occur.

With the advent of targeted therapies such as multikinase inhibitors (MKIs), a novel profile of cutaneous AEs has emerged. Since the MKI-related skin changes affecting the palms and soles differ from the ones caused by chemotherapy, the term HFSR is used when referring to the MKI-induced syndrome.

 The differences between HFS and HFSR are summarized in 

. HSFR has been associated with various MKIs, including regorafenib (Stivarga), cabozantinib (Cabometyx), sorafenib (Nexavar), sunitinib, axitinib (Inlyta), and pazopanib (Votrient).

 Although it isn’t life-threatening, HFSR can lead to cessation of therapy, dose reduction, and impaired quality of life.

 Differences Between Hand-Foot Syndrome and Hand-Foot Skin Reaction

HFSR affects 31.2% to 79.4% of patients using MKIs.

 The frequency of all-grade HFSR differs greatly among the MKIs—for instance, the frequency with regorafenib is 46% to 84%; with cabozantinib, 35%; sorafenib, 10% to 62%; and sunitinib, 10% to 28%. The corresponding frequencies for grade 3 or greater HFSR are 20.4%, 9.5%, 2% to 36%, and 4% to 12%, respectively. Notably, the incidence of HFSR from a specific MKI can vary among tumor types, as different doses might be indicated for them.

HFSR has several risk factors. In a meta-analysis of randomized controlled trials involving 24,956 patients, the main risk factors for HFSR were:

(A) Tumor type. The highest risk was with thyroid cancer, with a relative risk (RR) of 12.62; the RR for renal cell carcinoma was 8.10.

(B) MKI used. Cabozantinib represented the highest RR with 12.10; the RR with sunitinib was 2.97.

(C) Dosing. Severity and frequency of HFSR positively correlated with the dosage of MKI.12

(D) Additional risk factors. These include female sex, good performance status, preexisting calluses, poorly fitting shoes, and repeated friction to the hands and feet.5

The pathogenesis of HFSR is still unclear. Proposed mechanisms include direct cytotoxic effect of the MKIs to the epidermis, eccrine secretion of MKI, and MKI-induced deficient capillary maintenance in high-friction areas.

A crosstalk between vascular endothelial cells and keratinocytes has also been suggested as an etiological mechanism. In this model, MKI triggers the release of soluble heparin-binding epidermal growth factor from vascular endothelial cells. This stabilizes sirtuin 1, an essential keratinization inducer in keratinocytes, hence causing hyperkeratinization.

HFSR typically appears within the first 2 to 4 weeks of treatment initiation, with severity also likely to peak early.7,14,15 HFSR clinical presentation can be divided into several phases. In the prodromal phase, the patient notices dysesthesia, which progresses over several days to burning pain; palms and soles become symmetrically erythematous and edematous. The inflammatory phase follows: A well-defined symmetrical erythema and tense bullae appear on the palms and soles. The hyperkeratotic phase is next: Localized well-demarcated painful yellowish hyperkeratotic patches overlie erythematous base pressure-bearing areas.

 The patient can experience paresthesia, dysesthesia, and pain, which may be out of proportion to the clinical appearance of the lesions. Finally, the resolution phase is characterized by excessive desquamation and fissures.

 Other concomitant alterations have been described, including scalp dysesthesia, angular cheilitis, perianal rashes, and facial erythema resembling seborrheic dermatitis. It is uncertain whether the pathophysiology is the same.

Several prophylactic measures have been described. It is recommended that before initiating treatment with a kinase-targeted therapy, a patient’s hands and feet should be examined for existing hyperkeratotic lesions and, if present, debrided by a podiatrist or dermatologist. Patients should take measures to ensure that their skin remains extremely moisturized, utilizing 10% urea cream, and to avoid friction as much as possible (summarized in 

), and these measures should be maintained even if HFSR occurs.

Answer A is therefore incorrect: Hot compresses and scrubbing the lesions (no matter how hyperkeratotic they look) will worsen HFSR.

 Patient Skincare Dos and Don’ts for HFSR Prevention

Patients who use 10% urea cream prophylactically, 3 times a day, have lower rates of HFSR. This was observed in a randomized, open-label trial that included 871 patients with hepatocellular carcinoma being treated with sorafenib. The use of urea-based cream extended the time to the first occurrence of HFSR, and it improved patient quality of life compared with best supportive care.

 Other topical keratolytic agents (ammonium lactate 6%-12%; salicylic acid 5%-10%) can be used to treat focal hyperkeratosis. Higher concentrations of keratolytics (urea 40%) might be implemented once HFSR is established.

In addition, celecoxib has been suggested to lower incidence rates of HFSR. In an open-label prospective study of 116 patients with advanced hepatocellular cancer, patients who received sorafenib with celecoxib achieved lower grade 2 and grade 3 HFSR incidence rates compared with those who received sorafenib alone.

 Finally, a retrospective study found that prophylactic oral dexamethasone 2 mg, taken once a day, delayed dose modifications of regorafenib and decreased the incidence of grade 3 HFSR (3.2% in the experimental population vs 25.7% in the controls).

After establishing a diagnosis of HFSR, treatment should be individualized using the National Cancer Institute’s Common Terminology Criteria for Adverse Effects. HFSR of grade 1 is characterized by minimal changes, such as erythema, edema, or hyperkeratosis without pain, and it can be treated with topical lidocaine 2% to 6% in gel, cream, or patch form. In grade 2 HFSR, painful skin changes (eg, blisters, erythema, hyperkeratotic plaques) limit instrumental daily life activities, and grade 3 HFSR is characterized by severe skin changes (eg, moist desquamation, ulceration, blistering, fissures, or local injury causing infectious complications) and pain that limits self-care activities of daily life.

 Treatment of grade 2 and 3 HFSR involves pain control with systemic medications, including nonsteroidal anti-inflammatory drugs and opioids or γ-aminobutyric acid antagonists.

Superpotent topical steroids, such as clobetasol propionate ointment 0.05% or fluocinonide 0.05%, are recommended for treatment of the inflamed, erythematous areas.

 Topical steroids induce vasoconstriction, promote antimitotic actions, and have anti-inflammatory activity.

No studies have compared the different strengths of topical steroids in HFSR. Superpotent ones are usually recommended since the percutaneous absorption in hyperkeratotic or lichenified lesions on the palms and soles is diminished.23,24 Clobetasol, due to its superior potency, has also proved effective in treating “steroid-resistant dermatosis.”

 The vehicle also matters; an ointment base, not cream, is preferred for infiltrated, lichenified lesions. An ointment’s occlusive effect increases the hydration of the stratum corneum, enhancing the drug’s penetration.

Answer B is therefore incorrect: Hydrocortisone 1% cream is a low-potency steroid.

 Steroids are an adjuvant to and not a substitute for the aforementioned supportive measures. 

Answer C is therefore incorrect: Superpotent steroids are not recommended as HFSR monotherapy.

Other translational studies have suggested treatment with sildenafil, heparin-containing ointments,

 but more research is needed.15 In a randomized multicenter phase 2 trial, patients with metastatic renal cell carcinoma who were being treated with sorafenib found that hydrocolloid dressing containing ceramide improved symptom management of HFSR.

 An ongoing phase 3 randomized trial is investigating this therapy.

 Several other therapy trials with topical sildenafil (NCT03229512), tazarotene (NCT04071756), and nicotinamide (NCT04242927) are ongoing.

The option of holding MKI, as a measure to improve HFSR, should be reserved for severe cases (grade 3) or refractoriness to supportive measures. When holding is needed, most HFSR treatment algorithms recommend holding MKI for 7 days (or until HFSR symptoms resolve), then resuming at a lower dose. If HFSR worsens or does not improve, dose interruption or discontinuation is suggested. If severe HFSR recurs despite supportive measures, therapy should be discontinued.

Answer E is therefore incorrect: For grade 2 HFSR, try supportive measures before discontinuing the MKI. D, then, is the best answer.

Prognosis for patients with HFSR is good, since this AE is reversible and treatable. It has been suggested that HFSR occurrence is a predictor of prolonged survival. In individuals with renal cell carcinoma treated with sunitinib and sorafenib, HFSR is associated with significantly better progression-free survival (PFS).

 A similar observation was made in patients with metastatic colorectal cancer treated with regorafenib who experienced severe HFSR.

 Imaging Findings Pre- (superior) and Post (inferior) Sunitinib Treatment

The patient was treated with a high-potency topical steroid (clobetasol 0.05% ointment twice daily) and a keratolytic agent (urea 40% cream once daily), which improved the symptoms to grade less than or equal to 1 in 2 weeks. Clobetasol was tapered after 2 weeks. Rechallenge courses with urea were given when hyperkeratosis relapsed. Supportive care recommendations were reinforced. Sunitinib dose did not need to be delayed or adjusted. The patient had a partial response in his first CT response evaluation, which is maintained to this day (

). He has had a PFS of 12 months to date, with no grade greater than or equal to 2 HFSR recurrence.

 The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. 

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Another installment of Clinical Quandaries is presented by Karen Férez-Blando, MD, and colleagues of a 45-year-old man with a diagnosis of intermediate-risk stage IV clear cell renal carcinoma who develops grade 2 hand-foot skin reaction on sunitinib therapy. 

