Bryant Furlow

1.  Preliminary clinical findings suggest CAR T cells may be more effective against multiple myeloma if they are manufactured from patients before they experience relapsed or refractory disease.

Recently reported findings from a phase I clinical cohort study of 38 patients with multiple myeloma found that post-induction manufactured CAR T cells exhibit higher proportions of biomarker immunophenotypes that have been shown to be associated with clinical response.

2. Development of anti-B-cell maturation antigen CAR T-cell therapy (BCMA CART) for multiple myeloma has built on earlier findings among patients with chronic lymphocytic leukemia (CLL), including the finding that which of the following at the time of leukapheresis is/are associated with clinical response?

Lower frequency of CD8+/CD45RO-/CD27+ T cells

 Among patients undergoing CAR T-cell therapy for CLL, a higher frequency of CD8+/CD45RO-/CD27+ T cell immunophenotype and higher CD4/CD8 ratio at the time of leukapheresis were associated with clinical response.

3.  Chimeric antigen receptor (CAR) T-cell therapies against multiple myeloma include which of the following targets?

CAR T-cell therapies against multiple myeloma that target several antigens are under clinical development, including strategies that target CD19, CD138 and BCMA. A recent single-arm phase 2 trial showed that anti-CD19 and anti-BCMA combination CAR T-cell therapy is feasible in patients with relapsed/refractory multiple myeloma.

4.  Among heavily pretreated patients with relapsed/refractory multiple myeloma in phase I clinical trials, BCMA CAR T-cell therapy has yielded up to ___% overall response rates.

At higher cell doses, BCMA CAR T-cell therapy has achieved 64%-90% overall response rates among patients with relapsed/refractory multiple myeloma who had received up to 8 previous lines of therapy.

5.  ___% of patients with relapsed/refractory multiple myeloma achieved complete response (CR) with combination anti-CD19 and BCMA CAR T-cell therapy in a recent phase 2 clinical trial.

Fifty-seven percent of patients in a small (n=21) phase 2 clinical trial experienced CR. Eighty-one percent of patients had ongoing responses at 6-month median follow-up.

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How much do you know about the role of CAR T cells in multiple myeloma? Here's your chance to find out.

Quiz: The Role of CAR T Cells in Multiple Myeloma

Innovative treatment strategies such as chimeric antigen receptor (CAR) T-cell therapy offer dramatic benefits for some cancer patients, but integrating them into clinical practice can be challenging and may require new models of reimbursement, according to panelists at the 2019 National Comprehensive Cancer Network (NCCN) Annual Conference, held March 21–23 in Orlando, Florida.

“Innovation has very broad implications, like pebbles dropped in a pond,” said roundtable moderator 

, of The Lewin Group in Falls Church, Virginia. “There are differences between outcomes and patient experiences in clinical trials and in the real world.”

Integrating CAR T-cell therapies into clinical practice has required hard work and organization, said panelist 

, of the Moffitt Cancer Center in Tampa, Florida. The expertise required means that CAR T is administered at relatively few regional centers, and the astronomical cost of the engineered T cells themselves-which can run anywhere from $500,000 to $1.5 million per patient-are just part of the overall cost of these treatment strategies, panelists noted.

Less frequently discussed are the “hidden costs” of coordinating care and managing adverse events, said 

, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City. “It’s important to take a holistic approach to the true cost of treatment, rather than just the cost of the agent,” he said.

In the United States, physician practices or hospitals, rather than biopharmaceutical companies, are reimbursed by insurance systems, noted panelist Jennifer Malin, MD, PhD, of the UnitedHealth Group-typically at a margin above the actual cost of the product.

“That can be as low as 6% or as high as three or four times the cost of the product at elite institutions,” she said. “The ‘margin’ approach from the early days of Medicare made sense for, say, doxorubicin, but a number of new innovative therapies are very expensive.”

Immune checkpoint inhibition can cost just under $20,000 per month, for example-just for the agent. “So, a three or four-times multiplier is quite a bit,” Malin said.

Therapeutic radiopharmaceuticals are in the range of $50,000 to $100,000 per dose, she noted.

“One big challenge-the elephant in the room-is, what is the reasonable profit margin for administering a drug for a practice or hospital?” Malin said. “Is $50,000 or $100,000 reasonable for administrative costs for a patient’s treatment? A million dollars seems excessive.”

The high cost of innovative cancer treatments makes it difficult to cover the costs of treatment under current Medicare fee schedules, Malin added. And demand for such treatments will climb.

“Hospitals performing CAR T therapy are adhering to the FDA label, but we anticipate studies showing it’s effective outside the FDA label,” Malin noted. “So how will we ensure there isn’t regional variation in who gets it? We don’t want to see inequities based on where patients live.”

It is not yet clear how best to reimburse for such therapies. However, because CAR T-cell therapies require weeks to prepare for each patient, it’s important to begin patient education conversations early, panelists agreed.

“The price tag is expensive, but that should not stop you from referring your patients,” Locke said. “You need to advocate for your patient and get them to centers. Get patients to centers early.”

One urgent goal that could benefit patients while reducing costs is identification of better biomarkers and risk-stratification systems that can spare patients who are unlikely to benefit from a given therapy due to its potential side effects.

“As we develop these therapies, the better you can identify the patient population that [will] benefit, the better able you are to cover that population,” noted 

It is also important to consider how innovative treatments fit into “the total continuum of care” a patient will undergo during her cancer treatment, Wilfong added. New treatments represent “tremendous innovation for some patients who are living longer and better lives, but for others, innovation’s benefits have been small,” he noted.

Patient-reported outcomes (PROs) are playing an increasingly important role in clinical trials, roundtable panelists agreed. Doing so ensures that patients are not only living longer, but are also enjoying a good quality of life, Malin said.

“How are we going to know which additional supportive care products or approaches will produce the best outcomes for patients, as opposed to just survival time?” Malin asked.   

“When we are asked only a few specific, limited questions, that limits what data are available,” said panelist Stefanie Joho, a cancer survivor and patient advocate. “I know from my experience, I was very frustrated because I experienced side effects [not included in the study] that I felt were important to get on record for an entirely new drug or modality. I think until we really treat patients as research partners, we’re selling ourselves short.”

Successfully implementing innovative treatments like CAR-T cell therapies requires a coordinated team approach, Joho said. “That includes everything from managing side effects [and working with] ER doctors [and] nurses-it really takes a team to make these treatments effective.”

The roundtable was sponsored by Bristol-Myers Squibb

Abbvie; Astellas; AstraZeneca; Celgene Corporation; Eisai Inc.; Foundation Medicine; Gilead Sciences Inc; Halozyme; Janssen; Karyopharm Therapeutics Inc.; Loxo Oncology; Novartis; Pharmacyclics, an AbbVie Company; and Sanofi-Genzyme. Sponsored by Bristol-Myers Squibb.

The Lewin Group is owned by Optum, a UnitedHealth Group company.

Experts shared the challenges they've encountered in integrating novel treatments such as CAR T-cell therapy into practice at the 2019 NCCN Annual Conference.

NCCN: Costly Innovative Cancer Therapies Pose New Challenges-Financial and Otherwise

Adjuvant therapy with the vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) sunitinib after nephrectomy was associated with increased mortality among older women with renal cell carcinoma (RCC), according to a post-hoc subgroup analysis of data from the ASSURE (E2805) clinical trial, presented (

) at the 2018 Genitourinary Cancers Symposium, held February 8–10 in San Francisco.

“Any post-hoc exploratory analysis requires confirmatory studies,” cautioned lead study author Ronac Mamtani, MD, of the University of Pennsylvania in Philadelphia. “These findings, if validated, highlight the importance of considering sex and age on VEGF-TKI treatment outcomes, future study designs, and RCC tumor biology.”

The benefit of adjuvant VEGF TKIs for RCC has been a matter of debate. The ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable RCC) trial found no overall or disease-free survival (DFS) benefit for patients undergoing adjuvant sunitinib or sorafenib-but the STRAC study found a DFS benefit for sunitinib, Dr. Mamtani said.  

VEGF pharmacokinetics are known to differ by sex. Older patients and women are at higher risk of toxicity from both sunitinib and sorafenib.

“Given the uncertain risk–benefit ratio, identifying subgroups expected to derive benefit or harm from therapy could lead to a more precise approach to therapy,” Dr. Mamtani said. “Because of known sex-differences in the pharmacokinetics and tissue distribution of VEGF-TKIs, we assessed the interaction of age and sex on treatment outcomes among patients in the phase III ASSURE trial.”

The study authors’ post-hoc analysis included data from 1,943 patients with ≥ pT1b resected grade 3–4 and/or node-positive RCC.

Disease recurrence risk among women older than the median trial population age of 56 years and who received adjuvant sunitinib was significantly increased compared to those receiving placebo (hazard radio [HR] for DFS, 1.53; 95% CI, 1.03–2.28)-as was the risk of mortality (HR for overall survival, 2.38; 95% CI, 1.39–4.07; 

= .017). The DFS finding was “only marginally” statistically significant, Mamtani noted.

There were not similarly increased risks of mortality for younger women or men of any age treated with sunitinib, nor for male or female patients of any age who were treated with sorafenib.

Older patients were “slightly more likely” to develop toxicity with sunitinib regardless of sex, Dr. Mamtani said.

If the reported increase in sunitinib risk for older women is confirmed, potential explanations might include sex differences in sunitinib metabolism related to estrogen. Statistical analyses were not adjusted for multiple tests of correlation, and the post-hoc study design precluded determining mechanisms that may underlie the reported association, acknowledged Dr. Mamtani.

Dr. Mamtani disclosed an advisory or consulting role with Takeda.

Adjuvant therapy with sunitinib after nephrectomy was associated with increased mortality among older women with renal cell carcinoma, according to a subgroup analysis of data from the ASSURE trial.

Are Older Women With RCC at Increased Risk With Adjuvant Sunitinib?

Continuous lenalidomide therapy improves outcomes among patients with newly diagnosed myeloma who are not autologous stem cell transplant candidates, according to findings from the large phase III UK National Cancer Research Institute Myeloma XI clinical trial presented in a poster presentation (

) at the 59th American Society of Hematology Annual Meeting and Exposition, held December 9–12 in Atlanta.

The findings support continued lenalidomide treatment until disease progression for this patient population, concluded Charlotte Pawlyn, PhD, of the Institute of Cancer Research in London, and coauthors.

“When long-term treatment with lenalidomide is administered the induction regimen used does not seem critical in older age groups and therapeutic choice can be driven by the side-effect profile and tolerability,” the research team reported.

Immunomodulators of the E3 ubiquitin ligase complex are effective antimyeloma agents and longer treatment is associated with improved disease control. Lenalidomide has previously been shown to involve a lower rate of toxicities than thalidomide, allowing longer treatment durations.

Triplet induction combination treatments induce deeper and longer remissions than doublet induction regimens, likely because they target different clonal populations, the authors noted. Among transplant non-eligible patients with myeloma, continuing lenalidomide in combination with dexamethasone offers improved outcome, but the optimal combination of immunomodulatory agents for induction and maintenance therapy are unclear.

The authors therefore compared triplet induction with lenalidomide vs thalidomide and maintenance lenalidomide vs observation. The randomized phase III Myeloma XI trial was a multicenter, open-label study of newly diagnosed patients. The study included both transplant-eligible and non-eligible patients. Patients with dialysis-dependent renal failure were not eligible to participate in the study.

For transplant non-eligible patients, patients were randomly assigned to undergo induction therapy with cyclophosphamide and dexamethasone plus attenuated doses of either lenalidomide (CRDa, 928 patients) or thalidomide (CTDa, 924 patients) for a minimum of 6 treatment cycles. Patients were then randomly assigned to lenalidomide maintenance therapy or observation. The primary endpoints were progression-free and overall survival. Secondary endpoints were toxicity and response.

The CRDa and CTDa study arms were well balanced for patient gender, age, performance score, paraprotein type, International Staging System (ISS) stage, cytogenetic risk, and risk category. 

At a median follow-up of 34.4 months, patients in the CRDa (lenalidomide) group saw better objective response rates than those assigned to the CTDa (thalidomide) group (51% vs 43%; 

However, induction therapy survival rates were nearly identical between the two groups (progression-free survival hazard ratio [HR], 0.96; 

A similar proportion of patients in each group discontinued treatment because of toxicity (11% in CRDa vs 12% in CTDa). Grade 3 or higher neutropenia occurred in 34% of CRDa-assigned patients and 22% of CTDa patients. More CRDa patients also experienced grade 3 or higher thrombocytopenia (10% vs 2%) and anemia (16% vs 12%), the authors reported.

Lenalidomide maintenance outperformed observation (progression-free survival HR, 0.42; 

< .0001). All subgroup analyses (for gender, age, performance status, ISS, and cytogenetic risk) favored lenalidomide maintenance over observation. Overall survival rates for maintenance therapy outcomes were not reported.

CRDa induction and lenalidomide maintenance represent the “optimum combination” regimens for prolonged progression-free survival, driven by the benefits of maintenance lenalidomide, the authors concluded.

Dr. Pawlyn disclosed honoraria and travel support payments from Celgene, which markets lenalidomide as Revlimid.

Continuous lenalidomide therapy improves outcomes among patients with newly diagnosed myeloma who are not autologous stem cell transplant candidates, according to findings from a large phase III clinical trial.

Lenalidomide Maintenance Therapy Outperforms Observation in Newly Diagnosed Multiple Myeloma

Epacadostat plus pembrolizumab, a novel combination immunotherapy treatment, yielded “encouraging response outcomes” among patients with 0 or 1 prior lines of therapy for advanced renal cell carcinoma (RCC), according to preliminary results from the ongoing phase I/II open-label ECHO-202/KEYNOTE-037 study, presented (abstract 

) at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting by lead study author Primo Lara, MD, of the University of California Davis Comprehensive Cancer Center in Sacramento.

“Epacadostat plus pembrolizumab was generally well tolerated,” reported Lara.

Epacadostat is an oral inhibitor of indoleamine 2,3-dioxygenase 1, an enzyme that induces T-cell suppression and immune tolerance. Previous research has suggested that in combination with immune checkpoint inhibitors, epacadostat exhibits antitumor activity.

The ECHO-202/KEYNOTE-037 trial is an ongoing study of epacadostat plus pembrolizumab immunotherapy in multiple tumor types. For the kidney cancer cohort, the researchers enrolled adult patients diagnosed with histologically confirmed metastatic or recurrent clear-cell RCC, with ECOG performance status scores of 0 or 1, and no prior immune checkpoint inhibitor therapy.

Thirty-three patients participated in the study. The phase I dose-escalation component of the study (n = 11) involved patients receiving epacadostat (25, 50, 100, or 300 mg twice daily) plus pembrolizumab (2 mg/kg or 200 mg IV every 3 weeks). Maximum tolerated dose was not exceeded. In the phase II portion, 22 patients received epacadostat 100 mg twice daily plus 200-mg pembrolizumab every 3 weeks. Tolerability and safety were assessed in patients receiving at least 1 dose of the combination.

Treatment-related adverse events included fatigue (36%) and rash (36%), as well as arthralgia, diarrhea, pruritus, and pyrexia (12% each). Grade ≥ 3 treatment-related adverse events occurred in 15% of patients. Two patients discontinued treatment following these events. One had grade 3 autoimmune hepatitis; the other had grade 3 aseptic meningitis with headache, nausea, vomiting, and anxiety.

Thirty patients were evaluable for efficacy; 19 (63%) had 0 to 1 prior lines of therapy, and 11 (37%) had 2 or more prior lines of therapy. The objective response rate among patients with 0–1 prior lines of therapy was 47% (9/19), including 1 complete response and 8 partial responses.

Epacadostat plus pembrolizumab yielded “encouraging response outcomes” among patients with 0 or 1 prior lines of therapy for advanced renal cell carcinoma.

Epacadostat Plus Pembrolizumab Shows Early Promise in Advanced RCC

Despite immune-related adverse events, concurrent ibrutinib and anti-CD19 chimeric antigen receptor (CAR) T-cell therapy may improve response rates in patients with chronic lymphocytic leukemia (CLL), according to early results (

) from a small study presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago.

Among high-risk CLL patients on the combination, 89% had complete responses with minimal residual disease (MRD) negativity in the marrow, reported lead author Saar Gill, MD, PhD, of the University of Pennsylvania in Philadelphia, and colleagues.

Ten patients were included in the study. Eight of nine evaluable patients “have no CLL in the marrow by flow and/or MRD testing,” at a median follow-up of 6 months, they reported. “Radiologic responses are less clear-cut and may require longer follow-up.”

Nine patients developed cytokine release syndrome (grade 1/2 in eight patients and grade 3 in one patient). However, treatment was nevertheless “well tolerated,” the authors reported, noting that none of these patients required therapy for cytokine release syndrome. One patient developed grade 4 tumor lysis syndrome.

Alone, anti-CD19 CAR T-cell immunotherapy induces durable complete tumor responses in between 25% and 45% of patients with CLL, the authors noted. Preclinical research suggests possible synergism for this immunotherapy and ibrutinib. The authors sought to evaluate complete response rates for CLL patients treated with ibrutinib prior to and concurrent with anti-CD19 CAR T-cell immunotherapy.

Adult patients who had not achieved a complete response after 6 months or more of ibrutinib therapy were enrolled. Bendamustine or fludarabine and cyclophosphamide were used for lymphodepletion 1 week before treatment. Patients were administered CAR T cells and ibrutinib, and marrow CLL burden was measured with flow cytometry and next-generation deep sequencing for 

 gene rearrangement. Radiographic evaluations of lymph nodes and the spleen were conducted using computed tomography.

Five patients had complete responses in the spleen, and two patients each experienced partial responses and stable disease.

The team plans to treat 25 patients with the combination.

“Longer follow-up will reveal the durability of these results and could support evaluation of a first-line combination approach in an attempt to obviate the need for chronic therapy,” they reported.

Despite immune-related adverse events, concurrent ibrutinib and anti-CD19 CAR T-cell therapy may improve response rates in patients with chronic lymphocytic leukemia.

CAR T Cell/Ibrutinib Combination May Improve CLL Response Rates

It is increasingly important that oncology nurses and other healthcare providers recognize cytokine release syndrome (CRS) and other side effects that can be triggered by anticancer treatment with engineered chimeric antigen receptor (CAR) T-cell therapies, and that they understand the importance of early detection, a speaker emphasized at the Oncology Nursing Society (ONS) 42nd Annual Congress, held May 4–7 in Denver.

“Careful monitoring is essential for early detection of CAR T-cell side effects,” said study coauthor Brenna Hansen, BSN, RN, OCN, a research nurse specialist at the Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. “Early recognition of symptoms results in early intervention and safe management of the patient by the multidisciplinary team.”

CAR T-cell therapy involves equipping immune T cells with engineered receptors to facilitate immune attack on tumor cells expressing specific surface proteins. Patient T cells are collected and modified in a lab to express cancer-specific receptors. These are then infused back into the patient.

CAR T-cell therapies show promise against hematologic malignancies and other cancers but can trigger a range of initially subtle but potentially life-threatening side effects. Perhaps chief among these adverse reactions is CRS and neurologic side effects that might or might not occur with CRS. Most of these are reversible with corticosteroids or other treatment.

CRS symptoms include fever, tachycardia, and hypotension occurring within a week (typically 4–7 days) after CAR T-cell infusion, though CRS can occur more quickly. “I’ve seen CRS as soon as a day after infusion,” Hansen cautioned.

Heart arrhythmias, fatigue, hypoxia, pulmonary edema, pneumonitis, electrolyte imbalances, nausea, vomiting, diarrhea, cytopenias, infections, elevated creatinine kinase, myalgia, and muscle weakness can all be signs of CRS.

Neurologic side effects can include tremors, headaches, confusion, loss of balance, trouble speaking, encephalopathy, seizures, long periods of somnolence, and sometimes, hallucinations, Hansen noted.

These symptoms can be subtle initially. Hansen described a CAR T-cell therapy patient’s transportation by ambulance to the hospital after detection of a subtle hand tremor because clinicians were concerned it could quickly worsen.

CAR T-cell therapies can also trigger receptor/cell-type specific side effects such as CAR19-associated B-cell aplasia and graft-vs-host disease. New side effects will likely emerge as new targets are found and CAR T-cell therapies become more commonly administered, she predicted.

Nurses play key roles in every stage of CAR T-cell toxicity monitoring and management, from inpatient monitoring at the bedside, including frequent assessments and checks of vital signs during high-risk periods, to outpatient and long-term monitoring, Hansen said.

Outpatient monitoring for patients who are infused as outpatients, or post-discharge, is key to spotting delayed toxicities, she emphasized. Clinic and triage nurses play key roles in the timely recognition of late CAR T-cell side effects.

Long-term monitoring is important, as well. Home oncology clinic nurses should monitor serum IgG (IVIG) and blood cell counts with differential.

“If symptoms become severe, cells may be tempered with tocilizumab or corticosteroids,” she said. “However, this is avoided if possible to prevent damaging the anti-malignancy effects of the CAR T cells.”

It is crucial that nursing staff be educated on side effects unique to CAR T-cell treatments, and that nursing guidance be provided specifying the signs and symptoms that should be communicated to patients’ other healthcare providers-and patients themselves-to allow early detection and intervention. “Having a written plan can help prevent confusion and provide clear guidelines for the patient’s care,” she noted.

It is increasingly important that nurses recognize cytokine release syndrome and other side effects that can be triggered by treatment with engineered CAR T-cell therapies.

Oncology Nurses Must Watch for CAR T-Cell Therapy Side Effects

Kinase oncoproteins and growth factors both activate the proto-oncogene 

, allowing the persistence of residual leukemia cell populations despite tyrosine kinase inhibitor (TKI) therapy, according to findings from a new preclinical study 

Leukemia stem cells appear to become addicted to elevated c-FOS and DUSP1 during TKI therapy, which could lead to intrinsic TKI resistance and eventual relapse, they concluded.

“Our data demonstrate that c-FOS and DUSP1 expression levels determine the threshold of TKI efficacy, such that growth factor-induced expression of c-FOS and DUSP1 confers intrinsic resistance to TKI therapy in a wide-ranging set of leukemias, and might represent a unifying Achilles’ heel of kinase-driven cancers,” reported study co-author Mohammad Azam, PhD, Cincinnati Children’s Hospital Medical Center in Cincinnati, and colleagues. “

TKI therapy is not curative for cancer, the authors noted; persisting cancer cell populations, known as minimal residual disease (MRD), eventually lead to relapse.

The research team experimentally manipulated expression of c-FOS and DUSP1 in animal models, in an effort to overcome this intrinsic resistance and destroy residual tumor cells after TKI therapy.

 suppressed tumor growth in a BCR-ABL fusion protein kinase-induced mouse model of chronic myeloid leukemia (CML),” they reported. “Pharmacological inhibition of c-FOS, DUSP1 and BCR-ABL eradicated MRD in multiple 

models, as well as in mice xenotransplanted with patient-derived primary CML cells.”

They subsequently demonstrated that growth factor signaling similarly induces 

expression and underlies TKI resistance in animal models of other leukemias, such as BCR-ABL-induced B-cell acute lymphoblastic leukemia (B-ALL).

The team also showed that higher FOS and DUSP1 levels induced anti-apoptosis gene expression, and that these and pro-survival genes’ expression could be suppressed with FOS and DUSP1 inhibitors.

“Taken together, these data provide evidence that higher levels of Fos and Dusp1 are required to maintain growth factor-induced expression of pro-survival and anti-apoptotic genes,” they concluded.

Kinase oncoproteins and growth factors both activate the proto-oncogene c-FOS and DUSP1, allowing the persistence of residual leukemia cell populations despite tyrosine kinase inhibitor therapy. 

 An ‘Achilles' Heel’ for Kinase-Driven Leukemias?

Active surveillance prior to initiating targeted therapy might benefit some patients with metastatic renal cell carcinoma (mRCC), according to a retrospective study (abstract 

) presented at the 2017 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, held February 16–18 in Orlando, Florida.

“Active surveillance does not affect the efficacy of subsequent therapies,” reported lead study author Davide Bimbatti, MD, of the Azienda Ospedaliera Universitaria Integrata, University of Verona in Verona, Italy. “In selected patients, active surveillance allows us to delay the start of systemic treatment; patients in active surveillance rarely have a worsening of prognostic class.”

Targeted therapies can improve survival among patients with mRCC, but treatment-related adverse events can worsen quality of life and force discontinuation of treatment. Active surveillance delays systemic therapy and toxicities.

To determine how active surveillance affects tumor burden and patient prognosis in patients with indolent disease, the research team conducted a single-institution study to test time on surveillance, overall survival and post-surveillance overall survival, progression-free survival, and tumor burden outcomes among 48 patients with mRCC who underwent active surveillance between 2007 and 2016. Changes in International mRCC Database Consortium (IMDC) prognostic class and tumor burden were analyzed for associations with these outcomes.

The baseline IMDC prognostic class was favorable in 69% of patients, intermediate in 25%, and poor in 6%. At a median follow-up of 37.3 months, 79.2% of patients were still alive.

At a median surveillance duration of 16.7 months, 71% of patients had started a targeted therapy.

Only four patients changed from good to intermediate IMDC prognostic class; overall, IMDC classes “maintained their prognostic value” among patients who underwent active surveillance, Bimbatti said. IMDC class was the “sole factor” that was associated with time on surveillance.

Significant differences in time on surveillance were found for patients with good or intermediate vs poor prognosis (19.9, 17.7, and 5.2 months, respectively; 

Change in tumor burden was not associated with time on surveillance. It was associated with post-surveillance overall survival (hazard ratio [HR], 1.23; 

< .01), but not with overall survival. Higher baseline number of metastatic sites was associated with significantly worse overall survival (HR, 3.3; 

< .01). Time on surveillance and overall survival were similar to previous studies.

The decision to end surveillance was “not mandated per objective criteria but left to the physician’s and patient’s discretion,” cautioned Bimbatti.

The findings offer “reassuring data,” said Primo N. Lara, Jr, MD, of the University of California, Davis Comprehensive Cancer Center. “Very few active surveillance patients evolved into a worse prognostic group.”

The study was retrospective and conducted at a single institution, and “failed to account for psychosocial issues like anxiety,” Lara cautioned. “But the bottom line is that active surveillance remains a reasonable option for highly selected patients.”

Active surveillance prior to initiating targeted therapy might benefit patients with metastatic renal cell carcinoma, since it delays therapy and toxicities.

Does Active Surveillance Benefit Patients With Metastatic RCC?

Dacomitinib induction therapy is active in human papillomavirus (HPV)-negative, locally advanced or metastatic penile squamous cell carcinoma (PSCC), according to findings from an open-label, single-arm, phase II study (abstract 

“Dacomitinib is endowed with one of the highest single-agent objective response rates in PSCC,” said lead study author Andrea Necchi, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy. “Overall survival rates were not influenced by post-dacomitinib chemotherapy.”

Long-term survival is rare for patients with PSCC involving the inguinal or pelvic lymph nodes. The standard treatment is surgery but it is “insufficient” as a stand-alone treatment, Necchi emphasized. “Multimodal approaches are warranted” but long-term chemotherapy outcomes are poor, he said. No effective treatments are available for patients with visceral metastases.

However, previous research suggests that anti-EGFR targeted therapy is active against PSCC in patients who have undergone chemotherapy.

Dacomitinib is an oral, irreversible pan-HER tyrosine kinase inhibitor that targets EGFR/HER1, HER2, and HER4. The study authors administered 45 mg/d to patients with PSCC who had not previously taken chemotherapy. CT and PET/CT scans were done every 8 weeks, and patients with responding locally advanced tumors were offered the choice of radical surgery. Objective response rates were evaluated using RECIST v1.1 criteria.

Between 2013 and 2016, 26 evaluable patients of an intent-to-treat sample of 28 patients, ages 18–75 years, participated in the study; 7 (26.9%) had visceral metastases. The objective response rate was 32.1% overall. Only 1 patient experienced a complete response; 8 patients (28.6%) experienced partial responses. Thirteen (46.4%) experienced stable disease, and 6 (21.4%) suffered disease progression. Necchi noted that 60.7%, or 17 patients, experienced a decrease in target lesions from baseline.

Overall progression-free survival (PFS) was 4.1 months, with a 6-month rate of 40.4%. Median PFS for patients with nodal involvement was 4.3 months, with a 6-month rate of 48.7%; and the median PFS for patients with visceral metastases was 3.2 months, with a 6-month rate of 16.7%.

Median overall survival was 13.7 months, with a 12-month rate of 54.9%. For patients with nodal involvement, the median was 20 months; and for those with visceral metastases, the median was 9.9 months.

gene mutations were associated with better objective response. The mechanisms of response appeared to be 

 mutation–independent, although downstream EGFR effectors such as 

 pathway genes require additional study. Angiogenesis gene mutations were associated with a larger proportion of non-responses. 

 mutations did not appear to affect response rates.

Treatment-related adverse events included grade 3 skin toxicity (3 patients (10.7%), as well as low-grade diarrhea, bleeding, and inguinal abscess.

Subsequent dacomitinib studies will need to evaluate longer treatment durations with or without chemotherapy or radiotherapy, concluded Necchi.

Dacomitinib induction therapy has shown activity in HPV-negative, locally advanced or metastatic penile squamous cell carcinoma.