Publications by authors named "Igor Puzanov"

160 Publications

Editorial: Advancements in Molecular Diagnosis and Treatment of Melanoma.

Front Oncol 2021 9;11:728113. Epub 2021 Jul 9.

Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori Fondazione G. Pascale, Naples, Italy.

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http://dx.doi.org/10.3389/fonc.2021.728113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299098PMC
July 2021

Clinical and immunologic implications of COVID-19 in patients with melanoma and renal cell carcinoma receiving immune checkpoint inhibitors.

J Immunother Cancer 2021 07;9(7)

Renal and Skin Units, Royal Marsden NHS Foundation Trust, London, UK

The clinical and immunologic implications of the SARS-CoV-2 pandemic for patients with cancer receiving systemic anticancer therapy have introduced a multitude of clinical challenges and academic controversies. This review summarizes the current evidence, discussion points, and recommendations regarding the use of immune checkpoint inhibitors (ICIs) in patients with cancer during the SARS-CoV-2 pandemic, with a focus on patients with melanoma and renal cell carcinoma (RCC). More specifically, we summarize the theoretical concepts and available objective data regarding the relationships between ICIs and the antiviral immune response, along with recommended clinical approaches to the management of melanoma and RCC patient cohorts receiving ICIs throughout the course of the COVID-19 pandemic. Additional insights regarding the use of ICIs in the setting of current and upcoming COVID-19 vaccines and broader implications toward future pandemics are also discussed.
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http://dx.doi.org/10.1136/jitc-2021-002835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288220PMC
July 2021

Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma.

J Clin Oncol 2021 Sep 13;39(26):2914-2925. Epub 2021 Jul 13.

Yale School of Medicine, New Haven, CT.

Purpose: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma.

Methods: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers.

Results: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response.

Conclusion: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed.
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http://dx.doi.org/10.1200/JCO.21.00675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425826PMC
September 2021

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 3rd-5th, 2020, Italy).

J Transl Med 2021 06 30;19(1):278. Epub 2021 Jun 30.

Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, NCI, NIH, Rockville, MD, USA.

Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall survival for patients with advanced melanoma. Single agent checkpoint PD-1 blockade and combination with BRAF/MEK targeted therapy demonstrated benefit in overall survival (OS). Superior response rates have been demonstrated with combined PD-1/CTLA-4 blockade, with a significant OS benefit compared with single-agent PD-1 blockade. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers but they have yet to be fully characterized and implemented clinically. Overall, the progress in melanoma therapeutics and translational research will help to optimize treatment regimens to overcome resistance and develop robust biomarkers to guide clinical decision-making. During the Melanoma Bridge meeting (December 3rd-5th, 2020, Italy) we reviewed the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine.
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http://dx.doi.org/10.1186/s12967-021-02951-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243582PMC
June 2021

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events.

J Immunother Cancer 2021 Jun;9(6)

Division of Cancer Treatment & Diagnosis, National Cancer Institute, Rockville, Maryland, USA

Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.
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http://dx.doi.org/10.1136/jitc-2021-002435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237720PMC
June 2021

Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis.

J Immunother Cancer 2021 Jun;9(6)

CPL Associates, Buffalo, New York, USA.

Background: Immune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs.

Methods: We retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors.

Results: Among patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes.

Conclusions: Routine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.
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http://dx.doi.org/10.1136/jitc-2021-002553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231054PMC
June 2021

Perspectives in immunotherapy: meeting report from the immunotherapy bridge (December 2nd-3rd, 2020, Italy).

J Transl Med 2021 06 2;19(1):238. Epub 2021 Jun 2.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Improved understanding of tumor immunology has enabled the development of therapies that harness the immune system and prevent immune escape. Numerous clinical trials and real-world experience has provided evidence of the potential for long-term survival with immunotherapy in various types of malignancy. Recurring observations with immuno-oncology agents include their potential for clinical application across a broad patient population with different tumor types, conventional and unconventional response patterns, durable responses, and immune-related adverse events. Despite the substantial achievements to date, a significant proportion of patients still fail to benefit from current immunotherapy options, and ongoing research is focused on transforming non-responders to responders through the development of novel treatments, new strategies to combination therapy, adjuvant and neoadjuvant approaches, and the identification of biomarkers of response. These topics were the focus of the virtual Immunotherapy Bridge (December 2nd-3rd, 2020), organized by the Fondazione Melanoma Onlus, Naples, Italy, in collaboration with the Society for Immunotherapy of Cancer and are summarised in this report.
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http://dx.doi.org/10.1186/s12967-021-02895-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173810PMC
June 2021

Safety and Efficacy of the Combination of Nivolumab Plus Ipilimumab in Patients With Melanoma and Asymptomatic or Symptomatic Brain Metastases (CheckMate 204).

Neuro Oncol 2021 Apr 21. Epub 2021 Apr 21.

Department of Medical Oncology, City of Hope, Duarte, CA.

Background: In patients with melanoma and asymptomatic brain metastases (MBM), nivolumab plus ipilimumab provided an intracranial response rate of 55%. Here, we present first report for patients who were symptomatic and/or required corticosteroids and updated data for asymptomatic patients.

Methods: Patients with measurable MBM, 0.5-3.0 cm, were enrolled into Cohort A (asymptomatic) or Cohort B (stable neurologic symptoms and/or receiving corticosteroids). Nivolumab, 1 mg/kg, and ipilimumab, 3 mg/kg, were given intravenously every 3 weeks x4, followed by nivolumab, 3 mg/kg, every 2 weeks until progression, unacceptable toxicity, or 24 months. The primary endpoint was intracranial clinical benefit rate (CBR; complete response [CR], partial response [PR], or stable disease ≥6 months).

Results: Symptomatic patients (N = 18) received a median of one nivolumab and ipilimumab combination dose, and had an intracranial CBR of 22.2%. Two of 12 patients on corticosteroids had CR; 2 responded among the 6 not on corticosteroids. Median intracranial progression-free survival (PFS) and overall survival (OS) were 1.2 and 8.7 months, respectively. In contrast, with 20.6 months of follow-up, we confirmed an intracranial CBR of 58.4% in asymptomatic patients (N = 101); median duration of response, PFS, and OS were not reached. No new safety signals were observed.

Conclusions: Nivolumab plus ipilimumab provides durable clinical benefit for asymptomatic patients with MBM and should be considered for first-line therapy. This regimen has limited activity in MBM patients with neurologic symptoms and/or requiring corticosteroids, supporting the need for alternative approaches and methods to reduce the dependency on corticosteroids.
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http://dx.doi.org/10.1093/neuonc/noab094DOI Listing
April 2021

The "Great Debate" at Immunotherapy Bridge 2020, December 3rd, 2020.

J Transl Med 2021 04 7;19(1):144. Epub 2021 Apr 7.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

As part of the 2020 Immunotherapy Bridge virtual congress (December 2nd-3rd, Italy), the Great Debate session featured counterpoint views from leading experts on three clinical questions in immunotherapy today. The first of these was whether antitumoral vaccination is still a treatment option. The second topic debated whether anti-programmed death (PD)-1/PD-ligand (L)1 blockade should be the backbone for immunotherapy combination. Finally, the use of innovative study designs and surrogate endpoints was considered from both an academic and industry perspective. For each topic, two experts presented the argument and counter-argument in support of two different points of view. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. The views summarised in this article are based on available evidence but may reflect personal interpretation of these data, clinical experience and subjective opinion of the speaker.
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http://dx.doi.org/10.1186/s12967-021-02811-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025454PMC
April 2021

The "Great Debate" at Melanoma Bridge 2020: December, 5th, 2020.

J Transl Med 2021 04 7;19(1):142. Epub 2021 Apr 7.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

The Great Debate session at the 2020 Melanoma Bridge virtual congress (December 3rd-5th, Italy) featured counterpoint views from experts on five specific controversial issues in melanoma. The debates considered whether or not innate immunity is important in the response to cancer and immunotherapy, how useful are the revised American Joint Committee on Cancer (AJCC) classification for the staging of patients, the use of sentinel node biopsy for staging patients, the use of triplet combination of targeted therapy plus immunotherapy versus combined immunotherapy, and the respective benefits of neoadjuvant versus adjuvant therapy. As is usual with Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their own personal opinion.
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http://dx.doi.org/10.1186/s12967-021-02808-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028182PMC
April 2021

Neoadjuvant Pembrolizumab and High-Dose IFNα-2b in Resectable Regionally Advanced Melanoma.

Clin Cancer Res 2021 Aug 22;27(15):4195-4204. Epub 2021 Mar 22.

H. Lee Moffit Cancer Center and Research Institute, Tampa, Florida.

Purpose: Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.

Patients And Methods: Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m/day i.v., 5 days per week for 4 weeks, then 10 MU/m/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.

Results: A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2-43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5-85.8], with a 43% (95% CI: 27.3-60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR ( = 0.002 and = 0.008, respectively).

Conclusions: Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator..
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8338751PMC
August 2021

Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma.

Cancer Discov 2021 Aug 11;11(8):1996-2013. Epub 2021 Mar 11.

Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1- resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. SIGNIFICANCE: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1546DOI Listing
August 2021

T-cell CX3CR1 expression as a dynamic blood-based biomarker of response to immune checkpoint inhibitors.

Nat Commun 2021 03 3;12(1):1402. Epub 2021 Mar 3.

Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Immune checkpoint inhibitors (ICI) have revolutionized treatment for various cancers; however, durable response is limited to only a subset of patients. Discovery of blood-based biomarkers that reflect dynamic change of the tumor microenvironment, and predict response to ICI, will markedly improve current treatment regimens. Here, we investigate CX3C chemokine receptor 1 (CX3CR1), a marker of T-cell differentiation, as a predictive correlate of response to ICI therapy. Successful treatment of tumor-bearing mice with ICI increases the frequency and T-cell receptor clonality of the peripheral CX3CR1CD8 T-cell subset that includes an enriched repertoire of tumor-specific and tumor-infiltrating CD8 T cells. Furthermore, an increase in the frequency of the CX3CR1 subset in circulating CD8 T cells early after initiation of anti-PD-1 therapy correlates with response and survival in patients with non-small cell lung cancer. Collectively, these data support T-cell CX3CR1 expression as a blood-based dynamic early on-treatment predictor of response to ICI therapy.
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http://dx.doi.org/10.1038/s41467-021-21619-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930182PMC
March 2021

Angiokines Associated with Targeted Therapy Outcomes in Patients with Non-Clear Cell Renal Cell Carcinoma.

Clin Cancer Res 2021 Jun 16;27(12):3317-3328. Epub 2021 Feb 16.

Department of Biostatistics, Duke University, Durham, North Carolina.

Purpose: Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC) to inform treatment selection but also to identify novel therapeutic targets. We thus sought to profile circulating angiokines in the context of a randomized treatment trial of everolimus versus sunitinib.

Patients And Methods: ASPEN (NCT01108445) was an international, randomized, open-label phase II trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC with no prior systemic therapy. Patients were randomized to everolimus or sunitinib and treated until disease progression or unacceptable toxicity. The primary endpoint was radiographic progression-free survival (PFS) defined by RECIST 1.1. Plasma angiokines were collected at baseline, cycle 3, and progression and associated with PFS and overall survival (OS).

Results: We enrolled 108 patients, 51 received sunitinib and 57 everolimus; of these, 99 patients had evaluable plasma for 23 angiokines. At the final data cutoff, 94 PFS and 64 mortality events had occurred. Angiokines that were independently adversely prognostic for OS were osteopontin (OPN), TIMP-1, thrombospondin-2 (TSP-2), hepatocyte growth factor (HGF), and VCAM-1, and these were also associated with poor-risk disease. Stromal derived factor 1 (SDF-1) was associated with improved survival. OPN was also significantly associated with worse PFS. No statistically significant angiokine-treatment outcome interactions were observed for sunitinib or everolimus. Angiopoeitin-2 (Ang-2), CD-73, HER-3, HGF, IL6, OPN, PIGF, PDGF-AA, PDGF-BB, SDF-1, TGF-b1-b2, TGFb-R3, TIMP-1, TSP-2, VCAM-1, VEGF, and VEGF-R1 levels increased with progression on everolimus, while CD-73, ICAM-1, IL6, OPN, PlGF, SDF-1, TGF-b2, TGFb-R3, TIMP-1, TSP-2, VEGF, VEGF-D, and VCAM-1 increased with progression on sunitinib.

Conclusions: In patients with metastatic NC-RCC, we identified several poor prognosis angiokines and immunomodulatory chemokines during treatment with sunitinib or everolimus, particularly OPN.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4504DOI Listing
June 2021

Axitinib plus pembrolizumab in patients with advanced renal-cell carcinoma: Long-term efficacy and safety from a phase Ib trial.

Eur J Cancer 2021 03 4;145:1-10. Epub 2021 Jan 4.

Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA. Electronic address:

Background: Axitinib plus pembrolizumab showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) versus sunitinib in a randomised phase III trial in patients with advanced renal-cell carcinoma (RCC). We report long-term efficacy and safety of the axitinib/pembrolizumab from the phase I trial (NCT02133742), after 46-55 months from study initiation (data cut-off date, 23rd July 2019).

Methods: Fifty-two treatment-naïve patients with advanced RCC were treated with oral axitinib 5 mg twice daily and intravenous pembrolizumab 2 mg/kg every 3 weeks. PFS, duration of response (DoR) and OS were summarised using the Kaplan-Meier method.

Results: At a median follow-up of 42.7 months (95% confidence interval [CI]: 41.1-44.1), median OS was not reached; 38 (73.1%) patients were alive. The probability of being alive at 4 years was 66.8% (95% CI: 49.1-79.5). Median PFS in the overall population was 23.5 months (95% CI: 15.4-30.4). ORR was 73.1%; five patients had complete response. Median DoR was 22.1 months (95% CI: 15.1-34.5). Grade III/IV adverse events (AEs) were reported in 38 (73.1%) patients and 20 (38.5%) discontinued treatment because of AEs: 17 (32.7%) discontinued axitinib, 13 (25.0%) discontinued pembrolizumab, and 10 (19.2%) discontinued both drugs. Common AEs included diarrhoea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%) and dysphonia (48.1%). There were no new AE terms reported and no treatment-related deaths.

Conclusions: In patients with advanced RCC with ~4 years of follow-up, combination axitinib/pembrolizumab continued to demonstrate clinical benefit, with no new safety signals.
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http://dx.doi.org/10.1016/j.ejca.2020.12.009DOI Listing
March 2021

Perspectives in immunotherapy: meeting report from the "Immunotherapy Bridge" (December 4th-5th, 2019, Naples, Italy).

J Transl Med 2021 01 6;19(1):13. Epub 2021 Jan 6.

Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Over the last few years, numerous clinical trials and real-world experience have provided a large amount of evidence demonstrating the potential for long-term survival with immunotherapy agents across various malignancies, beginning with melanoma and extending to other tumours. The clinical success of immune checkpoint blockade has encouraged increasing development of other immunotherapies. It has been estimated that there are over 3000 immuno-oncology trials ongoing, targeting hundreds of disease and immune pathways. Evolving topics on cancer immunotherapy, including the state of the art of immunotherapy across various malignancies, were the focus of discussions at the Immunotherapy Bridge meeting (4-5 December, 2019, Naples, Italy), and are summarised in this report.
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http://dx.doi.org/10.1186/s12967-020-02627-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789268PMC
January 2021

Long-term safety of pembrolizumab monotherapy and relationship with clinical outcome: A landmark analysis in patients with advanced melanoma.

Eur J Cancer 2021 02 24;144:182-191. Epub 2020 Dec 24.

Melanoma Institute Australia, The University of Sydney, 40 Rocklands Rd, Wollstonecraft, NSW, 2065, Australia; Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, 610 University Ave, Toronto, ON, M5G2C1, Canada; The Kinghorn Cancer Centre at St Vincent's Hospital, 370 Victoria St, Darlinghurst, NSW, 2010, Australia; St Vincent's Clinical School, UNSW Sydney, Victoria St, Darlinghurst, NSW, 2010, Australia. Electronic address:

Objective: Long-term safety of pembrolizumab in melanoma was analyzed in KEYNOTE-001, KEYNOTE-002, and KEYNOTE-006.

Patients And Methods: Analysis involved patients who received ≥1 pembrolizumab dose. Lead-time bias was addressed via landmark analyses in patients who were progression-free before day 147.

Results: Adverse events (AEs) were analyzed for 1567 patients (median follow-up, 42.4 months). Most AEs were mild/moderate; grade 3/4 treatment-related AEs occurred in 17.7% of patients. Two pembrolizumab-related deaths occurred. Any-grade immune-mediated AEs (imAEs) occurred in 23.0%, most commonly hypothyroidism (9.1%), pneumonitis (3.3%), and hyperthyroidism (3.0%); grade 3/4 imAEs occurred in 6.9% of patients. Most imAEs occurred within 16 weeks of treatment. In landmark analysis, patients who did (n = 79) versus did not (n = 384) develop imAEs had similar objective response rates (ORRs) (64.6% versus 63.0%); median time to response (TTR), 5.6 months for both; median duration of response (DOR), 20.0 versus 25.3 months; median progression-free survival (PFS), 17.0 versus 17.7 months; median overall survival (OS), not reached (NR) versus 43 months (p = 0.1104). Patients who did (n = 17) versus did not (n = 62) receive systemic corticosteroids had similar ORRs (70.6% vs. 62.9%) and median TTR (6.4 vs. 5.6 months) but numerically shorter median PFS (9.9 vs. 17.0 months); median DOR, 14.2 months versus NR; median OS, NR for both.

Conclusions: These results enhance the knowledge base for pembrolizumab in advanced melanoma, with no new toxicity signals after lengthy follow-up of a large population. In landmark analyses, pembrolizumab efficacy was similar regardless of imAEs or systemic corticosteroid use.

Clinical Trial Registry: NCT01295827, NCT01704287, NCT01866319.
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http://dx.doi.org/10.1016/j.ejca.2020.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388128PMC
February 2021

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity.

Clin Cancer Res 2021 01 30;27(1):87-95. Epub 2020 Oct 30.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

Purpose: Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma.

Patients And Methods: A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months.

Results: Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders.

Conclusions: Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785669PMC
January 2021

Phase 1 study of mTORC1/2 inhibitor sapanisertib (TAK-228) in advanced solid tumours, with an expansion phase in renal, endometrial or bladder cancer.

Br J Cancer 2020 11 11;123(11):1590-1598. Epub 2020 Sep 11.

Sarah Cannon Research Institute/Tennessee Oncology, Drug Development Unit, 250 25th Ave., North Nashville, TN, 37203, USA.

Background: This Phase 1 dose-escalation/expansion study assessed safety/tolerability of sapanisertib, an oral, highly selective inhibitor of mTORC1/mTORC2, in advanced solid tumours.

Methods: Eligible patients received increasing sapanisertib doses once daily (QD; 31 patients), once weekly (QW; 30 patients), QD for 3 days on/4 days off QW (QD × 3dQW; 33 patients) or QD for 5 days on/2 days off QW (QD × 5dQW; 22 patients). In expansion cohorts, 82 patients with renal cell carcinoma (RCC), endometrial or bladder cancer received sapanisertib 5 mg QD (39 patients), 40 mg QW (26 patients) or 30 mg QW (17 patients).

Results: Maximum tolerated doses of sapanisertib were 6 mg QD, 40 mg QW, 9 mg QD × 3dQW and 7 mg QD × 5dQW. Frequent dose-limiting toxicities (DLTs) included hyperglycaemia, maculo-papular rash (QD), asthenia and stomatitis (QD × 3dQW/QD × 5dQW); expansion phase doses of 5 mg QD and 30 mg QW were selected based on tolerability beyond the DLT evaluation period. One patient with RCC achieved complete response; nine experienced partial responses (RCC: seven patients; carcinoid tumour/endometrial cancer: one patient each). Sapanisertib pharmacokinetics were time-linear and supported multiple dosing. Pharmacodynamic findings demonstrated treatment-related reductions in TORC1/2 biomarkers.

Conclusions: Sapanisertib demonstrated a manageable safety profile, with preliminary antitumour activity observed in RCC and endometrial cancer.

Clinical Trial Registration: ClinicalTrials.gov, NCT01058707.
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http://dx.doi.org/10.1038/s41416-020-01041-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686313PMC
November 2020

Perspectives in melanoma: meeting report from the "Melanoma Bridge" (December 5th-7th, 2019, Naples, Italy).

J Transl Med 2020 09 7;18(1):346. Epub 2020 Sep 7.

Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, MD, USA.

The melanoma treatment landscape changed in 2011 with the approval of the first anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 checkpoint inhibitor and of the first BRAF-targeted monoclonal antibody, both of which significantly improved overall survival (OS). Since then, improved understanding of the tumor microenvironment (TME) and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. The approval of new immune and targeted therapies has further improved outcomes for patients with advanced melanoma and other combination modalities are also being explored such as chemotherapy, radiotherapy, electrochemotherapy and surgery. In addition, different strategies of drugs administration including sequential or combination treatment are being tested. Approaches to overcome resistance and to potentiate the immune response are being developed. Increasing evidence emerges that tissue and blood-based biomarkers can predict the response to a therapy. The latest findings in melanoma research, including insights into the tumor microenvironment and new biomarkers, improved understanding of tumor immune response and resistance, novel approaches for combination strategies and the role of neoadjuvant and adjuvant therapy, were the focus of discussions at the Melanoma Bridge meeting (5-7 December, 2019, Naples, Italy), which are summarized in this report.
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http://dx.doi.org/10.1186/s12967-020-02482-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487701PMC
September 2020

The Great Debate at 'Immunotherapy Bridge', Naples, December 5, 2019.

J Immunother Cancer 2020 08;8(2)

Early Phase Clinical Trials Program, Developmental Therapeutics Program, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.

As part of the 2019 Immunotherapy Bridge congress (December 4-5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report.
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http://dx.doi.org/10.1136/jitc-2020-000921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449295PMC
August 2020

Observational study of talimogene laherparepvec use in the anti-PD-1 era for melanoma in the US (COSMUS-2).

Melanoma Manag 2020 Jun 15;7(2):MMT41. Epub 2020 Jun 15.

Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA.

Aim: Talimogene laherparepvec (T-VEC) is an intralesional therapy for unresectable, metastatic melanoma. T-VEC real-world use in the context of anti-PD1-based therapy requires further characterization.

Materials & Methods: A retrospective review of T-VEC use from 1 January 2017 and 31 March 2018 for melanoma patients was conducted at seven US institutions.

Results: Among 83 patients, three categories of T-VEC and anti-PD-1 therapy were identified: T-VEC used without anti-PD-1 (n = 29, 35%), T-VEC after anti-PD-1-based therapy (n = 22, 27%) and concurrent T-VEC and anti-PD-1-based therapy (n = 32, 39%). 25% of patients discontinued T-VEC therapy due to no remaining injectable lesions, 37% discontinued T-VEC due to progressive disease. Discontinuation of T-VEC did not differ by anti-PD-1-based therapy use or timing.

Conclusion: In real-world settings, T-VEC may be used concurrently with or after anti-PD-1-based therapy.
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http://dx.doi.org/10.2217/mmt-2020-0005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426742PMC
June 2020

Angiogenic and Immune-Related Biomarkers and Outcomes Following Axitinib/Pembrolizumab Treatment in Patients with Advanced Renal Cell Carcinoma.

Clin Cancer Res 2020 11 18;26(21):5598-5608. Epub 2020 Aug 18.

Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC.

Purpose: Combined axitinib/pembrolizumab is approved for advanced renal cell carcinoma (aRCC). This exploratory analysis examined associations between angiogenic and immune-related biomarkers and outcomes following axitinib/pembrolizumab treatment.

Patients And Methods: Prospectively defined retrospective correlative exploratory analyses tested biospecimens from 52 treatment-naïve patients receiving axitinib and pembrolizumab (starting doses 5 mg twice daily and 2 mg/kg respectively, every 3 weeks). Tumor tissue, serum, and whole blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and end of treatment (EOT) for blood-based samples. Clinical outcomes were objective response rate (ORR) and progression-free survival (PFS).

Results: Higher baseline tumor levels of CD8 showed a trend toward longer PFS (HR 0.4; = 0.091). Higher baseline serum levels of CXCL10 ( = 0.0197) and CEACAM1 ( = 0.085) showed a trend toward better ORR and longer PFS, respectively. Patients for whom IL6 was not detected at baseline had longer PFS versus patients for whom it was detected (HR 0.4; = 0.028). At C2D1 and/or EOT, mainly immune-related biomarkers showed any association with better outcomes. The genes ( = 0.084), ( = 0.064), and ( = 0.073) showed trending associations with ORR, and ( = 0.0145), ( = 0.0726), ( = 0.0666), (; = 0.0267), and ( = 0.0287) with PFS.

Conclusions: With combined axitinib/pembrolizumab treatment in patients with aRCC, mostly immune-related biomarkers are associated with better treatment outcomes. This exploratory analysis has identified some candidate biomarkers to consider in future prospective testing.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1408DOI Listing
November 2020

Association of BRAF V600E/K Mutation Status and Prior BRAF/MEK Inhibition With Pembrolizumab Outcomes in Advanced Melanoma: Pooled Analysis of 3 Clinical Trials.

JAMA Oncol 2020 08;6(8):1256-1264

The Angeles Clinic and Research Institute, Los Angeles, California.

Importance: The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAF V600E/K-mutant melanoma is not well established.

Objective: To assess the association of BRAF wild-type (WT) or BRAF V600E/K-mutant status and BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy with response to pembrolizumab.

Design, Setting, And Participants: This study is a post hoc subgroup analysis of pooled data from 3 multinational, multisite studies: KEYNOTE-001 (data cutoff September 1, 2017), KEYNOTE-002 (data cutoff May 30, 2018), and KEYNOTE-006 (data cutoff December 4, 2017). Patients included in this analysis were adults with advanced melanoma and known BRAF V600E/K tumor status who had received pembrolizumab.

Interventions: Patients received pembrolizumab in dosages of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks.

Main Outcomes And Measures: End points were objective response rate (ORR) and progression-free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival (OS). Objective response rates, 4-year PFS, and OS rates were compared in the following patient subgroups: BRAF WT vs BRAF V600E/K-mutant melanoma and BRAF V600E/K-mutant melanoma with vs without previous treatment with BRAFi with or without MEKi therapy.

Results: The overall study population (N = 1558) included 944 men (60.6%) and 614 women (39.4%). The mean (SD) age was 60.0 years (14.0). The ORR was 38.3% (596/1558), 4-year PFS rate was 22.0%, and 4-year OS rate was 36.9%. For patients with BRAF WT (n = 1124) and BRAF V600E/K-mutant melanoma (n = 434), ORR was 39.8% (n = 447) and 34.3% (n = 149), 4-year PFS rate was 22.9% and 19.8%, and 4-year OS rate was 37.5% and 35.1%, respectively. Patients with BRAF V600E/K-mutant melanoma who had (n = 271) vs had not (n = 163) previously received BRAFi with or without MEKi therapy had baseline characteristics with worse prognosis; ORR was 28.4% (n = 77) and 44.2% (n = 72), 4-year PFS rate was 15.2% and 27.8%, and 4-year OS rate was 26.9% and 49.3%, respectively.

Conclusions And Relevance: Results of this subgroup analysis support the use of pembrolizumab for treatment of advanced melanoma regardless of BRAF V600E/K mutation status or receipt of prior BRAFi with or without MEKi therapy.
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http://dx.doi.org/10.1001/jamaoncol.2020.2288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366279PMC
August 2020

Ipilimumab plus nivolumab for patients with metastatic uveal melanoma: a multicenter, retrospective study.

J Immunother Cancer 2020 06;8(1)

Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York, USA.

Background: Uveal melanoma (UM) is the most common intraocular malignancy in adults. In contrast to cutaneous melanoma (CM), there is no standard therapy, and the efficacy and safety of dual checkpoint blockade with nivolumab and ipilimumab is not well defined.

Methods: We conducted a retrospective analysis of patients with metastatic UM (mUM) who received treatment with ipilimumab plus nivolumab across 14 academic medical centers. Toxicity was graded using National Cancer Institute Common Terminology Criteria for Adverse Events V.5.0. Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier methodology.

Results: 89 eligible patients were identified. 45% had received prior therapy, which included liver directed therapy (29%), immunotherapy (21%), targeted therapy (10%) and radiation (16%). Patients received a median 3 cycles of ipilimumab plus nivolumab. The median follow-up time was 9.2 months. Overall response rate was 11.6%. One patient achieved complete response (1%), 9 patients had partial response (10%), 21 patients had stable disease (24%) and 55 patients had progressive disease (62%). Median OS from treatment initiation was 15 months and median PFS was 2.7 months. Overall, 82 (92%) of patients discontinued treatment, 34 due to toxicity and 27 due to progressive disease. Common immune-related adverse events were colitis/diarrhea (32%), fatigue (23%), rash (21%) and transaminitis (21%).

Conclusions: Dual checkpoint inhibition yielded higher response rates than previous reports of single-agent immunotherapy in patients with mUM, but the efficacy is lower than in metastatic CM. The median OS of 15 months suggests that the rate of clinical benefit may be larger than the modest response rate.
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http://dx.doi.org/10.1136/jitc-2019-000331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319717PMC
June 2020

Rechallenge patients with immune checkpoint inhibitors following severe immune-related adverse events: review of the literature and suggested prophylactic strategy.

J Immunother Cancer 2020 06;8(1)

Centre Hospitalier Universitaire Vaudois (CHUV), Department of Medicine, Service of Immunology and Allergy, rue du Bugnon 46, CH-1011 Lausanne, Switzerland

Patients with cancer who developed severe, grade 3 or 4 immune-related adverse events (irAEs) during therapy with immune checkpoint inhibitors are at risk for developing severe toxicities again on rechallenge with checkpoint inhibitors. Consequently, medical oncologists and multidisciplinary teams are hesitant to retreat in this scenario, despite the fact that a number of patients may derive clinical benefit from this approach. Balancing such clinical benefit and treatment-related toxicities for each patient is becoming increasingly challenging as more and more patients with cancer are being treated with checkpoint inhibitors. In this manuscript, we provide an extensive overview of the relevant literature on retreatment after toxicity, and suggest prophylactic approaches to minimize the risk of severe irAE following rechallenge with immune checkpoint blockade, since treatment may be lifesaving in a number of occasions.
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http://dx.doi.org/10.1136/jitc-2020-000604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295425PMC
June 2020

Optimal Management of First-Line Advanced Renal Cell Carcinoma: Focus on Pembrolizumab.

Onco Targets Ther 2020 13;13:4021-4034. Epub 2020 May 13.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.

Renal cell carcinoma (RCC) is among the 10 most common cancers in the USA. One-third of the patients diagnosed with this cancer present with locally advanced or metastatic disease. In the past, advanced disease conferred poor survival outcomes; however, the treatment paradigm for RCC has been revolutionized twice since 2005. The initial wave of revolution came with the emergence of vascular endothelial growth factor (VEGF) inhibitors and a second wave arose more recently with the emergence and unprecedented success of checkpoint inhibitors in RCC. A third wave combining these two strategies is well underway and likely represents the new paradigm to improve survival outcomes for afflicted patients. In this review, we discuss the current treatment landscape for patients with advanced RCC, focusing on approved VEGF and checkpoint inhibitors in the first-line setting as well as highlighting landmark combination clinical trials.
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http://dx.doi.org/10.2147/OTT.S215173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231754PMC
May 2020

COVID-19 and Cancer: a Comprehensive Review.

Curr Oncol Rep 2020 05 8;22(5):53. Epub 2020 May 8.

Department of Medicine, Roswell Park Comprehensive Cancer Center, Elm and Carlton Street, Buffalo, NY, 14263, USA.

Purpose Of Review: The outbreak of the novel coronavirus disease 2019 (COVID-19) has emerged to be the biggest global health threat worldwide, which has now infected over 1.7 million people and claimed more than 100,000 lives around the world. Under these unprecedented circumstances, there are no well-established guidelines for cancer patients.

Recent Findings: The risk for serious disease and death in COVID-19 cases increases with advancing age and presence of comorbid health conditions. Since the emergence of the first case in Wuhan, China, in December 2019, tremendous research efforts have been underway to understand the mechanisms of infectivity and transmissibility of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a fatal virus responsible for abysmal survival outcomes. To minimize the mortality rate, it becomes prudent to identify symptoms promptly and employ treatments appropriately. Even though no cure has been established, multiple clinical trials are underway to determine the most optimal strategy. Managing cancer patients under these circumstances is rather challenging, given their vulnerable status and the aggressive nature of their underlying disease. In this comprehensive review, we discuss the impact of COVID-19 on health and the immune system of those affected, reviewing the latest treatment approaches and ongoing clinical trials. Additionally, we discuss challenges faced while treating cancer patients and propose potential approaches to manage this vulnerable population during this pandemic.
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http://dx.doi.org/10.1007/s11912-020-00934-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206576PMC
May 2020
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