Department of Medicine, Division of Solid Tumor Oncology

Malignant mesothelioma remains an uncommon malignancy of the pleura. Standard systemic therapy involves the use of pemetrexed and cisplatin. Recent results of a phase III, randomized clinical trial presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in June 2015 support the addition of bevacizumab to this regimen. The study showed that the addition of bevacizumab improved progression-free survival and overall survival in those without contraindications to vascular endothelial growth factor inhibitor therapy. Second-line therapies yield modest efficacy, but commonly used agents include vinorelbine and gemcitabine, largely based on small phase II trials prior to the first-line use of pemetrexed. Efforts are ongoing to improve systemic options in all lines of therapy. Based on the success in other disease, promising new drugs are being explored that target key aberrant pathways in mesothelioma. Additionally, the advent of immunotherapies has led to some exciting results in mesothelioma. Promising results from a phase IB study of the programmed cell death-1 inhibitor pembrolizumab were presented at the American Association for Cancer Research Annual Meeting in 2015. Moreover, results from a phase I study of live-attenuated bacterial vaccine engineered to express mesothelin (CRS-207) given in combination with standard chemotherapy were presented at the ASCO Annual Meeting in 2015. Furthermore, results from a large randomized trial of the cytotoxic T-lymphocyteassociated protein 4 inhibitor tremelimumab are imminent.

Malignant mesothelioma is an uncommon malignancy of the pleura that is usually associated with asbestos exposure. In the United States, there are approximately 3000 new cases annually, and the incidence continues to increase globally, particularly in locations where asbestos use continues.

While mesothelioma is capable of spreading to distant sites, it typically spreads locally within the chest, invading critical thoracic structures and causing respiratory distress and chest wall pain. While some patients, particularly those with epithelioid histology, can have an indolent disease course, median overall survival (OS) is poor, ranging from 9 to 15 months, depending on the stage at diagnosis.

Even with aggressive multimodality therapy for early-stage disease, the disease recurs and survival is short.

For recurrent disease or disease that cannot be resected, systemic therapies are the mainstay of treatment. However, only one US Food and Drug Administration chemotherapy regimen is approved for the treatment of mesothelioma. In the landmark EMPHACIS trial, 456 patients who were chemotherapy-na&iuml;ve with unresectable malignant pleural mesothelioma (MPM) were randomized to cisplatin or cisplatin and pemetrexed.

Response rate (RR), progression-free survival (PFS), and OS were all improved. Median OS improved to 12.1 months for the combination compared with 9.3 months with cisplatin alone. Several other phase III trials of cisplatin with and without antifolates have replicated these results (

Subsequent data support the use of carboplatin with pemetrexed in those unable to tolerate cisplatin.

In the expanded access program for pemetrexed, 861 patients who were chemotherapyna&iuml;ve received pemetrexed and carboplatin with a response rate of 21.7%.

A multicenter, phase II trial further evaluated the efficacy of pemetrexed and carboplatin and found that 19 patients (18.6%) achieved a response and 47% had stable disease.

Median OS was 12.7 months in this cohort. Another small phase II trial confirmed these results with a RR with pemetrexed and carboplatin of 25% among 76 treated patients and median OS was 14 months.

For patients who cannot receive pemetrexed, cisplatin in combination with gemcitabine is a viable option. In a multicenter trial of cisplatin and gemcitabine, partial responses were observed in 16% of 25 patients and median OS was 9.6 months. Similarly, another multicenter, phase II study of this combination demonstrated 17 partial responses among 57 previously untreated patients (33%) and 31 (60%) achieved stable disease.

Median OS in this study was 17.3 months. As with the combination of cisplatin and pemetrexed, carboplatin can be substituted for cisplatin in combination with gemcitabine based on a multicenter, phase II study in which 50 patients were treated with gemcitabine and carboplatin.

In that study, 26% of patients had partial responses and median PFS was 40 weeks.

Table 1. Studies of cisplatin with and without anti-folate therapy.

ITT indicates intention to treat; OS, overall survival; RR, response rate; TTP, time to progression.

Over the past 12 years, there have been no major advances with respect to first-line chemotherapy. However, at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, the results of a phase III, randomized, open-label trial were presented examining the impact of adding the vascular endothelial growth factor (VEGF) inhibitor bevacizumab to standard chemotherapy in patients with MPM.

The study enrolled 448 patients with unresectable MPM from 73 centers in France and these patients were randomized to receive cisplatin and pemetrexed or cisplatin, pemetrexed, and bevacizumab. In the intention to treat (ITT) analysis, median OS and median PFS were improved in the group that received bevacizumab, 18.8 months versus 16 months (

= .0127) and 9.6 months versus 7.5 months (

<.0001), respectively. There were, however, additional grade 3 and 4 toxicities among those who received bevacizumab, 71% versus 62% in the standard chemotherapy-alone group (

However, a previous multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine and cisplatin with bevacizumab or placebo in patients with mesothelioma did not find a benefit with the addition of bevacizumab.

In this trial with 108 evaluable patients, response rates were 24.5% and 21.8% (

= .74) for the bevacizumab and placebo arms, respectively. Median PFS and OS also did not demonstrate statistically significant differences. Additionally, a prior multicenter, phase II study of cisplatin, pemetrexed, and bevacizumab did not meet its primary endpoint of a 33% improvement in the PFS rate at 6 months compared with historical controls treated with cisplatin and pemetrexed alone.

Fifty-two evaluable patients who received pemetrexed, cisplatin, and bevacizumab had a PFS of 6.9 months, compared with 5.7 months in historical controls. Finally, a phase II, double-blind, placebocontrolled trial of pemetrexed/cisplatin with nintedanib, an inhibitor of VEGF 1-2, platelet-derived growth factor, and fibroblast growth factor receptor, has completed accrual and results are pending. In this study, 86 patients with unresectable MPM were randomized to either 6 cycles of pemetrexed and cisplatin with nintedanib followed by nintedanib maintenance or pemetrexed and cisplatin alone.

The primary endpoint of this trial is PFS with OS as a secondary endpoint.

While the available data are somewhat conflicting, the recent randomized, phase III clinical trial does demonstrate a survival benefit with the addition of bevacizumab to standard pemetrexed and cisplatin chemotherapy and thus justifies its addition to the National Comprehensive Cancer Network&rsquo;s Mesothelioma Guidelines. While there is a modest increase in associated toxicity, the addition of bevacizumab to first-line therapy should be considered in all patients without contraindications to VEGF-inhibitor therapy. Researchers hope that the pending results of the nintedanib study will confirm these findings.

Given its use as maintenance in non-small cell lung cancer, pemetrexed has also been explored in MPM. In one study, 13 of 27 patients who received induction therapy containing pemetrexed had no progression of disease and were eligible to continue pemetrexed until disease progression.

The median number of maintenance cycles received was 4 but ranged from 2 to 14. Therapy was well tolerated and, interestingly, 23% of patients with stable disease after induction therapy achieved a partial response during pemetrexed maintenance. Time to progression and OS were improved among those who received pemetrexed maintenance: 3.4 and 6.0 months versus 8.5 months and 17.9 months, respectively. A randomized, phase II trial of maintenance pemetrexed versus observation in patients with MPM is being conducted by the Alliance for Clinical Trials in Oncology (CALGB 30901) to address this question. In the meantime, until these results are available, it is reasonable to consider maintenance pemetrexed in a very select patient population.

Unfortunately, there is no proven benefit of secondline therapy. If patients had a good initial response and significant time has elapsed since initial treatment, there are data to support rechallenge with pemetrexed-based therapy from case reports, from the expanded access to pemetrexed program, and from a small observational study.

In the observational study, 31 patients were retreated with pemetrexed-based therapy and 19% achieved a partial response. The disease control rate was 48%.

Median PFS and OS were 3.8 months and 10.5 months, respectively. It was also noted that those who were retreated less than 12 months after their first-line pemetrexed-based therapy had a median PFS of 2.5 months as opposed to 5.5 months among those who had not received pemetrexed-based therapy in more than 12 months. These findings are corroborated by the report from the expanded access program for pemetrexed in mesothelioma.

Other options include vinorelbine and gemcitabine based on first-line data and other small trials. In an open-label, phase II trial among 63 patients who were pemetrexed na&iuml;ve, there was a 16% response rate with vinorelbine, but more than 50% of these patients also experienced severe toxicity.

Also, in an exploratory subgroup analysis of a firstline multicenter, randomized trial comparing active symptom control plus chemotherapy with mitomycin, vinblastine, and cisplatin or weekly vinorelbine, there was a suggestion of a survival advantage with weekly vinorelbine.

One retrospective study examined the efficacy of vinorelbine in 59 patients with MPM who had previously received pemetrexedbased chemotherapy and found a RR of 15% and median PFS of 2.3 months.

The addition of bevacizumab to standard first-line pemetrexed-based therapy should be considered in patients without contraindication to VEGF inhibitor therapy.

Second-line therapies are limited, but vinorelbine and gemcitabine are the most commonly used agents with the most robust data.

Whenever possible, patients should be enrolled in clinical trials for this rare and almost universally lethal disease.

Gemcitabine&rsquo;s efficacy in MPM was initially demonstrated in a phase II screening of drugs; 27 patients who were chemotherapy na&iuml;ve received weekly gemcitabine and there was a RR of 7% and median OS was 8 months.

Additional analysis of the poststudy treatment of patients who participated in the EMPHACIS trial identified gemcitabine as the most commonly used agent.

In a CALGB phase II trial, 17 patients who were chemotherapy na&iuml;ve received gemcitabine. While there were no complete or partial responses, median OS was 4.7 months.

However, the efficacy of these agents was not confirmed in a recent retrospective analysis of the Memorial Sloan Kettering Cancer Center experience.

Among 56 patients treated with vinorelbine or gemcitabine after pemetrexed-based therapy, only one patient had a partial response to treatment. However, 46% did achieve stable disease. While these data certainly support the use of vinorelbine and gemcitabine as second-line and beyond therapies, their efficacy is modest at best and, whenever possible, patients should be treated on clinical trials.

Because of the rarity of this disease and the nihilism about outcomes, clinical research in this area has historically been challenging. It was long believed that large, randomized, clinical trials would be difficult to execute and take many years to complete. Consequently, there was a lack of interest from pharmaceutical companies and funding agencies to support studies in this orphan disease. Yet, the recent brisk accrual to several large multinational studies has debunked this belief, and interest has exploded in pursuing clinical trials to explore novel agents against a wide range of targets in mesothelioma.

One way to try to break past the current therapeutic plateau is to improve our understanding of the biology of this disease so that it can be exploited with novel agents, an approach that has been successful in other malignancies. That work is ongoing in mesothelioma and is being translated into clinical trials with several novel agents that have strong biologic rationale, such and phosphatidylinositol-3 kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, focal adhesion kinase (FAK) inhibitors, mesothelin-directed therapies, and other small molecules that target commonly aberrant pathways (

). Additionally, the advent of immunotherapy has brought some exciting preliminary results to mesothelioma research and further investigations are ongoing (

). At the American Association for Cancer Research Annual Meeting in 2015, results from a phase IB study of pembrolizumab demonstrated that this PD-1 inhibitor was safe and tolerable for patients with MPM.

A disease control rate of 76% among 25 patients with MPM was achieved. At the ASCO Annual Meeting in 2015, results were presented from a single-arm study of vaccination with live-attenuated Listeria monocytogenes engineered to express mesothelin in combination with pemetrexed and cisplatin in patients who were chemotherapy na&iuml;ve. Not only was the combination safe, but an amazing disease control rate of 92% was achieved.

A large, randomized, phase II trial of the cytotoxic T-lymphocyte-associated protein--4 (CTLA- 4) inhibitor tremelimumab versus placebo recently completed accrual and results are imminent. Clearly, additional studies are needed but this represents a promising new avenue for advances.

Table 2. Partial List of Ongoing Trials in MPM With Novel Agents and Immunotherapies

Anti-PD-1 indicates anti-programmed cell death 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FGFR, fibroblast growth factor receptor; FAK, focal adhesion kinase; pem/cis, pemetrexed and cisplatin; PDGFR, platelet-derived growth factor receptor; PI3K/mTOR, phosphatidylinositol-3 kinase/mammalian target of rapamycin inhibitors; TNF&alpha;, tumor necrosis factor &alpha;; VEGF, vascular endothelial growth factor.

The current treatment options for mesothelioma are limited and advances have been slow and incremental. However, many new drugs and novel approaches are being investigated. Therefore, whenever possible, patients should be treated in clinical trials. Yet, with the abundance of ongoing studies, vigilance is needed to design trials that have a strong biologic rationale and the greatest potential for meaningful clinical impact. This is the only way the bar of therapy in this almost universally lethal disease will be raised.

Price B, Ware A. Mesothelioma trends in the United States: an update based on Surveillance, Epidemiology, and End Results Program data for 1973 through 2003.

Zellos L, Christiani DC. Epidemiology, biologic behavior, and natural history of mesothelioma.

Vogelzang NJ, Rusthoven JJ, Symanowski J, et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.

Castagneto B, Botta M, Aitini E, et al. Phase II study of pemetrexed in combination with carboplatin in patients with malignant pleural mesothelioma (MPM).

Ceresoli GL, Zucali PA, Favaretto AG, et al. Phase II study of pemetrexed plus carboplatin in malignant pleural mesothelioma.

Santoro A, O&rsquo;Brien ME, Stahel RA, et al. Pemetrexed plus cisplatin or pemetrexed plus carboplatin for chemonaive patients with malignant pleural mesothelioma: results of the International Expanded Access Program.

Nowak AK, Byrne MJ, Williamson R, et al. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma.

Favaretto AG, Aversa SM, Paccagnella A, et al. Gemcitabine combined with carboplatin in patients with malignant pleural mesothelioma: a multicentric phase II study.

Zalcman G, Mazieres J, Margery J. Bevacizumab 15 mg/kg plus cisplatin-pemetrexed (CP) triplet versus CP doublet in malignant pleural mesothelioma (MPM): Results of the IFCT-GFPC-0701 MAPS randomized phase 3 trial.

Kindler HL, Karrison TG, Gandara DR, et al. Multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab or placebo in patients with malignant mesothelioma.

Dowell JE, Dunphy FR, Taub RN, et al. A multicenter phase II study of cisplatin, pemetrexed, and bevacizumab in patients with advanced malignant mesothelioma.

Scagliotti GV, Leighl NB, Nowak A, et al. Nintedanib plus pemetrexed/ cisplatin followed by maintenance nintedanib for unresectable malignant pleural mesothelioma (MPM): An international, multicenter, randomized, double-blind, placebo-controlled phase II study.

. van den Bogaert DP, Pouw EM, van Wijhe G, et al. Pemetrexed maintenance therapy in patients with malignant pleural mesothelioma.

Ceresoli GL, Zucali PA, De Vincenzo F, et al. Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural mesothelioma.

Razak AR, Chatten KJ, Hughes AN. Retreatment with pemetrexed-based chemotherapy in malignant pleural mesothelioma (MPM): a second line treatment option.

Taylor P, Castagneto B, Dark G, et al. Single-agent pemetrexed for chemonaive and pretreated patients with malignant pleural mesothelioma: results of an International Expanded Access Program.

Stebbing J, Powles T, McPherson K, et al. The efficacy and safety of weekly vinorelbine in relapsed malignant pleural mesothelioma.

Muers MF, Stephens RJ, Fisher P, et al. Active symptom control with or without chemotherapy in the treatment of patients with malignant pleural mesothelioma (MS01): a multicentre randomised trial.

Zucali PA, Perrino M, Lorenzi E, et al. Vinorelbine in pemetrexedpretreated patients with malignant pleural mesothelioma.

van Meerbeeck JP, Baas P, Debruyne C, et al. A phase II study of gemcitabine in patients with malignant pleural mesothelioma. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

Manegold C, Symanowski J, Gatzemeier U, et al. Second-line (poststudy) chemotherapy received by patients treated in the phase III trial of pemetrexed plus cisplatin versus cisplatin alone in malignant pleural mesothelioma.

. Kindler HL, Millard F, Herndon JE 2nd, Vogelzang NJ, Suzuki Y, Green MR. Gemcitabine for malignant mesothelioma: a phase II trial by the Cancer and Leukemia Group B.

Zauderer MG, Kass SL, Woo K, Sima CS, Ginsberg MS, Krug LM. Vinorelbine and gemcitabine as second- or third-line therapy for malignant pleural mesothelioma.

Alley EW, Molife LR, Santoro A, et al. Clinical safety and efficacy of pembrolizumab (MK-3475) in patients with malignant pleural mesothelioma: Preliminary results from KEYNOTE-028.

Hassan R, Antonia SJ, Alley EW, et al. Mesothelin-targeted immunotherapy CRS-207 in combination with standard of care chemotherapy as treatment for malignant pleural mesothelioma (MPM).

van Meerbeeck JP, Gaafar R, Manegold C, et al. Randomized phase III study of cisplatin with or without raltitrexed in patients with malignant pleural mesothelioma: an intergroup study of the European Organisation for Research and Treatment of Cancer Lung Cancer Group and the National Cancer Institute of Canada.

Articles

Clinical Articles

Malignant mesothelioma is an uncommon malignancy of the pleura that is usually associated with asbestos exposure. 

Current Systemic Management of Pleural Malignant Mesothelioma

Therapy that targets angiogenesis has been extensively investigated in differentiated thyroid cancer (DTC) and has demonstrated significant antitumor activity. Lenvatinib is a vascular endothelial growth factor receptor (VEGFR)-targeting tyrosine kinase inhibitor (TKI) approved by the US Food and Drug Administration (FDA) for radioactive iodine-refractory metastatic DTC. It has shown marked progression-free survival (PFS) benefit in a phase III study (18.3 vs 3.6 months, HR, 0.21; 99% CI, 0.14-0.31; P <.001). The benefit was also evident in patients who were previously treated with VEGFR-targeting kinase inhibitors. Common toxicities of lenvatinib include hypertension (any grade, 69.3%; grade &ge;3, 42.9%), diarrhea (any grade, 59.4%; grade &ge;3, 41.8%), fatigue or asthenia (any grade, 59%; grade &ge;3, 27.5%), decreased weight (any grade, 46.4 %; grade &ge;3, 9.2%), nausea (any grade, 41%; grade &ge;3, 13.7%), and proteinuria (any grade, 32.2%; grade &ge;3, 10.0%). Data for quality of life (QoL) were not collected in this study, although frequent treatment interruption (82.4%) and dose reduction (67.8%) because of toxicities were observed, suggesting that the decision to initiate treatment should be made carefully to preserve QoL.

Differentiated thyroid cancer (DTC) has an excellent prognosis in general, but patients with radioactive iodine-refractory metastatic DTC have a significantly lower 10-year survival.

Because conventional cytotoxic chemotherapy has poor tolerability and low activity, it is rarely used. With advances in the understanding of molecular pathogenesis of DTC, angiogenesis has been identified as an attractive target for therapeutic development in DTC. Sorafenib, a small molecule kinase inhibitor targeting

, was approved by the FDA for patients with metastatic DTC in November 2013.

Thyroid cancer is the most common endocrine malignancy, with an estimated 62,450 new cases and 1950 deaths in 2015.

Thyroid cancers may originate from either follicular cells, which give rise to differentiated or anaplastic thyroid cancers, or from calcitonin-producing C or parafollicular cells, which give rise to medullary thyroid carcinoma (MTC). Differentiated thyroid cancers are divided into two main histology types, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), accounting for about 90% of all thyroid cancers. For DTC, cure can be achieved after surgical resection with or without radioactive iodine ablation (

I-RAI) and thyroidstimulating hormone (TSH) suppression. The 5-year overall survival rate of patients with thyroid cancer is 97.9%.

I-RAI-refractory DTC have a significantly worse prognosis, with a 5-year survival of less than 50%.

For this subset of patients, doxorubicin is the only FDA approved cytotoxic chemotherapy, although it is rarely used because of poor tolerability and low efficacy, with response rates around 25% or less.

In recent years, understanding the molecular pathogenesis of DTC has led to advances in therapy and to regulatory approval of new therapeutic agents for radioactive iodine-refractory metastatic DTC. The key oncogenic genetic alterations in DTC include BRAF (35%-70% in PTC, rarely in FTC), RAS (15%-20% in PTC and 40%-50% in conventional-type FTC), RET/ PTC rearrangement (10%-20% in adult sporadic PTC, 50%-80% in patients with PTC with a history of radiation exposure, and 4%-70% in PTC of children and young adults), and

rearrangement (30%- 40% in conventional-type FTC).

In addition to molecular alterations, tumor angiogenesis supporting tumor cell growth and metastasis represents another critical target in DTC therapeutic development.

The VEGF family comprises seven glycoproteins (VEGF A-E and placental growth factor [PlGF-1 and -2]) and three tyrosine kinase receptors (VEGFR- 1-3).

The interactions of VEGFs with their receptors activate downstream signaling, which results in the release of angiogenic factors, exerting pro-angiogenic effects. Among all VEGFRs, VEGFR2 is considered the main mediator of the angiogenic effects of VEGF.

In addition to VEGF, other pathwayssuch as platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) and fibroblast growth factor (FGF) and FGF receptor (FGFR) pathways&mdash;have been found to contribute to tumor angiogenesis and may potentially provide escape mechanisms from anti-VEGF/ VEGFR therapy.

Increased vascularity has been reported in thyroid cancer, and the activity of VEGF/ VEGFR has been found to be associated with disease recurrence and metastasis.

VEGF-targeted therapeutics, including sorafenib, sunitinib, axitinib, pazopanib, vadentinib, lenvatinib, and motesanib, have been extensively tested in preclinical and clinical settings, with various levels of activity.

gene rearrangements are one of the most frequent genetic alterations in PTC. It is particularly common in PTC associated with ionizing radiation exposure

Various RET translocation partners have been identified. Through the translocations, the promoters and Nterminal domain coding region of unrelated gene(s) are linked with the RET tyrosine kinase coding region, leading to constitutively active RET tyrosine kinase, the signaling subunit of a receptor complex for ligands of the glial-cell-line-derived neurotrophic factor (GDNF).

Overexpression of RET/PTC can lead to transformation of thyroid cells in transgenic mice.

Figure 1. Structure of lenvatinib and VEGFR2 complex. A: overall structure of the complex. B: binding pocket of VEGFR2 complex.

Reprinted and adapted with permission from &ldquo;Distinct Binding Mode of Multikinase Inhibitor Lenvatinib Revealed by Biochemical Characterization&rdquo; by Okamoto K, et al. ACS Med Chem Lett. Jan 1, 201541 with permission from the American Chemical Society.

Lenvatinib (previously E7080) is an oral multikinase inhibitor that selectively inhibits VEGFR 1-3 and other angiogenic pathway receptor tyrosine kinases, including FGFR 1-4 and PDGFR, as well as oncogenic tyrosine kinases KIT and RET.

Cocrystal structure analyses demonstrated that lenvatinib interacts with both the ATP binding site and the neighboring allosteric region of VEGFR2 in DFG-in conformation (

Lenvatinib potently inhibits VEGFR3 and VEGFR2 kinase activities with a half maximal inhibitory concentration (IC

) of 5.2 nmol/L and 4.0 nmol/L, respectively, and inhibits VEGFR1, FGFR1, and PDGF-R&beta; kinases with a four times to ten times lower activity.

Lenvatinib inhibits RET kinase with Ki values of 1.5 nmol/L in cell-free kinase assays.

Lenvatinib demonstrated antitumor activity in preclinical human thyroid cancer models, mainly through angiogenesis inhibition, although inhibition in RET and FGFR may also contribute to its antitumor activity.

Lenvatinib was evaluated in an 82-patient phase I study of advanced refractory solid tumors. Doselimiting toxicities (DLTs) were found to be grade 3 proteinuria at the dose of 32 mg; 25 mg once daily was determined as the maximally tolerated dose (MTD) in this study.

Of note, although two patients developed DLT of grade 3 proteinuria at the dose of 12.5 mg, the decision was made to continue dose escalation. The most frequently observed cumulative toxicities of all grades were hypertension (40%), diarrhea (45%), nausea (37%), stomatitis (32%), and vomiting (23%). Seven patients (9%) had a partial response (PR), and 38 patients (46%) had stable disease as best response. Confirmed PRs were observed in patients diagnosed with renal cell carcinoma, melanoma, and soft tissue sarcoma. In this study, maximum concentration (C

) was achieved within 3 hours, and the median half-life (t

) was between 5.3 and 8.3 hours. No effect of food on exposure or maximum achieved plasma concentrations were observed, but a significant shift of t

from 2 hours in the fasted group to 5 hours in the fed group was observed.

Researchers also found that lenvatinib had no clinically relevant effect on the QTc interval in healthy volunteers.

In another phase I study, E7080 was administered twice daily with a 2-week-on/1-week-off schedule in 27 patients with advanced solid tumors.

DLTs of grade 3 elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT) (in one patient at the 16-mg dose level) and grade 3 platelet count decrease (in two patients at the 20-mg dose level) were reported. The MTD was eventually determined to be 13 mg twice a day after patients experienced poor tolerability at the 16-mg dose level. The most frequent AEs (&ge;50% of patients) included hematuria (74.1%), fatigue (70.4%), hypertension (66.7%), elevated AST (63.0%), headache (63.0%), proteinuria (63.0%), elevated ALT (55.5%), diarrhea (55.5%), and elevated lactate dehydrogenase (LDH) (51.9%). A durable PR was achieved in one patient with colon cancer. Stable disease was observed in 21 (84%) patients.

In a phase II study of 58 patients with radiative iodine-refractory DTC who had disease progression during the 12 months preceding enrollment, lenvatinib 24 mg once daily was given in 28-day cycles.

As the primary endpoint of the study, objective response rate (ORR) was found to be 50% (95% CI, 37%-63%). The median PFS was 12.6 months (95% CI, 9.9-16.1 months). Among these patients, 29 had prior VEGFR-targeted therapy, including sorafenib, sunitinib, axitinib, and motesanib; 14% of patients received prior anthracycline therapy. No significant ORR difference was detected between VEGFR-targeted therapy treatment-naive and treated patients (46% vs 59%). ORR among patients who received prior sorafenib treatment (14 patients) was 71%.

All patients experienced treatment-related AEs, with the most frequent being hypertension (76%), weight decrease (69%), diarrhea (67%), proteinuria (64%), fatigue (60%), decreased appetite (52%), and nausea (50%). Grade 3 or 4 treatment-related toxicities occurred in 42 patients (72%). Six grade 4 treatment-related AEs were reported, including hypocalcemia, hyperkalemia, abasia, and acute myocardial infarction. Most common grade 3 treatment-related AEs were weight loss (12%), hypertension, proteinuria (10%), diarrhea (10%), fatigue (9%), dehydration (9%), and arthralgia (5%).  Seventy-four percent of patients underwent dose interruptions, 66% of patients required dose reduction, and 26% of patients discontinued treatment because of treatment-related AEs.

Based on the encouraging results of the phase II study, a randomized, double-blind, placebo-controlled, multicenter international phase III study (SELECT) was carried out from August 2011 through October 2012 in 392 patients.

In this study, crossing over from placebo to the lenvatinib arm was allowed upon disease progression. To be enrolled, the patient had to have: at least one measurable lesion without iodine uptake on any RAI scan; or at least one measurable lesion that had progressed within 12 months after RAI therapy; or cumulative activity of iodine-131 that was >600 mCi. Radiologic evidence of progression within the previous 13 months was required for enrollment. Twenty-five percent of patients on lenvatinib and 20.6% patients received one prior TKI. Lenvatinib was given at a daily dose of 24 mg to patients on the treatment arm. The study met its primary endpoint, with a significant median PFS benefit seen in the lenvatinib arm (18.3 vs 3.6 months; HR, 0.21; 99% CI, 0.14-0.31;

<.001) across all prespecified subgroups, including TKI-treated patients and TKI-na&iuml;ve patients (18.7 months and 15.1 months, respectively). Additionally, patient&rsquo;s

mutation status failed to predict PFS benefit associated with lenvatinib. Similar to the results of phase II study, a response rate of 64.8% was observed in the lenvatinib group, with complete responses occurring in 4 (1.5%) patients.

In this study, almost all patients on the lenvatinib arm (97.3%) reported treatment-related AEs, whereas treatment-related AEs were experienced by 59.5% patients in the placebo group. However, treatment duration of lenvatinib was significantly longer than placebo (298.8 vs 67.1 person-years), which may have contributed to the more frequent AEs observed with lenvatinib.

Most patients (75.9%) on the lenvatinib arm reported grade 3 or higher treatmentrelated AEs, versus 9.9% in the placebo group. Frequent treatment-related AEs included hypertension (any grade, 69.3%; grade &ge;3, 42.9%), diarrhea (any grade, 59.4%; grade &ge;3, 41.8%), fatigue or asthenia (any grade, 59%; grade &ge;3, 27.5%), decreased weight (any grade, 46.4%; grade &ge;3, 9.2%), nausea (any grade, 41%; grade &ge;3, 13.7%), proteinuria (any grade, 32.2%; grade &ge;3, 10%), arterial thromboembolic effects (any grade, 5.4%; grade &ge;3, 2.7%), and venous thromboembolic effects (any grade, 5.4%; grade &ge;3, 3.8%). Six deaths (2.3%) that occurred on the lenvatinib arm were deemed to be treatment related. The direct causes of these deaths included pulmonary embolism, hemorrhagic stroke, and general deterioration of physical health, one in each case, but no specific causes of death in the other three patients were reported. Treatment discontinuation, dose reduction, and treatment interruption occurred in 14.2%, 82.4%, and 67.8% patients in the lenvatinib group, respectively. The mean lenvatinib dose was 17.2 mg per day.

Lenvatinib demonstrated significant antitumor activity in radioactive iodine-refractory DTC with a marked PFS benefit when compared with placebo. The activity is observed in both angiogenesis-targeting kinase inhibitor treatment-na&iuml;ve patients and treated patients.

Frequent toxicities include hypertension, diarrhea, fatigue or asthenia, decreased weight, nausea, and proteinuria; therefore, close monitoring of, and adequate management of, side effects are important for patients receiving this agent.

Since DTC often has a relatively indolent disease course, treatment should only be offered to patients with clinically significant disease to preserve QoL.

Efficacy and Tolerability of Lenvatinib and Sorafenib for Radioactive Iodine-Refractory DTC

Sorafenib, an oral small molecule kinase inhibitor that inhibits C-RAF, BRAF, RET, c-KIT, PDGF-R, and VEGFR 1-3, was approved by FDA in November 2013 for the treatment of patients with metastatic DTC based on the data from the phase III DECISION study.

Based on the SELECT study, the FDA approved lenvatinib for patients with radioactive iodine-refractory progressive DTC, which makes this agent the second FDA approved TKI for this disease.

Both the SELECT and DECISION studies have demonstrated improved PFS compared with placebo groups, as well as significant toxicities as evidenced by the frequent dose modifications and interruptions (

). Although no definitive conclusion can be drawn from interstudy comparison, the efficacy data from these two studies suggested a significantly higher PFS and response rate (RR) of lenvatinib. Quality of life was evaluated in the DECISION study, and a slight decrease of QoL was reported at the 2013 annual meeting of the American Thyroid Association.

Unfortunately, no QoL data are available in the SELECT study. Nevertheless, the data of lenvatinib-related toxicity suggest that treatment should only be offered to patients with clinically significant disease.

Table 1. Efficacy of Lenvatinib and Sorafenib in DTC

PFS indicates progression-free survival; OS, overall survival; RR, relative risk; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

The TKI lenvatinib targets multiple kinases, including VEGFR with low IC.

It has demonstrated marked antitumor activity in radioactive iodine-refractory DTC, with impressive improvement across all efficacy parameters in comparison with placebo. Lenvatinib has also demonstrated activities in patients who had previously received VEGFR targeting agents. It appears to be significantly more active than sorafenib; however, both are associated with frequent treatment-related toxicities leading to dose interruption and reduction. Quality of life data of lenvatinib are lacking, although a slight reduction of QoL associated with sorafenib has been reported in patients with thyroid cancer. Thus, the decision of when to initiate treatment for this group of patients must be made carefully, and treatment should be reserved for patients with clinically significant disease, such as those with substantial disease burden, rapidly growing disease or symptomatic disease, to preserve QoL. Although inhibition of angiogenesis has achieved significant success in the treatment of this disease, treatment options for patients whose disease no longer responds to VEGF targeting agents remain to be investigated.

Table 2. Tolerability of Lenvatinib and Sorafenib in DTC

AE indicates adverse effect; HTN, hypertension.

Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy.

Klein M, Vignaud JM, Hennequin V, et al. Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma.

Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodinerefractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial.

SEER (Surveillance Research Program). SEER Stat Fact Sheets: Thyroid Cancer. May 24, 2015. http://seer.cancer.gov/statfacts/html/thyro. html. Accessed August 10, 2015.

. Devita VT, Rosenberg SA, Depinho RA, Weinberg RA.

Devita, Hellman, and Rosenberg&rsquo;s Cancer: Principles and Practice of Oncology

. Ninth ed. Treatment of Well and Intermediately Differentiated Thyroid Carcinoma. March 16, 2011.

Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments].

Shaha AR, Shah JP, Loree TR. Differentiated thyroid cancer presenting initially with distant metastasis.

Argiris A, Agarwala SS, Karamouzis MV, et al. A phase II trial of doxorubicin and interferon alpha 2b in advanced, non-medullary thyroid cancer.

Sherman SI. Cytotoxic chemotherapy for differentiated thyroid carcinoma.

Woyach JA, Shah MH. New therapeutic advances in the management of progressive thyroid cancer.

Nikiforov YE. Molecular analysis of thyroid tumors.

Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors.

Zhao Y, Adjei AA. Targeting angiogenesis in cancer therapy: moving beyond vascular endothelial growth factor.

Zhou ZH, Cui XN, Xing HG, et al. Changes and prognostic value of serum vascular endothelial growth factor in patients with differentiated thyroid cancer.

Karaca Z, Tanriverdi F, Unluhizarci K, et al. VEGFR1 expression is related to lymph node metastasis and serum VEGF may be a marker of progression in the follow-up of patients with differentiated thyroid carcinoma.

Klubo-Gwiezdzinska J, Junik R, Kopczynska E, et al. The comparison of serum vascular endothelial growth factor levels between patients with metastatic and non-metastatic thyroid cancer, and patients with nontoxic multinodular goiter.

Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer.

Therapy that targets angiogenesis has been extensively investigated in differentiated thyroid cancer (DTC) and has demonstrated significant antitumor activity.

Levantinib in the Management of Differentiated Thyroid Cancer

Recent therapeutic advances have almost doubled the survival of patients with metastatic pancreatic cancer, and the availability of highly active chemotherapy regimens is making personalized medicine a reality. The role of chemoradiation following induction chemotherapy in locally advanced, unresectable pancreatic cancer was clarified by the LAP 07 study. A major development has been the identification of the group of patients with resectable disease who have a high risk of margin-positive resection (borderline resectable). The use of neoadjuvant therapy in this group has many potential advantages and is currently under active clinical investigation. Tools available for treating pancreatic cancer have certainly multiplied and improved over last few decades, but the long-term survival rate is still dismal; as such, novel treatments and approaches are still urgently needed, and palliative/supportive care is equally important to improve the lives of patients with pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States.

The survival for metastatic disease has doubled over the last 2 decades, though at the expense of increased adverse events (AEs), and the 2-year survival remains approximately 10%.

The advances over the last few years, albeit small compared with other cancers, have provided several more options for patients with pancreatic cancer.

Many anticancer drugs including molecularly targeted agents have been evaluated in randomized trials since the approval of gemcitabine in advanced pancreatic cancer. A major milestone was reported by Conroy et al in the PRODIGE4/ACCORD11 trial that randomized 342 patients with chemotherapyna&iuml;ve metastatic pancreatic cancer to FOLFIRINOX or gemcitabine.

The FOLFIRINOX regimen consisted of oxaliplatin 85 mg/m

as a 46-hour continuous infusion every 2 weeks. Pertinent eligibility criteria included ECOG performance status (PS) 0 or 1 and bilirubin less than or equal to the upper limit of normal range. Patients aged 76 years or older were excluded. The FOLFIRINOX arm achieved a superior median overall survival (OS) of 11.1 months versus 6.8 months in the gemcitabine arm (HR, 0.57;

<.001). The OS of the FOLFIRINOX group at 6, 12, and 18 months were 75.9%, 48.4%, and 18.6% respectively, compared with 57.6%, 20.6%, and 6.0% respectively in the gemcitabine group. The objective response rates were 31% versus 9.4% in the FOLFIRINOX and gemcitabine arms respectively.

The regimen is now a standard for metastatic disease in the first-line setting, though the higher frequency of toxicities such as neutropenia, febrile neutropenia, fatigue, and diarrhea have required dose modification for better quality of life (QoL). Despite the increased toxicity associated with FOLFIRINOX, a follow-up QoL analysis of the ACCORD11 trial showed that the FOLFIRINOX arm had improvement in global health status (GHS) by the European Organization for Research and Treatment of Cancer (EORTC) QoL Questionnaire C30 method, and had longer time to definitive deterioration &ge;20 points than the gemcitabine arm.

The domains that showed improvement included GHS, functioning (physical, cognitive, and social), fatigue, nausea/vomiting, pain, dyspnea, anorexia, and constipation. A single-institution retrospective report of real-world experience showed that dose reduction occurred in >80% of patients during the first cycle: irinotecan was reduced/omitted in 80%, oxaliplatin in 28%, bolus fluorouracil in 45%, and infusional fluorouracil in 8%.

The analysis showed that comparable efficacy to the PRODIGE

trial was achieved with the ACCORD11 trial even with dose attenuation. In terms of health economics, an analysis by the Ontario health system in Canada showed that FOLFIRINOX was the most cost-effective option for quality life-year gain compared with gemcitabine/capecitabine, gemcitabine/erlotinib, and gemcitabine in patients with metastatic pancreatic cancer.

As such, this regimen is recommended as a first-line option for younger and fit patients with adequate hepatic and other organ reserves, and modification to the published regimen is generally used and accepted to avoid compromising the expected efficacy.

Another milestone soon followed, with the positive results from the Metastatic Pancreatic Adenocarcinoma Trial (MPACT), that randomized 861 patients with metastatic pancreatic cancer to receive nabpaclitaxel plus gemcitabine or gemcitabine.

Nabpaclitaxel is an albumin-bound paclitaxel, which is advantageous in lieu of the Cremaphor formulation of paclitaxel and has significantly lower risk for infusion reactions, and neutropenia, while offering more rapid recovery of neuropathy upon halting the therapy.

In an updated analysis, the median OS for the nabpaclitaxel/gemcitabine arm was 8.7 months versus 6.6 months (HR, 0.72; P <.001).

At 36 months, 4% of patients in the study arm were alive compared with none in the gemcitabine arm. The addition of nab-paclitaxel tripled the response rate, with 23% versus 7% (P <.001) in the study and control arms, respectively. The regimen was well tolerated, and the most common grade 3 and above AEs in the study arm were neutropenia, fatigue, and neuropathy. When compared with FOLFIRINOX, Conroy et al reported that the frequency of neutropenia, febrile neutropenia, diarrhea, and fatigue were lower for nab-paclitaxel/gemcitabine, although the risk for thrombocytopenia and neuropathy were higher for nab-paclitaxel/gemcitabine. The nab-paclitaxelrelated neuropathy improved from grade 3 or higher to grade 1 or lower in a median of 29 days upon discontinuation, which potentially allows re-introduction of nab-paclitaxel in a real-world scenario; whereas, neuropathy related to oxaliplatin may be typically prolonged, and a long recovery interval is needed before reintroduction of the therapy in patients treated with FOLFIRINOX.

The MPACT trial enrolled patients with Karnofsky performance-status score 70 or better which, when compared with the ACCORD11 trial that enrolled ECOG performance status 0 to 1, included patients with better ECOG PS 2. The ACCORD11 trial excluded patients age 76 years or older whereas the MPACT trial included patients up to ages 88 years, though the median age was comparable between both. The MPACT trial excluded patients with bilirubin level above the upper limit of normal (ULN) whereas the ACCORD11 trial included patients with higher bilirubin level (1.5 times ULN). Together with the difference in the toxicity profile between both regimens, these factors can help oncologists to personalize their recommendation for patients in the first-line metastatic pancreatic cancer setting.

The availability of two active regimens now offers meaningful options for patients who progress, or become intolerant to first-line treatment. Prior to the ACCORD11 trial, patients who failed first-line gemcitabinecontaining therapy received fluoropyrimidine-based regimens, typically those containing oxaliplatin.

Several retrospective studies showed that FOLFIRINOX was efficacious in second-line setting after failure of gemcitabine-based therapy, with an acceptable safety profile.

Conversely, patients who progressed on FOLFIRINOX in the first-line setting may receive gemcitabine alone or gemcitabinebased combination, provided they have good performance status in the second-line setting. The efficacy of nab-paclitaxel/gemcitabine in the second-line setting and beyond was reported in a single-institution restrospective study.

However, the appropriate sequencing of these regimens in first- and second-line settings to maximize survival has yet to be investigated clinically, and the decisions are currently based on patient&rsquo;s performance status, organ reserves, and preferences. Several randomized trials specifically for the second-line setting and beyond seemed to be promising, including an on-going trial using ruxolitinib (JAK1/2 inhibitor; [NCT02117479, NCT02119663]) and another using nano-liposal irinotecan (MM398; NAPOLI trial)

The management of locally advanced unresectable pancreatic cancer has been similar to metastatic disease with certain extrapolations from that of metastatic disease. The main difference has been the use of chemoradiation in the locally advanced setting, which the role was investigated in several recently reported randomized trials. The LAP 07 trial investigated the use of chemoradiation after an initial systemic chemotherapy, and the results was reported at the ASCO Annual Meeting in 2013.

In this international phase III trial, 442 patients with locally advanced pancreatic cancer started treatment by receiving 4 months of systemic chemotherapy (gemcitabine or gemcitabine/erlotinib), and those who did not progress (269 patients) were then randomized to receive chemoradiation with capecitabine or to continue another 2 months of systemic chemotherapy. The planned interim analysis showed that the median OS achieved in the systemic chemotherapy and chemoradiation arms were 16.5 months versus 15.3 months (HR, 1.03; P = .83), concluding that chemoradiation was not superior to continuing systemic chemotherapy in patients who did not progress after an initial 4 months of systemic chemotherapy.

The role of upfront chemoradiation was investigated in two randomized trials. The ECOG 4201 trial randomized 74 patients with locally advanced pancreatic cancer to systemic gemcitabine therapy and chemoradiation with gemcitabine.

The trial was terminated early due to poor accrual though an intention-to-treat analysis showed a trend toward better survival in the chemoradiation arm of 11.1 months versus 9.2 months in the chemotherapy arm (

= .017). The 2000-01 FFCD/SFRO study randomized 119 patients to receive induction chemoradiation using fluorouracil and cisplatin or induction gemcitabine. Both groups then received maintenance gemcitabine until disease progression or toxicity.

The median OS was inferior in the chemoradiation group, with 8.6 months compared with 13 months in the chemotherapy group (

= .03), and patients in the chemoradiation arm experienced more grade 3 to 4 toxicities. As such, evidence so far has shown that upfront chemoradiation does not show a clear survival benefit; and, chemoradiation after induction chemotherapy is not superior to continuing systemic chemotherapy in patients who have disease control following induction chemotherapy. Chemoradiation should be considered in situations where local control is needed, including patients who develop local progression following induction chemotherapy, bleeding, poorly controlled pain, or local obstructive symptoms.

The availability of more active combination chemotherapy such as FOLFIRINOX and gemcitabine/nab-paclitaxel may also impact the effect of chemoradiation.

Resectable and Borderline Resectable Disease

Surgical resection remains the only curative modality in pancreatic cancer, and postoperative adjuvant therapy had been shown to confer survival benefit.

Currently accepted standards for adjuvant therapy consist of systemic gemcitabine for 6 cycles (CONKO-001) or systemic gemcitabine with chemoradiation (RTOG 97-04).

Despite that, the recurrence rate remains unacceptably high, and the 5-year survival rate is ~20% for patients with resected disease.

FOLFIRINOX and gemcitabine/nab-paclitaxel are highly active in metastatic pancreatic cancer and are recommended for patients with good performance status. The availability of these regimens allows for personalization of treatment plans according to a patient&rsquo;s performance status, preference, and liver function.

The LAP 07 trials showed that chemoradiation following induction chemotherapy did not add survival benefit in locally advanced, unresectable pancreatic cancer, though chemoradiation should be considered in patients who progress following induction chemotherapy, poorly controlled pain, bleeding, or local obstructive symptoms.

The use of highly active chemotherapy and chemoradiation has the potential of improving surgical outcomes in patients with resectable disease, and the approach is been evaluated in randomized trials.

As such, neoadjuvant, or preoperative, therapy is increasingly used for patients with borderline resectable pancreatic cancer. Borderline resectable disease, in general, refers to localized tumors with high likelihood of margin-positive resection, though the definition varies between various working groups, and readers should refer to the guidelines by the National Comprehensive Cancer Network and Alliance for Clinical Trials in Oncology group for details.

The theoretical advantages of neoadjuvant therapy include: downstaging of disease to improve surgical outcome, selection of patients with aggressive biology who might otherwise not benefit from surgery, and avoidance of therapy initiation delays due to postoperative complications.

Recent therapeutic advances have almost doubled the survival of patients with metastatic pancreatic cancer, and the availability of highly active chemotherapy regimens is making personalized medicine a reality.

August 2015 | The Journal of Targeted Therapies in Cancer

Current Systemic Management of Pleural Malignant Mesothelioma

Levantinib in the Management of Differentiated Thyroid Cancer

Current Management of Pancreatic Cancer