Regorafenib is a once-daily oral multikinase inhibitor approved for treatment of metastatic colorectal cancer following progression on chemotherapy, anti–vascular endothelial growth factor (VEGF) therapy, or anti–epidermal growth factor receptor therapy.[1] The US Food and Drug Administration approved regorafenib based on the results of the 2012 CORRECT trial, which demonstrated an improvement in overall survival with this agent vs best supportive care in patients with metastatic colorectal cancer (6.4 months vs 5 months, respectively; hazard ratio, 0.77; 95% CI, 0.64–0.94; 

The most common grade 3 or higher adverse events associated with regorafenib use are palmar-plantar erythrodysesthesia (PPE; 17%), diarrhea (7%), and hypertension (7%).[2] Most adverse events occur within the first cycle of treatment and decrease over time, suggesting that early recognition and management of drug-related toxicities can increase adherence and treatment duration.[3]

Management of Regorafenib-Associated Toxicities

The mechanism of PPE is theorized to be a result of dual VEGF receptor and beta-type platelet-derived growth factor receptor inhibition, which interferes with vascular repair mechanisms in high pressure areas exposed to repeated friction or pressure.[3] PPE is most likely to occur within the first 2 to 4 weeks of treatment and can be the most distressing adverse outcome to patients. Affected patients present with prodromal symptoms of dysesthesias in the palms and soles that progress to asymmetrical hyperkeratotic lesions. Lesions can be accompanied by redness, pain, and blisters, and escalation from grade 1 to 3 toxicity occurs quickly with continued dosing.[4]

It is ideal for management of PPE to begin before symptoms appear. Prophylactic measures-such as removal of preexisting hyperkeratotic lesions prior to treatment and assessing the need for orthotic devices in individuals with abnormal weight bearing-should be implemented. Patients can be educated to avoid activities that increase exposure of the hands/feet to heat and friction-such as washing dishes, taking hot showers, and exercising vigorously-and to wear non-constrictive clothing, thick socks, and padded shoes when needed.[3,4]

Non–urea-based creams should be utilized throughout treatment. Most importantly, close communication should be kept with patients during the first 21-day cycle of treatment to ensure compliance and observe for early signs of toxicity. For those with grade 1 PPE, supportive care measures should be reinforced. Treatment for the affected areas includes keratolytic creams containing urea or salicylic acid 6%, along with topical corticosteroids and analgesics if the PPE is grade 2 or higher, with possible dose reductions.[5]

If patients present with grade 3 or higher PPE, regorafenib must be stopped until symptoms resolve (typically within 1 to 2 weeks), and then restarted at a 50% lower dose.[6] Additional toxicities of regorafenib, such as hypertension, diarrhea, and hepatotoxicity, should be assessed within the first month of treatment initiation and then on an ongoing basis.[1]

The overall incidence rate of regorafenib-related hypertension has been reported to be as high as 44%, demonstrating the need for close monitoring and management.[7] Providers should instruct patients to monitor their blood pressure daily for the first 6 weeks of treatment, as in the CORRECT trial. If blood pressure increases, there is no single preferred antihypertensive agent, and selection of therapy should take into consideration the patient’s comorbidities. Diuretics should be avoided due to concern for dehydration in the setting of regorafenib-induced diarrhea. Pharmacologic treatment should be initiated for grade 2 or higher hypertension, and regorafenib should be discontinued if grade 4 toxicity occurs.[5,7]

Grade 1 or 2 diarrhea has been reported in 34% of patients on regorafenib.[1] As with other toxicities, early management can prevent dose reductions and drug discontinuation. Management of mild-to-moderate diarrhea may include dietary changes, such as implementation of a lactose-free or high-fiber diet, as well as use of over-the-counter anti-diarrhea agents such as loperamide. Patients should be continually assessed and instructed to notify a provider if the number of stools increases by more than three daily, since severe diarrhea can lead to dehydration and electrolyte imbalances.[3]

Although various dosing strategies have been employed in practice to ameliorate toxicities resulting from regorafenib, little data support such approaches. In the ReDOS trial, Bekaii-Saab et al investigated dose titration over the first cycle of treatment to optimize regorafenib dosing. They hypothesized that increasing the dose slowly in weekly increments would reduce adverse events during the first cycle and early discontinuation of therapy.[8]

Patients were randomized to 160-mg regorafenib daily for 21 days or a weekly dose escalation of regorafenib over 3 weeks (80-mg regorafenib daily for week 1, 120 mg daily for week 2, and 160 mg daily for week 3). The patient’s tolerated dose at the end of cycle 1 became the starting dose for cycle 2. Within each treatment group, patients were further stratified to a preemptive strategy vs reactive strategy arm for PPE. The primary endpoint was the number of patients completing cycle 2 at 8 weeks. Secondary endpoints included overall survival (OS), progression-free survival, time to progression, cumulative dose, quality of life (QOL), and safety.[8]

At its conclusion, the study found that weekly dose escalation of regorafenib from 80 mg to 160 mg daily was superior to 160-mg regorafenib daily, with 43% vs 24% of patients, respectively, completing cycle 2 (

 = .281). There was a trend for improved OS in the dose-escalation arm (9 months vs 5.9 months; 

 = .94). At 2 weeks following therapy initiation, the dose-escalation strategy did not appear to compromise QOL, unlike the standard-dose administration. Grade 3 and 4 toxicities were lower in the dose-escalation arm vs the standard-dose arm (PPE, 15% vs 16%; hypertension, 7% vs 15%; and fatigue, 13% vs 18%). The authors concluded that a dose escalation strategy optimizes regorafenib dosing and appears to be better tolerated than standard dosing, with fewer adverse events.[8]

The National Comprehensive Cancer Network (NCCN) Colon Cancer Guidelines Version 4.2018 include the dose titration schedule as an option for patients receiving regorafenib for metastatic colorectal cancer.[9] Data regarding the outcomes of preemptive vs reactive PPE prevention strategies are forthcoming.[8] In practice, the dose-escalation strategy may allow for early intervention during the escalation cycle, before drug discontinuation is warranted due to grade 3 or 4 toxicities. Combined with education and supportive measures, patients may be able to maintain treatment and achieve an improvement in OS when the dose-escalation strategy for regorafenib dosing is utilized.

Additional Considerations for Regorafenib Usage

• Although regorafenib has demonstrated an improvement in overall survival in metastatic colorectal patients, many patients discontinue therapy within the first treatment cycle due to adverse events.

• Providers should educate patients about common toxicities associated with regorafenib use, especially palmar-plantar erythrodysesthesia, hypertension, and diarrhea.

• Patient education should include preventative and supportive measures, as well as when to contact the provider.

• Monitoring within the first treatment cycle helps to optimize therapy and to provide an early intervention due to side effects.

• Implementing a dose escalation strategy optimizes dosing, improves overall survival, and results in fewer adverse events.

Dr. Draper has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. 

 Drugs@FDA. STIVARGA (regorafenib) tablets, oral. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203085lbl.pdf

 Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT). Lancet. 2013;381:303-12.

 Khan G, Moss RA, Braiteh F, et al. Proactive strategies for regorafenib in metastatic colorectal cancer: implications for optimal patient management. Cancer Manag Res. 2014;6:93-103.

 Crona DJ, Keisler MD, Walko CM. Regorafenib: a novel multitargeted tyrosine kinase inhibitor for colorectal cancer and gastrointestinal stromal tumors. Ann Pharmacother. 2013;47:1685-96.â©

 Krishnamoorthy SK, Relias V, Sebastian S, et al. Management of regorafenib related toxicities: a review. Therap Adv Gastroenterol. 2015; 8:285-97.

 Lacouture ME, Shenhong W, Robert C, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist. 2008;13:1001-11.

 Wang Z, Xu J, Nie W, et al. Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis. Eur J Clin Pharmacol. 2014;70:225-31.

 Bekaii-Saab T, Ou F, Anderson D, et al. Regorafenib dose optimization study (ReDOS): randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC): an ACCRU Network study. J Clin Oncol. 2018 Feb 26. [Epub ahead of print]

 National Comprehensive Cancer Network Guidelines. Colon Cancer. Version 4.2018. 

https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf

An oncology pharmacist discusses how to prevent and treat the toxicities from regorafenib for the treatment of colorectal cancer.

Regorafenib for Metastatic Colorectal Cancer: Common Toxicities and Prevention Strategies

A 39-year-old woman with no significant medical history presented to the emergency department with progressive diffuse abdominal pain, involuntary weight loss, anemic syndrome, and limitation of mobility related to the presence of a right gluteal mass, all of which had persisted for the past 20 days. Physical examination revealed hepatomegaly, splenomegaly, ascites, right leg edema, and a palpable 6.0 × 5.3–cm mass in the right gluteus.

Blood tests were obtained following admission, revealing anemia (hemoglobin level, 9.9 g/dL), hyperglobulinemia (globulins level, 11.0 g/dL), hypercalcemia (calcium level, 14.15 mg/dL), and renal failure (creatinine level, 1.4 mg/dL), as well as coagulopathy with prolonged prothrombin time (PT), activated partial thromboplastin time (aPTT), and hypofibrinogenemia (fibrinogen level, 92.0 mg/dL). A CT scan showed ascites; splenomegaly; hepatomegaly dependent on multiple hypervascular intrahepatic tumoral lesions, the largest measuring 8.5 × 7.6 cm (segment 8 of

); a solid soft tissue–dependent mass in the right iliac branch measuring 9.1 × 8.4 cm (

Due to clinical suspicion of monoclonal gammopathy, the following tests were performed: serum quantitative immunoglobulin (Ig) levels (IgA level, 14.0 mg/dL; IgM level, 20.0 mg/dL; IgG level, 6,842 mg/dL); beta-2 microglobulin level (10.5 mg/dL); serum free light chains (kappa free light chains, 10.0 mg/L; lambda free light chains, 7,500 mg/L; kappa/lambda ratio, 0.002); and serum protein electrophoresis and immunofixation, which showed an IgG lambda monoclonal paraprotein (6.8 g/dL).

Bone marrow trephine biopsy established the presence of 60% lambda clonal plasma cells (CD138-positive, CD56-negative, cyclin D1–negative; 

), confirming a diagnosis of IgG lambda multiple myeloma. On cytogenetic analysis, the presence of chromosome 9 inversion and chromosome 17p11.2 deletion were identified: karyotype 5 = 46,XX,inv(9)(p13q13), del(17)(p11.2p11.2); karyotype 15 = 46,XX,inv(9)(p13q13). Fluorescence in situ hybridization from the bone marrow ruled out additional cytogenetic abnormalities. Peripheral blood immunophenotype ruled out plasma cell leukemia (4.8% CD138-positive plasma cells).

Regarding the presence of coagulopathy, additional tests were performed; the results of a thrombin time test were normal, and a mixing study found a correction of both PT and aPTT. Therefore, quantification of factor II (FII), factor V (FV), and factor X (FX) levels was completed, all of which were low (FII, 26%; FV, 50.7%; FX, 27.5%). During the visit, the patient demonstrated mild mucocutaneous bleeding and was treated with fresh frozen plasma transfusion and cryoprecipitate without clinical instability.

Within days of the initial visit, the patient presented with clinical deterioration, including worsened renal failure requiring hemodialysis, coagulopathy, and disseminated candidiasis that led to death. After the patient passed away, a scientific medical autopsy was performed. Macroscopic findings complemented with histopathology tests were consistent with multiple myeloma with extramedullary disease (EMD) affecting the liver (

), gluteus muscle, ovaries, kidneys, and peritoneum.

Which of the following hematopoietic stem cell transplant (HSCT) approaches would have been the best choice after initial chemotherapy in this case?

. Tandem autologous HSCT followed by allogeneic HSCT

Correct Answer: A. Single autologous HSCT

Multiple myeloma is a hematologic neoplasia characterized by a proliferation of clonal plasma cells, as well as evidence of related end organ damage. In most cases, the rapid reproduction of clonal plasma cells is restricted to the bone marrow; however, in some cases they can spread outside the bone marrow in patients diagnosed with multiple myeloma, which is recognized as EMD.[1-3] Currently, many questions remain regarding the clinical behavior, prognosis, and treatment of patients with EMD.

Over the last 2 decades, continuous debate has surrounded the definition of EMD. Initially, two clinical presentations were referred to as EMD: 1) a tumor mass adjacent to the bone that extends to the soft tissue and bone marrow (bone-related plasmacytoma), and 2) a tumor mass or diffuse infiltration by clonal plasma cells at a distant anatomical site not related to the bone.[4,5] In 2013, Weinstock and Ghobrial proposed that, taking into consideration the biological behavior and prognostic characteristics of this disease presentation, the term EMD should be restricted to the presence of EMD in patients with multiple myeloma, excluding bone-related plasmacytoma.[6]

The reported rate of patients presenting with EMD varies between 6% and 30%, depending on the time of EMD diagnosis, sites considered to be EMD, and the diagnostic method used for identification. When using adequate imaging techniques (ie, whole-body MRI or PET/CT), the incidence of EMD is approximately 7%.[2,5,7] In the relapsed/refractory setting, the prevalence of EMD has been reported to be as high as 10% to 30%; however, its real prevalence could be much higher when considering that autopsy studies have revealed extramedullary involvement in approximately 70% of suspected cases, with up to 40% infiltration to non–bone-related distant sites.[2,8-10]

To our knowledge, multiple myeloma with EMD affecting multiple distant-to-the-bone sites at diagnosis is rare; hepatic and ovarian involvement are particularly rare, with only a few cases reported in the literature.[11-13] In 2018, the European Society for Blood and Marrow Transplantation (EBMT) conducted a retrospective study that included 3,744 patients with multiple myeloma. Bone-related EMD was identified in 14.5% of the patients, only 3.7% of whom had non-paraskeletal involvement. The frequency of involved extramedullary sites was as follows: kidney (27.3%); skin (23%); lymph nodes (17.3%); central nervous system (10.1%); lung and respiratory tract (6.5%); gastrointestinal tract and liver (5.8%); pleura and heart (5.0%); and spleen, ovaries, and testicles (5.3%). In addition, 93.5% of patients presented with one involved site and only 6.5% with two or more.[7,14]

At the histopathology level, clonal plasma cells have an immature/plasmablastic appearance in patients with EMD, while they have a mature/plasmacytic appearance in bone-related plasmacytoma. Differences in morphology, as well as the deleterious clinical impact of EMD, suggest that the pathogenesis of these two presentations is different. Although the exact mechanisms that contribute to the spread of clonal plasma cells is unknown, some pathophysiologic mechanisms have been proposed. Oncogene and tumor suppressor gene mutations that affect protein expression related to cell survival, migration, and invasion play a crucial role in patients with EMD. Clonal mutations, mainly of the 

 genes, have been described in up to 50% of patients with multiple myeloma with an EMD presentation.[2,4,6,15]

In EMD, migration of plasma cells to distant sites has also been related to the upregulation or downregulation of different molecules. Regarding adhesion molecules, CD56 and P-selectin promoters of the adherence of cells to the bone marrow are markedly unexpressed, while CD44-involved in proliferation, migration, and tumor metastasis-was found to have increased expression. Angiogenesis- and hypoxia-related factors (VEGF, MMP-9, angiopoietin-1, and CD31) and dysregulation of cytosines (CCR1, CCR2, and CXCR-4/SDF-1Î±) are still undergoing laboratory and clinical research, but have been described as specific pathogenic steps that limit or promote hematogenous dissemination of plasma cells.[15,16]

Multiple myeloma with EMD is known to have a highly aggressive disease presentation at both the time of diagnosis and relapse.[5,17] Usmani et al reported that EMD at diagnosis was associated with a significantly lower progression-free survival rate at 5 years compared with multiple myeloma without EMD, regardless of treatment modality (21% vs 50%; 

 < .001).[18] More recently, the EBMT evaluated the impact of EMD on newly diagnosed multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT). They found that patients with EMD had significantly lower rates of progression-free survival (39.9% vs 47.9%; 

 = .001) and overall survival (58% vs 80.1%; 

 < .001) at 3 years compared with patients without EMD. They also observed that the progression-free survival rate at 3 years was similar among patients with EMD with involvement of a unique site and patients without EMD (49.4% vs 47.9%, respectively; 

 = .36). However, when compared with cases involving multiple disease sites, patients with EMD had worse outcomes (47.9% vs 22.7%, respectively; 

Considering the adverse impact that EMD has on clinical outcomes, the molecular and cytogenetic heterogeneity of multiple myeloma, and the lack of EMD-specific predictive scores, it is imperative that diagnostic strategies for this disease presentation be optimized. According to the current international recommendations, radiographs and MRI are acceptable methods for initial screening[19,20]; however, PET/CT has been recognized as a more effective technique, not only at diagnosis, but also during patient follow-up. Recent studies have demonstrated that PET/CT is a more sensible and specific tool to assess bone damage and extramedullary sites; distinguish between metabolically active and inactive disease; and determine response to therapy, including detection of minimal residual disease.[21-23]

Coagulopathy presenting in parallel with multiple myeloma has been described in 15% to 40% of cases.[24-26] Major hemorrhagic complications are rare, with clinically significant bleeding occurring in less than 15% of patients, with no relation to the degree of laboratory test abnormalities. Risk factors related to bleeding include increased serum viscosity and levels of monoclonal paraprotein, as well as conditions that interfere with platelet function, coagulation factors, and fibrinolysis.[27,28] Incidence of coagulopathy in patients with EMD is unknown; nevertheless, previous reports have linked hemostatic disorders with high-risk multiple myeloma.[29,30] Supportive care and timely control of primary neoplasia have been the only effective strategies to control related symptoms and complications.[24,31]

One limitation of current therapy recommendations is that no prospective clinical trials have focused specifically on multiple myeloma patients with EMD. Expert opinion favors considering EMD to be a high-risk disease feature, and therefore to treat it with an intensive regimen. In this context, the preferred regimen for a newly diagnosed transplant candidate is triplet induction therapy including a proteasome inhibitor and an immunomodulator (carfilzomib or bortezomib with lenalidomide/dexamethasone), followed by auto-HSCT with high-dose melphalan conditioning, triplet consolidation therapy, and maintenance therapy with lenalidomide (

).[3] For non-transplant candidates, standard-of-care triplet therapy with an alkylating agent and proteasome inhibitor (bortezomib plus melphalan and prednisone), or continuous lenalidomide with dexamethasone, are the most effective therapies with high response rates.[32]

) has been proposed by some groups. Evidence in patients with EMD is scarce, since the evidence supporting its use was based on its utility in high-risk patients.[33] Allogeneic HSCT (

) has been reserved for patients with disease that does not respond to therapy or those who experience relapse after initial therapy with auto-HSCT.[33,34] Although there are no prospective data, current ongoing trials evaluating various upfront therapies have been integrating the use of PET/CT into the diagnosis and follow-up of patients-a strategy that will hopefully aid in more precisely analyzing response to therapy and clinical outcomes in patients with EMD.

Dr. Maria Bourlon serves on the advisory boards and speakers’ bureaus of and receives travel grants from Bristol-Myers Squibb and Janssen. All other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. 

 Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-48.

 BladÃ© J, FernÃ¡ndez de Larrea C, RosiÃ±ol L, et al. Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol. 2011;29: 3805-12.

 Touzeau C, Moreau P. How I treat extramedullary myeloma. Blood. 2016;127:971-6.

 Short KD, Rajkumar SV, Larson D, et al. Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma. Leukemia. 2011;25:906-8.

 Varettoni M, Corso A, Pica G, et al. Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Ann Oncol. 2010;21:325-30.

 Weinstock M, Ghobrial IM. Extramedullary multiple myeloma. Leuk Lymphoma. 2013;54:1135-41.

 Weinstock M, Aljawai Y, Morgan EA, et al. Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation. Br J Hematol. 2015;169:851-8.

 Varga C, Xie W, Laubach J, et al. Development of extramedullary myeloma in the era of novel agents: no evidence of increased risk with lenalidomide-bortezomib combinations. Br J Hematol. 2015;169:843-50.

 Pasmantier MW, Azar HA. Extraskeletal spread in multiple plasma cell myeloma. A review of 57 autopsied cases. Cancer. 1969;1:167-74.

 Thomas FB, Clausen KP, Greenberger NJ. Liver disease in multiple myeloma. Arch Intern Med. 1973;132:195-202.

 Huang H, Bazerbachi F, Mesa H, and Gupta P. Asymptomatic multiple myeloma presenting as a nodular hepatic lesion: a case report and review of the literature. Ochsner J. 2015;15:457-67.

 Chemlal K, Couvelard A, Grange MJ, et al. Nodular lesions of the liver revealing multiple myeloma. Leuk Lymphoma. 1999;33:389-92.

 Stuver R, Petersen A, Guerrero-Garcia TA, et al. Multiple myeloma masquerading as ovarian carninosarcoma metastases: a case report and review of the approach to multiple myeloma screening and diagnosis. Case Rep Hematol. 2018 Sep 24. [Epub ahead of print]

 Gagelmann N, Eikema DJ, Iacobelli S, et al. Impact of extramedullary disease in patients with newly diagnosed multiple myeloma undergoing autologous stem cell transplantation: a study from the Chronic Malignancies Working Party of the EBMT. Haematologica. 2019;103:890-7.

 Rasche L, Bernard C, Topp M, et al. Features of extramedullary myeloma relapse: high proliferation, minimal marrow involvement, adverse cytogenetics: a retrospective single-center study of 24 cases. Ann Hematol. 2012;91:1031-7.

 Bink K, Haralambieva E, Kremer M, et al. Primary extramedullary plasmacytoma: similarities and differences with multiple myeloma revealed by interphase genetics. Haematologica. 2008;93:623-6.

 RosiÃ±ol L, Oriol A, Teruel AI, et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012;120:1589-96.

 Usmani SZ, Rodriguez-Otero P, Bhutani M, et al. Defining and treating high-risk multiple myeloma. Leukemia. 2015;11:2119-25.

 Walker RC, Brown TL, Jones-Jackson LB, et al. Imaging of multiple myeloma and related plasma cell dyscrasias. J Nucl Med. 2012;53:1091-101.

 Dimopoulos MA, Hilengass J, Usmani S, et al. Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement. J Clin Oncol. 2015;33:657-64.

 Bartel TB, Haessler J, Brown TL, et al. F-18 fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in multiple myeloma. Blood. 2009;114:2068-76.

 Cavo M, Terpos E, Nanni C, et al. Role of 18F-FDG PET/CT in the diagnosis and management of multiple myeloma and other plasma cell disorders: a consensus statement by the International Myeloma Working Group. Lancet Oncol. 2017;18:e206-17.

 Nanni C, Zamagni E, Versari A, et al. Image interpretation criteria for FDG PET/CT in multiple myeloma: a new proposal from an Italian expert panel. IMPeTUs (Italian Myeloma criteria for PET USe). Eur J Nucl Med Mol Imaging. 2016;43:414-21.

 Coppola A, Tufano A, Di Capua M, Franchini M. Bleeding and thrombosis in multiple myeloma and related plasma cell disorders. Semin Thromb Hemost. 2011;37:929-45.

 Perkins HA, MacKenzie MR, Fudenberg HH. Hemostatic defects in dysproteinemias. Blood. 1970;35:695-707.

 Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Semin Thromb Hemost. 2003;29:467-71.

 Shinagawa A, Kojima H, Berndt MC, et al. Characterization of a myeloma patient with a life-threatening hemorrhagic diathesis: presence of a lambda dimer protein inhibiting shear-induced platelet aggregation by binding to the A1 domain of von Willebrand factor. Thromb Haemost. 2005;93:889-96.

 Teng HW, Chen PM, Yang YH, Gau JP. The prolonged activated partial thromboplastin time at diagnosis indicates less favorable prognosis in IgA myeloma. Jpn J Clin Oncol. 2007;37:609-14.

 van Marion AM, Auwerda JJ, Lisman T, et al. Prospective evaluation of coagulopathy in multiple myeloma patients before, during and after various chemotherapeutic regimens. Leuk Res. 2008;32:1078-84.

 Glaspy JA. Hemostatic abnormalities in multiple myeloma and related disorders. Hematol Oncol Clin North Am. 1992;6:1301-14.

 Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127:2955-62.

 Mateus MV, Oriol A, MartÃ­nez-LÃ³pez J, et al. Outcomes with two different schedules of bortezomib, melphalan, and prednisone (VMP) for previously untreated multiple myeloma: matched pair analysis using long-term follow-up data from the phase 3 VISTA and PETHEMA/GEM05 trials. Ann Hematol. 2016;95:2033-41.

 Cavo M, Salwender H, RosiÃ±ol L, et al. Double vs single autologous stem cell transplantation after bortezomib-based induction regimens for multiple myeloma: an integrated analysis of patient-level data from phase European III studies. Blood. 2013;122:767.

 Badros A, Barlogie B, Siegel E, et al. Results of autologous stem cell transplant in multiple myeloma patients with renal failure. Br J Haematol. 2001;114:822-9.

A 39-year-old woman with no significant medical history presented to the emergency department with progressive diffuse abdominal pain, involuntary weight loss, anemic syndrome, and limitation of mobility. What is the best treatment course to follow?

Multiple Myeloma With Extramedullary Disease: A Challenging Clinical Dilemma

A 64-year-old man ultimately diagnosed with 

-rearranged non–small-cell lung cancer (NSCLC) with brain metastases initially presents to the emergency department with progressive dyspnea, a non-productive cough, and weight loss. His past medical history includes chronic obstructive pulmonary disease, nonalcoholic steatohepatitis, and non–insulin-dependent diabetes; he also has a 33 pack-year history of tobacco use, although he quit smoking 15 years prior to diagnosis. A chest x-ray is obtained, revealing questionable findings in the right hilum and a large right pleural effusion. A CT scan of the chest without contrast confirms right lung atelectasis, a large right pleural effusion, right lower lobe necrosis, and right hilar fullness.

Therapeutic and diagnostic thoracentesis was completed, with cytology positive for adenocarcinoma of the lung (thyroid transcription factor 1–positive, cytokeratin (CK)7-positive, CK20-negative, presence of 

, and calretinin-negative). Expression of programmed death ligand 1 (PD-L1) was 50%. 

 rearrangement was negative by fluorescence in situ hybridization (FISH) testing. The 

 genes were all wild-type. Due to rapidly reaccumulating symptomatic pleural effusion, video-assisted thoracoscopic surgery with right pleural tissue biopsy and talc pleurodesis were completed.

Pleural tissue was sent for pathology review and was once again consistent with adenocarcinoma of the lung. However, PD-L1 expression was 0%, and 

K rearrangement by immunohistochemistry was positive. 

 testing was repeated on this tissue sample with FISH (via the US Food and Drug Administration [FDA]–approved Vysis ALK Break Apart FISH Probe Kit), which detected the 

 (2p23) rearrangement in 52% of the cells analyzed.

Completion staging imaging was obtained, including a PET/CT scan and brain MRI with and without contrast. The PET/CT scan demonstrated a hypermetabolic lesion in the posterior right lower lobe, extensive hypermetabolic pleural-based disease in the right hemithorax with hypermetabolic right hilar and subcarinal lymph nodes, as well as lymph nodes at the left mediastinum and left neck base. Multiple foci of osseous metastases were visible, as was a possible small lesion in the left liver. Brain MRI revealed 3 metastatic lesions: a 12-mm lesion in the right caudate nucleus, a 10-mm lesion in the right temporal lobe, and a 3-mm lesion in the left cerebellar hemisphere.

The patient experienced an ongoing non-productive cough, dyspnea on exertion, right pleuritic pain, and back pain. He consulted with a radiation oncologist and received stereotactic radiosurgery to the right temporal lobe lesion (21 Gy) and the right parietal lobe lesion (21 Gy). The 3-mm lesion was not treated with radiation. First-line systemic treatment was initiated with 600-mg oral alectinib twice daily, which was well tolerated with no significant treatment-related toxicities. The patient’s disease-related symptoms improved. Imaging was repeated 6 weeks later. A brain MRI with and without contrast revealed a complete response in all 3 lesions, including the 3-mm lesion that was not initially treated with radiation. A CT scan of the chest/abdomen/pelvis with contrast exhibited a significant radiographic response in all previously identified sites of disease.

-rearranged metastatic NSCLC has substantially evolved since the initial identification of this aberration. Although 

+ metastatic NSCLC represents just 3% to 5% of all NSCLC cases, there are now five FDA-approved targeted therapies in this space. Crizotinib was the first-in-class therapeutic intervention against the driver alteration; its benefits were first confirmed in the PROFILE 1014 study.[1] However, since crizotinib is an ALK/ROS1/MET inhibitor, patients treated with this agent relapse, and the more potent and brain-penetrable next-generation ALK inhibitors have surpassed crizotinib in both efficacy and tolerability. While alectinib, ceritinib, and crizotinib are all FDA-approved as first-line and subsequent-line therapies, brigatinib and lorlatinib are approved for use as only subsequent-line treatment. The National Comprehensive Cancer Network guidelines recommend alectinib-a highly selective central nervous system (CNS)-active ALK inhibitor-as the preferred first-line therapy for 

Rationale Behind Targeted Therapy With Alectinib

The global phase III ALEX study compared alectinib with crizotinib in the first-line treatment of 

+ metastatic NSCLC. The primary analysis showed a significant improvement in the study’s primary endpoint, median progression-free survival (PFS), with alectinib,[3] leading to its FDA approval in the first-line setting. In this patient’s case, first-line targeted therapy with alectinib was chosen based on the results of this trial. Moreover, the efficacy of alectinib in the CNS limited the need for whole-brain irradiation in the setting of few, small, and asymptomatic brain metastases.

At the 2018 American Society of Clinical Oncology Annual Meeting, the ALEX study was updated with 10 months of additional follow-up data.[4] Among the findings were an unprecedented investigator-assessed median PFS of 34.8 months and an updated hazard ratio (HR) of 0.43. The duration of treatment was also longer. In addition, the depth of response was deeper: > 40% of responders treated with alectinib demonstrated > 75% tumor reduction compared with ~25% of responders treated with crizotinib. Rates of significant adverse events were lower, and subsequent dose adjustments and treatment discontinuations were fewer. Notably, among the 303 patients included in this analysis, about 40% in each arm had baseline CNS metastases; 122 patients harbored baseline CNS metastases (alectinib arm, n = 64; crizotinib arm, n = 58), and 43 harbored measurable lesions (alectinib arm, n = 21; crizotinib arm, n = 22). In addition, 46 patients had received prior radiotherapy (alectinib arm, n = 25; crizotinib arm, n = 21).[4]

PFS with alectinib was comparable between patients with baseline CNS metastases (HR, 0.40; 95% CI, 0.25–0.64) and those without CNS metastases (HR, 0.51; 95% CI, 0.33–0.80), despite prior radiotherapy status. Time to CNS progression was significantly longer with alectinib vs crizotinib and was similar to that of patients with and without baseline CNS metastases (

 < .0001). In patients who were administered prior radiotherapy, the CNS objective response rate (ORR) was 85.7% with alectinib vs 71.4% with crizotinib. Among those who had not been administered previous radiotherapy, the ORR was 78.6% for alectinib vs 40.0% for crizotinib.[4]

Of high significance, the endpoints in the ALEX trial were also assessed based on CNS involvement. The median PFS, duration of response, and depth of response were all upheld regardless of baseline CNS metastases.[4] For patients with small and asymptomatic brain metastases in the setting of 

-rearranged NSCLC, there is an opportunity to defer whole-brain irradiation until intracranial response to alectinib is assessed radiographically. With alectinib assuming this clear position as the first-line treatment for 

+ metastatic NSCLC, it will become even more important to understand 

 resistance patterns and appropriate drug sequencing when a patient progresses on alectinib.[3,4]

The decision not to administer immunotherapy was based on previous research involving 

-mutated metastatic NSCLC with characteristics similar to the patient in this current case study, whose tumor harbored an 

 rearrangement. Trials of second-line or later treatments for metastatic NSCLC have shown that patients with 

-mutant tumors do not benefit from checkpoint inhibitors. This seems to be the case regardless of PD-L1 expression. In a meta-analysis,[5] Lee et al found that, in patients with driver mutations, immune checkpoint inhibitors do not lengthen overall survival (OS) any more than docetaxel. The three studies included in this meta-analysis compared immune checkpoint inhibitors (nivolumab [n = 292], pembrolizumab [n = 691], and atezolizumab [n =144]) vs docetaxel (n = 776). In the overall population, immune checkpoint inhibitors resulted in longer OS compared with docetaxel (n = 1,903; HR, 0.68; 95% CI, 0.61–0.77; 

 < .0001). The same benefit was seen in the 

 wild-type subgroup (n = 1,362; HR, 0.66; 95% CI, 0.58–0.76; 

-mutant subgroup, no increase in OS was observed (n = 186; HR, 1.05; 95% CI, 0.70–1.55; 

The patient in this case study had a PD-L1 tumor proportion score (TPS) of 50% on pleural fluid but 0% on pleural tissue. In an abstract,[6] Hui et al showed that, among patients with a PD-L1 TPS higher than 50% treated with pembrolizumab, those with 

-mutant tumors had significantly reduced OS vs those with 

 wild-type tumors (median OS, 6.5 vs 15.7 months). Furthermore, OS did not change significantly based on PD-L1 expression in the 

-mutant group (TPS, > 50% vs < 1%; median OS, 6.5 vs 5.7 months). In the 

 wild-type subgroup, however, a difference was observed (TPS > 50% vs < 1%; median OS, 15.7 vs 9.1 months). Notably, the patient’s tumor in this case study had an 

 mutation. However, similar results have been demonstrated for both and are anticipated regardless of the driver mutation (ie, 

In a retrospective study,[7] Gainor et al found that NSCLC tumors possessing 

 rearrangements are significantly linked to lower ORR values when treated with programmed death 1 (PD-1)/PD-L1 inhibitors. The authors observed objective responses in only 1 of 28 

 = .053). Additionally, the ORR among never- or light-smokers (≤ 10 pack-years) was 4.2% vs 20.6% among heavy smokers (

 = .123). Not only did the patient in the current case study have 

-rearranged NSCLC, he would also be considered a heavy smoker per these cutoffs in pack-years, with a lower ORR in response to PD-1/PD-L1 inhibitors.[7]

Although immunotherapy has significantly impacted the treatment of metastatic NSCLC, regardless of the PD-L1 TPS, treatment with immunotherapy is not prioritized over targeted therapy in the first-line treatment of tumors with 

 driver mutations. When a driver mutation is identified in metastatic NSCLC, such as the 

 rearrangement seen in this case study, targeted therapy provides the best outcomes on multiple levels. In an era of immune checkpoint inhibition, it is important to remember that the driver mutation-not the PD-L1 expression-determines first-line treatment. The benefit of agents penetrating the CNS is important, since it may provide alternatives to whole-brain irradiation, which has potentially unwanted toxicities.

Dr. Mileham is on the speakers’ bureau for Merck. Dr. Ahmad and Dr. Kim have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Using Molecular Testing to Alter Treatment in Favor of Positive Patient Outcomes

In this article, Mileham et al highlight important concepts in the molecular testing of non–small-cell lung cancer (NSCLC). Specifically, the case study they present demonstrates the finding of discordance in molecular testing based on the tissue specimen. While the cytology sample showed programmed death ligand 1 (PD-L1) positivity, the core biopsy did not. More importantly, 

 fusion testing was negative in the initial cytology specimen, yet was found to be positive in the core biopsy.

For the practicing oncologist, this is extremely important to consider because tissue biopsies can often be difficult to obtain and may require additional procedures. The additional finding of the 

 fusion after repeat biopsy further highlights the importance of adequate tissue sampling. The therapy selected in this case (alectinib) was significantly different than what would have previously been considered (pembrolizumab) and led to a favorable outcome for the patient. In the end, this case supports the role of obtaining appropriate testing on the correct tissue specimens in order to help guide first-line therapy for NSCLC.

 Dr. Powell has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

Dr. Powell is a Hematologist/Oncologist at Sanford Cancer Center; an Assistant Scientist at the Cancer Biology Center at Sanford Research; and an Assistant Professor of Internal Medicine at the University of South Dakota’s Sanford School of Medicine, Sioux Falls, South Dakota.

 Solomon BJ, Cappuzzo F, Felip E, et al. Intracranial efficacy of crizotinib versus chemotherapy in patients with advanced ALK-positive non-small-cell lung cancer: results from PROFILE 1014. J Clin Oncol. 2016;34:2858-65.

 National Comprehensive Cancer Network guidelines. Non-small cell lung cancer. 

https://www.nccn.org/store/login/login.aspx?ReturnURL=https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

 Peters S, Camidge DR, Shaw AT, et al; ALEX trial investigators. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N Engl J Med. 2017;377:829-38.

 Camidge DR, Peters S, Mok T, et al. Updated efficacy and safety data from the global phase III ALEX study of alectinib (ALC) vs crizotinib (CZ) in untreated advanced ALK+ NSCLC. J Clin Oncol. 2018;15(suppl):abstr 9043.

 Lee CK, Man J, Lord S, et al. Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-A meta-analysis. J Thorac Oncol. 2017;12:403-7.

 Hui R, Gandhi L, Cost EC, et al. Long-term OS for patients with advanced NSCLC enrolled in the KEYNOTE-001 study of pembrolizumab (pembro). J Clin Oncol. 2016;15(suppl):abstr 9026.

 Gainor JF, Shaw AT, Sequist LV, et al. EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: A restrospective analysis. Clin Cancer Res. 2016;22:18.

In this article, important concepts in the molecular testing of non–small-cell lung cancer are highlighted.

Targeted Therapy for Mutation-Driven Metastatic Non–Small-Cell Lung Cancer: Considerations for ALK-Rearranged Tumors

Urothelial carcinoma is the most common type of bladder cancer. Recently, two clinical trials explored the use of immunotherapy to treat patients with urothelial carcinoma. Additional research is also underway. In this interview, 

 spoke with Arjun V. Balar, MD, the director of the Genitourinary Medical Oncology Program at New York University Langone’s Perlmutter Cancer Center. Dr. Balar, who specializes in the treatment of patients with bladder, prostate, kidney, and testicular cancers, discussed the treatment landscape for urothelial carcinoma, as well as promising advances that have the potential to change practice.

Q: Several immunotherapies have now been approved by the US Food and Drug Administration (FDA) for the treatment of urothelial carcinoma, both for treatment-naive patients and those with relapsed/refractory disease. Can you provide a brief overview of these therapies?

 The current landscape of available immunotherapies for advanced bladder cancer can be broken down into two disease states. The first group, the disease state that was tested during initial development, includes patients who are refractory to platinum-based chemotherapy-including cisplatin- or carboplatin-based treatments. In this setting, five different FDA-approved agents are available: two agents that target the programmed death 1 (PD-1) pathway, specifically the PD-1 receptor, and three agents that target programmed death ligand 1 (PD-L1), which is the ligand for PD-1 (

). Essentially, these drugs lead to a range of responses from 15% to 21%.

There are two trials involving two agents that have shown a benefit vs chemotherapy, which was the standard of care before immunotherapies were available: a study of pembrolizumab[1] and an intent-to-treat analysis from an atezolizumab study.[2] In the first-line setting, these two FDA-approved agents are available for patients who are cisplatin-ineligible. Both agents were tested in single-arm clinical trials focused on patients with advanced bladder cancer who were ineligible for cisplatin-containing chemotherapy. The data from these studies demonstrated a response rate in the range of 23% to 29% and a median survival as high as 15.9 months, which was observed with atezolizumab.[2]

More recently, we found more evidence from two separate randomized trials informing us how best to use these agents in the cisplatin-ineligible patient population. Specifically, safety alerts from two randomized phase III trials, KEYNOTE-361[3] and IMvigor130,[4] showed that patients with low levels of PD-L1 expression did better if they received platinum-based therapy rather than immunotherapy. As a result, in August 2018, the FDA amended the prescribing labels for both atezolizumab and pembrolizumab to limit their use to cisplatin-ineligible patients with advanced bladder cancer who have low PD-L1 expression or are ineligible for any platinum-containing chemotherapy. In addition, the prescribing information was updated to require the use of an FDA-approved test specific for each individual agent to better guide patient selection.[5]

Ongoing trials are now combining immunotherapy with either another immunotherapy agent or with another modality, such as a targeted agent or chemotherapy. In February of this year, the results of the PIVOT-02 trial were released.[6] This trial focused on front-line treatment of advanced or metastatic urothelial carcinoma with a combination of NKTR-214 and nivolumab, which is approved on its own to treat bladder cancer. Can you tell us more about the design and results of PIVOT-02?

 PIVOT-02 is a fairly large phase I study that served as the initial development platform for the agent NKTR-214. Specifically, this agent is essentially a reformulation of one of the oldest immunotherapy compounds to be tested in cancer, interleukin-2. Going back to the 1990s, interleukin-2 was administered as a high-dose intravenous bolus treatment for 5 consecutive days in a monitored intensive care treatment setting within the hospital because it causes an intense systemic immune response that causes patients to become quite sick; however, at the end of therapy, up to 10% of patients with advanced kidney cancer were essentially cured of their stage IV disease.

Now, fast forward to the 2010s, and this agent was reformulated by adding 6 polyethylene glycol (PEG) molecules to create a slow-release formulation. As the PEG molecules decrease from 6 PEGs down to 2, the active form of the cytokine is then present in the body, allowing immune stimulation, as well as preferential immune stimulation toward immune effector T cells, while minimizing stimulation of the suppressive T cells (regulatory T cells).

The PIVOT-02 study tested nivolumab in combination with NKTR-214, which was administered once every 3 weeks in the outpatient setting, so that the toxicities were much milder compared with patients receiving high-dose interleukin-2. In this particular study update, a cohort of 41 patients with advanced bladder cancer who were treatment-naive received first-line nivolumab and NKTR-214. The data were presented at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium and included the 27 efficacy-evaluable patients, defined as those who had at least one response-evaluable imaging after starting protocol therapy. Essentially, the researchers found that up to 48% of patients achieved an objective response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and 52% of patients had an immune-related RECIST response. Additionally, of the 15 patients with visceral metastases, 8 had responses to therapy. So, this agent seems to be quite active, even in patients with visceral metastases.[6]

Interestingly, 6 patients achieved a complete response, suggesting that NKTR-214 is quite active and may actually deepen responses in combination with nivolumab. A subgroup correlative analysis of this study found that, among patients who underwent an on-treatment biopsy vs a baseline biopsy, an influx of CD8+ T cells were present within tumors; in addition, the level of PD-L1 expression increased among patients who received combination therapy, suggesting that NKTR-214 can actually induce a more vigorous local immune response.[6] While these data are promising, they involve only the 27 efficacy-evaluable patients; the study is ongoing and will enroll more patients. Ultimately, randomized trials will be necessary to really understand what NKTR-214 truly adds to nivolumab monotherapy for patients with advanced bladder cancer.

Pembrolizumab is now being tested in earlier stages of disease. The results of the phase II PURE-01 clinical trial of pembrolizumab as a neoadjuvant therapy before cystectomy in patients with muscle-invasive bladder cancer were reported last year.[7] Can you tell us about the results of this trial and their potential significance for early-stage disease?

 PURE-01 was a very interesting study in that it tested neoadjuvant immunotherapy in patients with muscle-invasive bladder cancer who then underwent radical cystectomy. The historical standard of care for muscle-invasive bladder cancer is cisplatin-based chemotherapy for up to 4 cycles followed by a radical cystectomy. We use neoadjuvant therapy followed by cystectomy because we have level I evidence that the addition of chemotherapy in this setting improves survival and the rate of cure.

In the PURE-01 study, all patients were eligible for cisplatin-based chemotherapy but opted to participate in this trial; therefore, they received 3 doses of pembrolizumab immunotherapy administered every 3 weeks (6 to 9 weeks of treatment total) followed by a radical cystectomy, the standard-of-care surgical procedure with a curative intent. Essentially, the data showed that approximately 40% of patients achieved a complete pathologic response, suggesting that the addition of pembrolizumab elicited a significant local tumor immune response such that in 40% of patients, all cancer present in the bladder at the time of surgery was eradicated.[7]

These data are provocative because we have historically used the response rate to cisplatin chemotherapy as a surrogate for long-term survival. That is because data from the Southwest Oncology Group (SWOG) 8710 trial,[8] one of the pivotal studies that established cisplatin-based therapy as the neoadjuvant standard of care, showed that patients who achieved pT0 had a long-term cure rate of roughly 85% to 90%. The rate with which we see pT0 with cisplatin is estimated to be between 30% and 40%. So, to see a similar rate of pathologic complete response with neoadjuvant immunotherapy suggests that we may be able to see similar efficacy in the bladder.

These are promising data because more patients can tolerate pembrolizumab or immunotherapy in general compared with cisplatin. The challenge with this particular study is that it is a single-arm trial, so we don’t have any comparisons to other active treatments; furthermore, we don’t know whether the complete response in the bladder to pembrolizumab means the same thing as a complete response to cisplatin therapy. This is where long-term follow-up via randomized trials is absolutely necessary.

All of that being said, these data are very important and certainly lend a lot of background and evidence to support conducting larger randomized trials in which patients receive neoadjuvant immunotherapy followed by cystectomy and then are followed to see whether the rates of cure are improved compared with radical cystectomy alone. Not surprisingly, a subgroup analysis of the PURE-01 study showed that patients with high levels of PD-L1 expression in their baseline tumor sample were far more likely to achieve a pathologic complete response to immunotherapy,[7] which is in line with what we typically see in the metastatic setting. Additional data and analyses will be necessary to test if other biomarkers, such as tumor mutational burden or specific genetic mutations, might predict which patients will do best with neoadjuvant immunotherapy.

Q: Are there additional neoadjuvant studies utilizing immunotherapies in bladder cancer that are either ongoing or planned in order to better understand how these therapies fit into treatment?

Several randomized phase III trials testing immunotherapy in the neoadjuvant setting are either currently open or soon-to-be open. These include two studies focusing on pembrolizumab. The first is a randomized phase III trial evaluating cisplatin-based chemotherapy alone vs cisplatin-based chemotherapy plus pembrolizumab followed by radical cystectomy.[3] The second study is looking at neoadjuvant pembrolizumab alone followed by radical cystectomy vs radical cystectomy alone in patients who have muscle-invasive bladder cancer but are not candidates for cisplatin-based chemotherapy (KEYNOTE-905; not yet listed on ClinicalTrials.gov). Lastly, a randomized phase III trial testing the PD-L1 antibody durvalumab in combination with cisplatin-based chemotherapy followed by radical cystectomy vs cisplatin-based chemotherapy alone followed by radical cystectomy is underway (ClinicalTrials.gov identifier: NCT03732677). These three studies are just a sampling of the current trials that are better designed to ultimately answer the question, “How much does immunotherapy add to the neoadjuvant setting?”

Q: Besides the trials we already discussed, are there any additional ongoing trials focusing on immunotherapy for bladder cancer that you and your colleagues are excited about or that have the potential to be practice-changing?

 An additional area that I am particularly excited about is bladder preservation. The idea is definitive local treatment for muscle-invasive bladder cancer with a curative intent that does not require a radical cystectomy, which has a very high morbidity; up to two-thirds of patients who undergo radical cystectomy experience perioperative complications, and up to 1% to 2% of patients die from surgery-related complications. Trimodality bladder preservation is a well-established approach that first includes a maximal resection of the bladder, where the bulk of the tumor is removed. Patients are subsequently treated with a 4- to 6-week course of radiation; radiosensitizing chemotherapy is given concurrently to augment the effect of radiation, with the ultimate goal of curing the disease without having to surgically remove the bladder.

I am particularly interested in the addition of immunotherapy to trimodality bladder preservation. I am leading a phase II trial in which we are adding pembrolizumab in combination with trimodality bladder preservation (ClinicalTrials.gov identifier: NCT02621151). We have enrolled just over 30 patients in the last 2 years, and our goal is to enroll 54 patients total. So far, we are seeing encouraging outcomes and excellent safety results. The study is designed for patients who wish to preserve their bladder, as well as for older patients, who are commonly affected by this disease but are not surgical candidates.

A SWOG trial (ClinicalTrials.gov identifier: NCT03775265) is testing definitive chemoradiation and bladder preservation for muscle-invasive bladder cancer with and without atezolizumab as part of a randomized phase III trial that will enroll close to 500 patients. This study will activate in the coming months, and will more definitively test whether adding immunotherapy to chemoradiation will improve our ability to cure patients with muscle-invasive bladder cancer and, most importantly, help them to keep their bladders.

A great deal of evidence exists to support this strategy. Most recently, the PACIFIC trial evaluated patients with stage III non–small-cell lung cancer treated with definitive chemoradiation and then randomized to receive adjuvant durvalumab or adjuvant placebo. The updated data from that trial, published in the 

in fall 2018, showed significantly improved disease-free survival, with a hazard ratio close to 0.5, as well as significantly improved survival with the addition of durvalumab to chemoradiation.[9] These data suggest that immunotherapy truly does synergize with chemoradiation and hopefully induces a more potent and systemic immune response. This would allow us to eradicate not only the disease that is irradiated, but also systemic micrometastases, by initiating a more effective immune response.

Dr. Balar has a speaking agreement with and serves on advisory boards and as a consultant for AstraZeneca, Genentech, Incyte, Merck, and Pfizer/EMD Serono.

Present and Future Outlook for Immunotherapy in Urothelial Cancers

Immune checkpoint inhibitors have transformed the treatment landscape for urothelial cancers, with the approval of 5 different agents for patients with metastatic disease in less than 3 years. The enthusiasm for these therapies has been sustained by the potential durable response rates and tumor control combined with their safe and favorable adverse event profile.

However, a wave of disappointment surged when one of the confirmatory phase III trials with atezolizumab (IMvigor211) failed to demonstrate a survival advantage vs chemotherapy for the second-line treatment of metastatic urothelial carcinoma.[1] And it persisted when the US Food and Drug Administration restricted the front-line use of pembrolizumab and atezolizumab to those with elevated programmed death ligand 1 (PD-L1) expression[2] following the decrease in survival observed in patients with low PD-L1 status in the single-arm immune checkpoint inhibitor–treated cohorts of the IMvigor130[3] and KEYNOTE-361[4] studies.

As it stands today, overall response rates are still relatively low for unselected patients. For those fortunate patients who respond, however, the durability of the responses is typically high. Additionally, our ability to predict responders is limited, and more research on predictive biomarkers is needed.

Driven by our improved understanding of cancer immunology and the successful results seen in other diseases such as lung and kidney cancer, a wealth of very interesting clinical trials are currently testing immune checkpoint inhibitors in different clinical settings. This research is nicely summarized by Dr. Balar in this interview. Several studies are testing the combination of immunotherapy with chemotherapy, or with different immunotherapies, in the advanced-stage setting. Others are testing immune checkpoint inhibitors in curative stages, either as monotherapy or combined with other treatment modalities such as radiation therapy.

Preliminary efficacy data from these studies are very promising and open the door to significant changes in the management of this disease. Will immune checkpoint inhibitors replace chemotherapy as neoadjuvant therapy? Can we skip radical cystectomy in patients who achieve a complete response? Should we think about bladder preservation as a true alternative? Is a combination chemotherapy/immune checkpoint inhibitor regimen the next standard of care for metastatic cancer patients?

Dr. Barata has no significant financial interest or relationship with the manufacturer of any product or provider of any service mentioned in this article

Dr. Barata is an Assistant Professor in the Department of Internal Medicine, Section of Hematology and Medical Oncology, at Tulane Medical School, New Orleans, Louisiana, with a focus on genitourinary cancers and clinical trials.

Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376:1015-26.

Dr. Balar highlights promising evidence on the potential benefits of the use of immunotherapy in the advanced bladder cancer setting.

Oncology Vol 33 No 4