Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study.

BACKGROUND: Few treatment options are available for patients with advanced renal cell carcinoma who have received previous anti-PD-1-based or anti-PD-L1-based immunotherapy. Combining belzutifan, an HIF-2α inhibitor, with cabozantinib, a multitargeted tyrosine-kinase inhibitor of VEGFR, c-MET, and AXL, might provide more antitumoural effects than either agent alone. We aimed to investigate the antitumour activity and safety of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma that was previously treated with immunotherapy. METHODS: This open-label, single-arm, phase 2 study was conducted at ten hospitals and cancer centres in the USA. Patients were enrolled into two cohorts. Patients in cohort 1 had treatment-naive disease (results will be reported separately). In cohort 2, eligible patients were aged 18 years or older with locally advanced or metastatic clear cell renal cell carcinoma, measurable disease according to Response Evaluation Criteria in Solid Tumours version 1.1, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and had previously received immunotherapy and up to two systemic treatment regimens. Patients were given belzutifan 120 mg orally once daily and cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The primary endpoint was confirmed objective response assessed by the investigator. Antitumour activity and safety were assessed in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT03634540, and is ongoing. FINDINGS: Between Sept 27, 2018, and July 14, 2020, 117 patients were screened for eligibility, 52 (44%) of whom were enrolled in cohort 2 and received at least one dose of study treatment. Median age was 63·0 years (IQR 57·5-68·5), 38 (73%) of 52 patients were male, 14 (27%) were female, 48 (92%) were White, two (4%) were Black or African American, and two were Asian (4%). As of data cutoff (Feb 1, 2022), median follow-up was 24·6 months (IQR 22·1-32·2). 16 (30·8% [95% CI 18·7-45·1]) of 52 patients had a confirmed objective response, including one (2%) who had a complete response and 15 (29%) who had partial responses. The most common grade 3-4 treatment-related adverse event was hypertension (14 [27%] of 52 patients). Serious treatment-related adverse events occurred in 15 (29%) patients. One death was considered treatment related by the investigator (respiratory failure). INTERPRETATION: Belzutifan plus cabozantinib has promising antitumour activity in patients with pretreated clear cell renal cell carcinoma and our findings provide rationale for further randomised trials with belzutifan in combination with a VEGFR tyrosine-kinase inhibitor. FUNDING: Merck Sharp & Dohme (a subsidiary of Merck & Co) and the National Cancer Institute.

LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy.

The first-in-class, small molecule HIF-2α inhibitor, belzutifan, has demonstrated promising antitumor activity in previously treated patients with clear cell renal cell carcinoma (RCC). HIF-2α also regulates VEGF expression and is involved in resistance to anti-VEGF therapy. This study describes the rationale and design for a randomized, phase III study evaluating efficacy and safety of belzutifan plus the tyrosine kinase inhibitor (TKI) lenvatinib versus the TKI cabozantinib in patients with advanced RCC progressing after anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy. Considering the unmet need for effective and tolerable treatment of advanced RCC following immune checkpoint inhibitors, belzutifan plus lenvatinib may have a positive benefit/risk profile. Clinical Trial Registration: NCT04586231 (ClinicalTrials.gov).

Second-Line Therapies in the Changing Landscape of First-Line Therapies for Metastatic Clear Cell Renal Cell Cancer.

In recent years, first-line therapies for metastatic renal cell carcinoma (mRCC) have shifted to a combination of immune checkpoint inhibitors or a combination of antiangiogenesis tyrosine kinase inhibitors (TKIs) and immunotherapy. This has led to a need to address standard-of-care treatment in the second-line setting. Our review presents an analysis of current and upcoming data to guide treatment decisions. After progression on nivolumab plus ipilimumab, current data favor monotherapy TKI with cabozantinib or axitinib. Current literature for second-line therapy given after combination TKI plus immunotherapy shows the strongest evidence for either single-agent cabozantinib or combination everolimus with lenvatinib. Investigations are ongoing for the role of TKIs with immunotherapy in the second-line setting. Novel agents, such as HIF2α inhibitors, are currently being studied as single agents and in combination with other treatment modalities in efforts to improve patient outcomes in mRCC.

Integrating PARP Inhibitors Into Advanced Prostate Cancer Therapeutics.

DNA-damage repair (DDR) pathway mutations can sensitize cancer cells to a class of cancer therapeutics known as PARP inhibitors. Given that DDR alterations can be found in up to one-third of advanced prostate cancers, PARP inhibitors have recently been established in treatment-refractory settings. We provide an updated review of the clinical data supporting the 4 PARP inhibitors that have undergone the most investigation thus far in metastatic castrate-resistant prostate cancer (mCRPC). Two of these agents are currently approved for the treatment of DDR-altered mCRPC. We end with a discussion on integration of approved PARP inhibitors into advanced prostate cancer clinical practice.

Comparing Physician and Nurse Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Ratings as Predictors of Clinical Outcomes in Patients with Cancer.

BACKGROUND: The Eastern Cooperative Oncology Group Performance Status (ECOG-PS) scale is commonly used by physicians and nurses in oncology, as it correlates with cancer morbidity, mortality, and complications from chemotherapy and can help direct clinical decisions and prognostication. This retrospective cohort study aimed to identify whether ECOG-PS scores rated by oncologist versus nurses differ in their ability to predict clinical outcomes. MATERIALS AND METHODS: Over 19 months, 32 oncologists and 41 chemotherapy nurses from a single academic comprehensive cancer center independently scored ECOG-PS (range: 0-5) for a random sample of 311 patients with cancer receiving chemotherapy. Logistic regression models were fit to evaluate the ability of nurse and physician ECOG-PS scores, as well as the nurse-physician ECOG-PS score difference (nurse minus physician), to predict the occurrence of chemotherapy toxicity (CTCAE v4, grade ≥3) and hospitalizations within 1 month from ECOG-PS ratings, as well as 6-month mortality or hospice referrals. RESULTS: Physician/nurse ECOG-PS agreement was 71% (Cohen's κ = 0.486, p < .0001). Nurse ECOG-PS scores had stronger odds ratio for 6-month mortality or hospice (odds ratio [OR], 3.29, p < .0001) than physician ECOG-PS scores (OR, 2.71, p = .001). Furthermore, ECOG-PS ratings by nurses, but not physicians, correlated with 1-month chemotherapy toxicity (OR, 1.44, p = .021) and 1-month hospitalizations (OR, 1.57, p = .041). Nurse-physician disagreement, but only when physicians gave "healthier" (lower) ratings, was also associated with worse outcomes (chemotherapy toxicity OR = 1.51, p = .045; 1-month hospitalization OR, 1.86, p = .037; 6-month mortality or hospice OR, 2.99, p < .0001). CONCLUSION: Nurse ECOG-PS ratings seem more predictive of important outcomes than those of physicians, and physician-nurse disagreement in ECOG-PS ratings predicts worse outcomes; scoring by nurses may result in additional clinical benefit. IMPLICATIONS FOR PRACTICE: Nurse-rated Eastern Cooperative Oncology Group Performance Status (ECOG-PS) scores, compared with those rated by oncologists, better predicted hospitalizations and severe chemotherapy toxicity within 1 month from ECOG-PS assessment, as well as mortality or hospice referrals within 6 months. Physician-nurse disagreement in ECOG-PS scoring was associated with worse hospitalization, chemotherapy toxicity, and mortality and hospice referral rates. Rating performance statuses of patients with cancer by nurses instead or in addition to oncologists can result in additional clinical benefits, such as improved prognostication, as well as better informed clinical decision making regarding whether or not to administer chemotherapy, the need for additional supportive care, and goals of care discussions.

Sunitinib: Ten Years of Successful Clinical Use and Study in Advanced Renal Cell Carcinoma.

The oral multikinase inhibitor sunitinib malate was approved by the U.S. Food and Drug Administration in January 2006 for use in patients with advanced renal cell carcinoma (RCC). Since then, it has been approved globally for this indication and for patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors and advanced pancreatic neuroendocrine tumors. As we mark the 10-year anniversary of the beginning of the era of targeted therapy, and specifically the approval of sunitinib, it is worthwhile to highlight the progress that has been made in advanced RCC as it relates to the study of sunitinib. We present the key trials and data for sunitinib that established it as a reference standard of care for first-line advanced RCC therapy and, along with other targeted agents, significantly altered the treatment landscape in RCC. Moreover, we discuss the research with sunitinib that has sought to refine its role via patient selection and prognostic markers, improve dosing and adverse event management, and identify predictive efficacy biomarkers, plus the extent to which this research has contributed to the overall understanding and management of RCC. We also explore the key learnings regarding study design and data interpretation from the sunitinib studies and how these findings and the sunitinib development program, in general, can be a model for successful development of other agents. Finally, ongoing research into the continued and future role of sunitinib in RCC management is discussed. THE ONCOLOGIST: 2017;22:41-52 IMPLICATIONS FOR PRACTICE: Approved globally, sunitinib is established as a standard of care for first-line advanced renal cell carcinoma (RCC) therapy and, along with other targeted agents, has significantly altered the treatment landscape in RCC. Research with sunitinib that has sought to refine its role via patient selection and prognostic markers, improve dosing and adverse event management, and identify predictive efficacy biomarkers has contributed to the overall understanding and management of RCC. Key learnings regarding study design and data interpretation from the sunitinib studies and the sunitinib development program, in general, can be a model for the successful development of other agents.

Predicting Real-World Effectiveness of Cancer Therapies Using Overall Survival and Progression-Free Survival from Clinical Trials: Empirical Evidence for the ASCO Value Framework.

OBJECTIVES: To measure the relationship between randomized controlled trial (RCT) efficacy and real-world effectiveness for oncology treatments as well as how this relationship varies depending on an RCT's use of surrogate versus overall survival (OS) endpoints. METHODS: We abstracted treatment efficacy measures from 21 phase III RCTs reporting OS and either progression-free survival or time to progression endpoints in breast, colorectal, lung, ovarian, and pancreatic cancers. For these treatments, we estimated real-world OS as the mortality hazard ratio (RW MHR) among patients meeting RCT inclusion criteria in Surveillance and Epidemiology End Results-Medicare data. The primary outcome variable was real-world OS observed in the Surveillance and Epidemiology End Results-Medicare data. We used a Cox proportional hazard regression model to calibrate the differences between RW MHR and the hazard ratios on the basis of RCTs using either OS (RCT MHR) or progression-free survival/time to progression surrogate (RCT surrogate hazard ratio [SHR]) endpoints. RESULTS: Treatment arm therapies reduced mortality in RCTs relative to controls (average RCT MHR = 0.85; range 0.56-1.10) and lowered progression (average RCT SHR = 0.73; range 0.43-1.03). Among real-world patients who used either the treatment or the control arm regimens evaluated in the relevant RCT, RW MHRs were 0.6% (95% confidence interval -3.5% to 4.8%) higher than RCT MHRs, and RW MHRs were 15.7% (95% confidence interval 11.0% to 20.5%) higher than RCT SHRs. CONCLUSIONS: Real-world OS treatment benefits were similar to those observed in RCTs based on OS endpoints, but were 16% less than RCT efficacy estimates based on surrogate endpoints. These results, however, varied by tumor and line of therapy.

Circulating tumor cells in prostate cancer: beyond enumeration.

Circulating tumor cells (CTCs) are a population of rare cancer cells that have detached from the primary tumor and/or metastatic lesions and entered the peripheral circulation. Enumeration of CTCs has demonstrated value as a prognostic biomarker, and newer studies have pointed to information beyond enumeration that is of critical importance in prostate cancer. Technologic advances that permit examination of the morphology, function, and molecular content of CTCs have made it possible to measure these factors as part of liquid biopsy. These advances provide a way to study tumor evolution and the development of resistance to therapy. Recent breakthroughs have created new applications for CTCs that will affect the care of patients with prostate cancer.

Adjuvant treatment for renal cell carcinoma: do we finally have a major breakthrough?

Clinical parameters can be used to identify patients at greatest risk for recurrence following nephrectomy for clinically localized renal cell carcinoma (RCC). Molecular tools are being developed to improve risk stratification. An increasing list of available treatments for metastatic RCC continues to provide hope that an effective adjuvant therapy will be identified for patients with high-risk, clinically localized disease. In a phase 3 adjuvant therapy trial (S-TRAC), sunitinib increased median disease-free survival in patients with clear cell RCC who were at very high risk. This is the first positive phase 3 adjuvant therapy trial using a targeted therapy. However, a much larger phase 3 trial comparing sunitinib, sorafenib, and placebo (ASSURE) was negative. Careful review of recent adjuvant therapy trials reveals insights about who may benefit from adjuvant therapy and provides lessons for future trial design.

Randomized phase 2 trial of erlotinib in combination with high-dose celecoxib or placebo in patients with advanced non-small cell lung cancer.

BACKGROUND: Cyclooxygenase 2 (COX-2)-dependent signaling represents a potential mechanism of resistance to therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This is mediated in part through an EGFR-independent activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (Erk) by prostaglandin E2 (PGE2). PGE2 promotes downregulation of E cadherin and epithelial to mesenchymal transition. The current study investigated EGFR and COX-2 inhibition in patients with non-small cell lung cancer (NSCLC) and elevated baseline urinary metabolite of PGE2 (PGEM). METHODS: Patients with stage IIIB/IV (AJCC 6th edition) NSCLC who progressed after at least 1 line of therapy or refused standard chemotherapy were randomized to receive erlotinib and celecoxib versus erlotinib and placebo. The primary endpoint was progression-free survival (PFS) with 80% power to detect a 50% improvement with a 1-sided significance level of .2 in the intent-to-treat and elevated baseline PGEM populations. Secondary endpoints included response rate, overall survival, and evaluation of molecular markers to assess targeting COX-2-related pathways and evaluate EGFR tyrosine kinase inhibitor resistance. RESULTS: A total of 107 patients were enrolled with comparable baseline characteristics. Among the patients treated with celecoxib, those with wild-type EGFR were found to have an increased PFS (3.2 months vs 1.8 months; P = .03). PFS was numerically improved among patients in the intent-to-treat group who received erlotinib and celecoxib compared with those treated with erlotinib and placebo (5.4 months vs 3.5 months; P = .33) and was increased in patients in the erlotinib and celecoxib arm with elevated baseline PGEM (5.4 months vs 2.2 months; P = .15). Adverse events were similar in both treatment arms. CONCLUSIONS: The combination of erlotinib and celecoxib did not appear to improve outcomes in an unselected population, but selection by elevated baseline PGEM led to an increase in PFS with this combination. Patients with EGFR wild-type status may benefit from the combination of erlotinib and celecoxib.

Literature Review and Profile of Cancer Diseases Among Afghan Refugees in Iran: Referrals in Six Years of Displacement.

BACKGROUND: There is a paucity of research on the profile of cancers among displaced populations, specifically Afghan refugees in Iran. This study illustrates the pattern of cancers in this population, and highlights the challenges of cancer care in displaced people with the intent that this data will facilitate appropriate allocation of resources to improve care in this population. MATERIAL AND METHODS: This was a retrospective cross-sectional study, in which we collected the demographics and profile of cancers among Afghan refugees from 2005 to 2010 from referrals to the United Nations High Commissioner for Refugees (UNHCR) offices in Iran. Accrued evidence by other studies published between January 1993 and July 2014 pertaining to cancer diagnoses in refugees from Afghanistan, Tibet, Syria, Jordan, and Iraq was reviewed. RESULTS: Cancer diagnoses accounted for 3083 of 23 152 total referrals, with 49% female and 51% male cases; 23.3% were 0-17 years of age, 61.2% were 18-59, and 15.5% were above 60. The most common health referral for females and males (0-17) was malignant neoplasms of lymphatic and hematopoietic tissue, accounting for 34.2%. In the age groups 18-59 and above 60 for both male and females it was malignant neoplasm of the digestive system, occurring in 26.3% and 48.7%, respectively. CONCLUSIONS: In the setting of humanitarian crises especially war, cancer diagnoses among refugees is a major health burden both on the host countries and the international community with serious implications considering the recent growing trend in the Middle Eastern countries. The prevalence of certain cancer diagnoses among refugees, like gastrointestinal, respiratory, breast, and genitourinary cancers necessitates a multidirectional approach, primarily aimed at prevention and early detection. International partnerships are essential for improvement in cancer surveillance service availability, and delivery of the standard of care, in an overall effort to reduce the human cost, monetary, and resource associated burdens of cancer. Recommendations to implement effective prevention and management goals as well as improved record keeping in the refugee setting and the acquisition of secure and sustainable funding sources should be implemented in collaboration with global humanitarian agencies like UNHCR.

Characterizing fatigue associated with sunitinib and its impact on health-related quality of life in patients with metastatic renal cell carcinoma.

BACKGROUND: Using phase 3 trial data for sunitinib versus interferon (IFN)-α in treatment-naive patients with metastatic renal cell carcinoma, retrospective analyses characterized sunitinib-associated fatigue and its impact on patient-reported health-related quality of life (HRQoL). METHODS: Patients received sunitinib at a dose of 50 mg/day on a schedule of 4 weeks on/2 weeks off (375 patients) or IFN-α at a dose of 9 MU subcutaneously 3 times per week (360 patients). HRQoL was self-assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-15-item (FKSI-15) questionnaire, with fatigue assessed using its Disease-Related Symptoms subscale. Fatigue was also assessed by providers using Common Terminology Criteria for Adverse Events (CTCAE). A repeated-measures model (M1) and random intercept-slope model (M2) characterized sunitinib-associated fatigue over time. Another repeated-measures model examined the relationship between HRQoL scores and CTCAE fatigue grade. RESULTS: M1 demonstrated that the initial increase in patient-reported fatigue with sunitinib was worst during cycle 1, with mean values numerically better at subsequent cycles; most pairwise comparisons of consecutive CTCAE fatigue cycle means were not found to be statistically significant. M2 demonstrated that the overall trend (slope) for patient-reported and CTCAE fatigue with sunitinib was not statistically different from 0. The relationship between most HRQoL scores and CTCAE fatigue was close to linear regardless of treatment, with lower scores (worse HRQoL) corresponding to higher fatigue grade. The majority of HRQoL scores were better with sunitinib versus IFN-α for the same CTCAE fatigue grade. CONCLUSIONS: Patients reported worse fatigue during the first sunitinib cycle. However, in subsequent consecutive cycles, less fatigue was reported with no statistically significant worsening. CTCAE fatigue assessment may not fully capture patient treatment experience.

A phase II trial of AS1411 (a novel nucleolin-targeted DNA aptamer) in metastatic renal cell carcinoma.

BACKGROUND: DNA aptamers represent a novel strategy in anti-cancer medicine. AS1411, a DNA aptamer targeting nucleolin (a protein which is overexpressed in many tumor types), was evaluated in patients with metastatic, clear-cell, renal cell carcinoma (RCC) who had failed treatment with ≥1 prior tyrosine kinase inhibitor. METHODS: In this phase II, single-arm study, AS1411 was administered at 40 mg/kg/day by continuous intravenous infusion on days 1-4 of a 28-day cycle, for two cycles. Primary endpoint was overall response rate; progression-free survival (PFS) and safety were secondary endpoints. RESULTS: 35 patients were enrolled and treated. One patient (2.9 %) had a response to treatment. The response was dramatic (84 % reduction in tumor burden by RECIST 1.0 criteria) and durable (patient remains free of progression 2 years after completing therapy). Whole exome sequencing of this patient's tumor revealed missense mutations in the mTOR and FGFR2 genes which is of interest because nucleolin is known to upregulate mTOR pathway activity by enhancing AKT1 mRNA translation. No other responses were seen. Thirty-four percent of patients had an AS1411-related adverse event, all of which were mild or moderate. CONCLUSIONS: AS1411 appears to have minimal activity in unselected patients with metastatic RCC. However, rare, dramatic and durable responses can be observed and toxicity is low. One patient in this study had an excellent response and was found to have FGFR2 and mTOR mutations which will be of interest in future efforts to discover and validate predictive biomarkers of response to nucleolin targeted compounds. DNA aptamers represent a novel way to target cancer cells at a molecular level and continue to be developed with a view to improving treatment and imaging in cancer medicine.

Programmed death-1 inhibition in renal cell carcinoma: clinical insights and future directions.

The treatment of metastatic renal cell carcinoma (mRCC) has evolved markedly over the past decade, broaden- ing beyond immune-based strategies (eg, interleukin-2 and interferon-α) to include targeted agents (eg, sunitinib [Sutent, Pfizer] and sorafenib [Nexavar, Bayer]). Recently, there has been a renewed interest in immune-based strategies, with clinical trials underway to assess vaccines and other immunomodulatory agents. Of particular interest are agents that inhibit the interaction between the programmed death-1 (PD-1) receptor and its ligand (PD-L1) at the T-cell/antigen-presenting cell interface. This interaction produces T-cell anergy and therefore stifles the antitumor immune response. Monoclonal antibodies to PD-1 (eg, nivolumab, lambrolizumab, and pidilizumab) and PD-L1 (MPDL3280A and BMS-936559) are in various stages of clinical development. The clinical trajectory of these agents is discussed herein, with specific attention to the potential placement of PD-1/ PD-L1 inhibition in the crowded therapeutic landscape of mRCC.

Disparities With Systemic Therapies for Black Men Having Advanced Prostate Cancer: Where Do We Stand?

PURPOSE: Prostate cancer represents the most common cancer diagnosis in Black men and is the second leading cause of cancer death in this population. Multilevel disparities have been well-documented in Black men with prostate cancer and play a role in poorer survival outcomes when compared with White men with prostate cancer. In this review, we highlight the changing trend in disparities for systemic therapy outcomes in Black men diagnosed with metastatic prostate cancer. METHODS: We reviewed data from real-world registries and prospective clinical trials with a particular focus on equal access settings to compare outcomes to systemic therapies between Black and White men with metastatic prostate cancer. RESULTS: In metastatic prostate cancer, there is growing evidence to suggest that Black men may have similar, if not better, outcomes to systemic therapies than White men with advanced disease, as corroborated by prospective studies and clinical trials where health care delivery and follow-up are more likely to be standardized. CONCLUSION: This review illustrates the importance of nonbiological drivers of racial disparities in Black men with advanced prostate cancer. Mitigating barriers to health care access and delivery as well as including participation in clinical trials will be pivotal to ongoing efforts to address disparities in systemic therapy outcomes for Black men with metastatic prostate cancer.

Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: new strategies for overcoming resistance to VEGFR and mTORC1 inhibitors.

With the advent of molecularly targeted agents, treatment of metastatic renal cell carcinoma (mRCC) has improved significantly. Agents targeting the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin complex 1 (mTORC1) are more effective and less toxic than previous standards of care involving cytotoxic and cytokine therapies. Unfortunately, many patients relapse following treatment with VEGFR and mTORC1 inhibitors as a result of acquired resistance mechanisms, which are thought to lead to the reestablishment of tumor vasculature. Specifically, the loss of negative feedback loops caused by inhibition of mTORC1 leads to upregulation of downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway and subsequent activation of hypoxia-inducible factor, an activator of angiogenesis. De novo resistance involving activated PI3K signaling has also been observed. These observations have led to the development of novel agents targeting PI3K, mTORC1/2 and PI3K/mTORC1/2, which have demonstrated antitumor activity in preclinical models of RCC. Several agents--BKM120, BEZ235 and GDC-0980--are being investigated in clinical trials in patients with metastatic/advanced RCC, and similar agents are being tested in patients with solid tumors. The future success of mRCC treatment will likely involve a combination of agents targeting the multiple pathways involved in angiogenesis, including VEGFR, PI3K and mTORC1/2.

Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials.

BACKGROUND: Several targeted drugs are approved for treatment of patients with metastatic renal-cell cancer, but no validated biomarkers are available for prediction of clinical outcome. We aimed to assess the prognostic and predictive associations of pretreatment plasma concentrations of cytokine and angiogenic factors (CAFs) with data from a phase 2 and a phase 3 trial of pazopanib treatment. METHODS: We used a three-step approach for screening, confirmation, and validation of prospective CAF biomarkers. We screened 17 CAFs in 129 patients who had the greatest or least tumour shrinkage in a phase 2 trial of 215 patients treated with pazopanib. We confirmed associations of candidate CAFs (those identified in the screening and from previous studies) with tumour response and progression-free survival (PFS) in 215 patients from this phase 2 trial with an independent analytical platform. We validated confirmed markers in 344 patients from a randomised, placebo-controlled, phase 3 clinical study of pazopanib. FINDINGS: Five candidate markers emerged from initial screening-interleukin 6, interleukin 8, hepatocyte growth factor (HGF), tissue inhibitor of metalloproteinases (TIMP)-1, and E-selectin. Confirmatory analyses identified associations of interleukin 6, interleukin 8, VEGF, osteopontin, E-selectin, and HGF with continuous tumour shrinkage or PFS in patients treated with pazopanib. In the validation set of samples from the phase 3 trial, patients treated with pazopanib who had high concentrations (relative to median) of interleukin 8 (p=0·006), osteopontin (p=0·0004), HGF (p=0·010), and TIMP-1 (p=0·006) had shorter PFS than did those with low concentrations. In the placebo group, high concentrations of interleukin 6 (p<0·0001), interleukin 8 (p=0·002), and osteopontin (p<0·0001) were all prognostically associated with shorter PFS. These factors were stronger prognostic markers than were standard clinical classifications (Eastern Cooperative Oncology Group, Memorial Sloan-Kettering Cancer Center, and Heng criteria). High concentrations of interleukin 6 were predictive of improved relative PFS benefit from pazopanib compared with placebo (p(interaction)=0·009); standard clinical classifications were not predictive of PFS benefit. INTERPRETATION: CAF profiles could provide prognostic information beyond that of standard clinical classification and identify markers predictive of pazopanib benefit in patients with metastatic renal-cell carcinoma. Further studies of the predictive effects of these markers in different populations and with different drugs (eg, mTOR inhibitors) are warranted. FUNDING: GlaxoSmithKline.