Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study.

BACKGROUND: Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. METHODS: The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0-2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. FINDINGS: Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7-26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30-49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3-4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3-4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. INTERPRETATION: With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations. FUNDING: Janssen Research & Development.

Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.

BACKGROUND: Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition. METHODS: In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life. RESULTS: The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group. CONCLUSIONS: Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).

CheckMate 141: 1-Year Update and Subgroup Analysis of Nivolumab as First-Line Therapy in Patients with Recurrent/Metastatic Head and Neck Cancer.

Nivolumab significantly improved overall survival (OS) vs investigator's choice (IC) of chemotherapy at the primary analysis of randomized, open-label, phase 3 CheckMate 141 in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). Here, we report that OS benefit with nivolumab was maintained at a minimum follow-up of 11.4 months. Further, OS benefit with nivolumab vs IC was also noted among patients who received first-line treatment for R/M SCCHN after progressing on platinum therapy for locally advanced disease in the adjuvant or primary (i.e., with radiation) setting.

Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial.

BACKGROUND: Patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options and poor prognosis. Nivolumab significantly improved survival of this patient population when compared with standard single-agent therapy of investigator's choice in Checkmate 141; here we report the effect of nivolumab on patient-reported outcomes (PROs). METHODS: CheckMate 141 was a randomised, open-label, phase 3 trial in patients with recurrent or metastatic squamous cell carcinoma of the head and neck who progressed within 6 months after platinum-based chemotherapy. Patients were randomly assigned (2:1) to nivolumab 3 mg/kg every 2 weeks (n=240) or investigator's choice (n=121) of methotrexate (40-60 mg/m2 of body surface area), docetaxel (30-40 mg/m2), or cetuximab (250 mg/m2 after a loading dose of 400 mg/m2) until disease progression, intolerable toxicity, or withdrawal of consent. On Jan 26, 2016, the independent data monitoring committee reviewed the data at the planned interim analysis and declared overall survival superiority for nivolumab over investigator's choice therapy (primary endpoint; described previously). The protocol was amended to allow patients in the investigator's choice group to cross over to nivolumab. All patients not on active therapy are being followed for survival. As an exploratory endpoint, PROs were assessed at baseline, week 9, and every 6 weeks thereafter using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30), the EORTC head and neck cancer-specific module (EORTC QLQ-H&N35), and the three-level European Quality of Life-5 Dimensions (EQ-5D) questionnaire. Differences within and between treatment groups in PROs were analysed by ANCOVA among patients with baseline and at least one other assessment. All randomised patients were included in the time to clinically meaningful deterioration analyses. Median time to clinically meaningful deterioration was analysed by Kaplan-Meier methods. CheckMate 141 was registered with ClinicalTrials.org, number NCT02105636. FINDINGS: Patients were enrolled between May 29, 2014, and July 31, 2015, and subsequently 361 patients were randomly assigned to receive nivolumab (n=240) or investigator's choice (n=121). Among them, 129 patients (93 in the nivolumab group and 36 in the investigator's choice group) completed any of the PRO questionnaires at baseline and at least one other assessment. Treatment with nivolumab resulted in adjusted mean changes from baseline to week 15 ranging from -2·1 to 5·4 across functional and symptom domains measured by the EORTC QLQ-C30, with no domains indicating clinically meaningful deterioration. By contrast, eight (53%) of the 15 domains in the investigator's choice group showed clinically meaningful deterioration (10 points or more) at week 15 (change from baseline range, -24·5 to 2·4). Similarly, on the EORTC QLQ-H&N35, clinically meaningful worsening at week 15 was seen in no domains in the nivolumab group and eight (44%) of 18 domains in the investigator's choice group. Patients in the nivolumab group had a clinically meaningful improvement (according to a difference of 7 points or greater) in adjusted mean change from baseline to week 15 on the EQ-5D visual analogue scale, in contrast to a clinically meaningful deterioration in the investigator's choice group (7·3 vs -7·8). Differences between groups were significant and clinically meaningful at weeks 9 and 15 in favour of nivolumab for role functioning, social functioning, fatigue, dyspnoea, and appetite loss on the EORTC QLQ-C30 and pain and sensory problems on the EORTC QLQ-H&N35. Median time to deterioration was significantly longer with nivolumab versus investigator's choice for 13 (37%) of 35 domains assessed across the three questionnaires. INTERPRETATION: In this exploratory analysis of CheckMate 141, nivolumab stabilised symptoms and functioning from baseline to weeks 9 and 15, whereas investigator's choice led to clinically meaningful deterioration. Nivolumab delayed time to deterioration of patient-reported quality-of-life outcomes compared with single-agent therapy of investigator's choice in patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck. In view of the major unmet need in this population and the importance of maintaining or improving quality of life for patients with recurrent or metastatic squamous cell carcinoma of the head and neck, these data support nivolumab as a new standard-of-care option in this setting. FUNDING: Bristol-Myers Squibb.

Vismodegib or cixutumumab in combination with standard chemotherapy for patients with extensive-stage small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E1508).

BACKGROUND: Preclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer. METHODS: Patients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m(2) on day 1 and etoposide at 100 mg/m(2) on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline. RESULTS: One hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (≤100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006). CONCLUSIONS: There was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371-2378. © 2016 American Cancer Society.

Quantification of Anaplastic Lymphoma Kinase Protein Expression in Non-Small Cell Lung Cancer Tissues from Patients Treated with Crizotinib.

BACKGROUND: Crizotinib has antitumor activity in ALK (anaplastic lymphoma receptor tyrosine kinase)-rearranged non-small cell lung cancer (NSCLC). The current diagnostic test for ALK rearrangement is breakapart fluorescence in situ hybridization (FISH), but FISH has low throughput and is not always reflective of protein concentrations. The emergence of multiple clinically relevant biomarkers in NSCLC necessitates efficient testing of scarce tissue samples. We developed an anaplastic lymphoma kinase (ALK) protein assay that uses multiplexed selected reaction monitoring (SRM) to quantify absolute amounts of ALK in formalin-fixed paraffin-embedded (FFPE) tumor tissue. METHODS: After validation in formalin-fixed cell lines, the SRM assay was used to quantify concentrations of ALK in 18 FFPE NSCLC samples that had been tested for ALK by FISH and immunohistochemistry. Results were correlated with patient response to crizotinib. RESULTS: We detected ALK in 11 of 14 NSCLC samples with known ALK rearrangements by FISH. Absolute ALK concentrations correlated with clinical response in 5 of 8 patients treated with crizotinib. The SRM assay did not detect ALK in 3 FISH-positive patients who had not responded to crizotinib. In 1 of these cases, DNA sequencing revealed a point mutation that predicts a nonfunctional ALK fusion protein. The SRM assay did not detect ALK in any tumor tissue with a negative ALK status by FISH or immunohistochemistry. CONCLUSIONS: ALK concentrations measured by SRM correlate with crizotinib response in NSCLC patients. The ALK SRM proteomic assay, which may be multiplexed with other clinically relevant proteins, allows for rapid identification of patients potentially eligible for targeted therapies.

Building a statewide clinical trials network for cancer care in West Virginia.

In the United States, mortality rates have been declining for certain tumors, For the majority of advanced stage cancer types, cure is unattainable but treatment is still evolving. Advances in the treatment of cancer can be achieved by enrolling patients in cancer clinical trials. Presently, less than 3% of adult cancer patients participate on clinical trials in the United States. Providing cancer care and access to clinical trials are a challenge in a rural state, with a dispersed population base, such as West Virginia. Building upon recognition of barriers to clinical trials awareness and access, oncology leaders in the state are in the formative stages of developing a statewide cancer clinical trials network. Realization of this network will have an enormous impact on cancer care in our state and perhaps can serve as a model for other community and physician teams for other diseases.

A randomized, open-label, Phase III clinical trial of nivolumab vs. therapy of investigator's choice in recurrent squamous cell carcinoma of the head and neck: A subanalysis of Asian patients versus the global population in checkmate 141.

OBJECTIVES: To assess efficacy and safety of nivolumab versus investigator's choice of therapy (IC) in Asian patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Thirty-four patients from Japan, Taiwan, Hong Kong, and Korea received nivolumab 3mg/kg (n=23) every 2weeks or IC (n=11), as part of a global trial (n=361), until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). RESULTS: Median OS was 9.5months (95% confidence interval [CI] 9.1-NR) with nivolumab and 6.2months (95% CI 2.6-NR) with IC. Seven (30.4%) patients receiving nivolumab and six (54.5%) receiving IC died. The hazard ratio (HR) for risk of death (nivolumab vs. IC) was 0.50 (95% CI 0.17-1.48). Median progression-free survival was 1.9months (95% CI 1.6-7.5) with nivolumab and 1.8months (95% CI 0.4-6.1) with IC (HR 0.57 [95% CI 0.25-1.33]). Objective response rates (complete+partial responses) were 26.1% (6/23 patients; 95% CI 10.2-48.4) for nivolumab and 0% (0/11 patients; 95% CI 0.0-28.5) for IC. Sixteen (69.6%) nivolumab-treated patients and 10 (90.9%) patients receiving IC had a treatment-related adverse event, most commonly decreased appetite (21.7%), pruritus, rash, and fatigue (17.4% each) with nivolumab, and nausea, stomatitis, and decreased appetite (27.3% each) with IC. CONCLUSION: Nivolumab demonstrated a survival advantage compared with conventional treatments in Asian patients with platinum-refractory recurrent or metastatic SCCHN, and was well tolerated. Clinical trial registration NCT02105636.

Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma.

PURPOSE: The objective of this study was to define the maximum-tolerated dose (MTD), the recommended phase II dose, the dose-limiting toxicity, and determine the pharmacokinetic (PK) and pharmacodynamic profiles of MS-275. PATIENTS AND METHODS: Patients with advanced solid tumors or lymphoma were treated with MS-275 orally initially on a once daily x 28 every 6 weeks (daily) and later on once every-14-days (q14-day) schedules. The starting dose was 2 mg/m2 and the dose was escalated in three- to six-patient cohorts based on toxicity assessments. RESULTS: With the daily schedule, the MTD was exceeded at the first dose level. Preliminary PK analysis suggested the half-life of MS-275 in humans was 39 to 80 hours, substantially longer than predicted by preclinical studies. With the q14-day schedule, 28 patients were treated. The MTD was 10 mg/m2 and dose-limiting toxicities were nausea, vomiting, anorexia, and fatigue. Exposure to MS-275 was dose dependent, suggesting linear PK. Increased histone H3 acetylation in peripheral-blood mononuclear-cells was apparent at all dose levels by immunofluorescence analysis. Ten of 29 patients remained on treatment for > or = 3 months. CONCLUSION: The MS-275 oral formulation on the daily schedule was intolerable at a dose and schedule explored. The q14-day schedule is reasonably well tolerated. Histone deacetylase inhibition was observed in peripheral-blood mononuclear-cells. Based on PK data from the q14-day schedule, a more frequent dosing schedule, weekly x 4, repeated every 6 weeks is presently being evaluated.

Definitive Upfront Stereotactic Ablative Radiotherapy Combined with Image-Guided, Intensity Modulated Radiotherapy (IG-IMRT) or IG-IMRT Alone for Locally Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Image-guided (IG) intensity-modulated radiotherapy (IMRT) enables maximal tumor margin reduction for the sparing of organs at risk (OARs) when used to treat locally advanced non-small cell lung cancer (NSCLC) with definitive chemo-radiation. It also allows for the incorporation of stereotactic ablative radiotherapy (SABR) into the treatment regimen. Here, we describe our initial experience in combining definitive upfront SABR to the primary lesion with chemo-radiation delivered with conventionally fractionated IG-IMRT to the remaining regional disease; along with clinical outcome following chemo-radiation with conventionally fractionated IG-IMRT alone in the treatment of locally advanced NSCLC. METHODS: The clinical outcome of 29 patients with locally advanced NSCLC who underwent conventionally fractionated IG-IMRT, or definitive upfront SABR followed by IG-IMRT combined with chemotherapy (induction, concurrent, or both) was retrospectively reviewed. RESULTS: After a median follow up of 23.7 months, the median overall survival (OS) and progression-free survival (PFS) were 19.8 and 11.3 months, respectively. The 2 year local, regional, and distant control was 60%, 62%, and 38%, respectively. No local failure was observed in 3 patients following SABR + IG-IMRT while 6/26 patients failed locally following IG-IMRT alone. SABR + IG-IMRT was well tolerated. No ≥ grade 3 radiation-related toxicity was observed. CONCLUSION: Definitive upfront SABR followed by IG-IMRT in selected patients with locally advanced NSCLC warrants further investigation in future clinical trials, while chemo-radiation with IG-IMRT alone was well tolerated.

Breaking and entering into the CNS: clues from solid tumor and nonmalignant models with relevance to hematopoietic malignancies.

Various malignancies invade the CNS sanctuary site, accounting for the vast majority of CNS neoplastic foci and contributing to significant morbidity as well as mortality. The blood-brain barrier (BBB) exhibits considerable impermeability to chemotherapeutic agents, severely limiting therapeutic options available for patients developing metastatic CNS involvement, accounting for poor outcomes. The mechanisms by which malignant cells breach the highly exclusive BBB and subsequently survive in this unique anatomical site remain poorly understood, with most of the current knowledge stemming from nonmalignant and solid malignancy models. While solid and hematologic malignancies may face different challenges once within the CNS (e.g., solid tumor parenchymal metastasis compared to masses/nodules/leptomeningeal disease in hematologic malignancies), commonality exists in the process of migrating across the BBB from the circulation. Specifically considering this last point, this review aims to survey the current mechanistic knowledge regarding malignant migration across the BBB, necessarily emphasizing the better studied solid tumor and nonmalignant models with the intention of highlighting both the current knowledge gap and additional work required to effectively consider how hematopoietic malignancies breach the CNS.

Sorafenib and thyroid cancer.

The emergence of serine-threonine small molecule, multi-targeted kinase inhibitors over the past decade is greatly impacting the therapeutic armamentarium for numerous malignancies, especially thyroid carcinoma. Chief among them are a class of agents referred to as vascular endothelial growth factor signal pathway inhibitors. Sorafenib is a lead compound that has been recently approved by the US FDA for radioactive iodine-refractory differentiated thyroid cancer (DTC). Sorafenib clearly is altering the natural history of DTC. In the largest randomized Phase III study ever conducted in DTC, sorafenib significantly improved progression-free survival compared to placebo (10.8 vs 5.8 months) and had an acceptable and manageable safety profile, though commonly attributed side effects of hand-foot skin reaction, diarrhea and hypertension were more frequent than in other settings. This agent represents a new treatment option for patients with progressive radioactive iodine-refractory DTC.

Strategies of dose escalation in the treatment of locally advanced non-small cell lung cancer: image guidance and beyond.

Radiation dose in the setting of chemo-radiation for locally advanced non-small cell lung cancer (NSCLC) has been historically limited by the risk of normal tissue toxicity and this has been hypothesized to correlate with the poor results in regard to local tumor recurrences. Dose escalation, as a means to improve local control, with concurrent chemotherapy has been shown to be feasible with three-dimensional conformal radiotherapy in early phase studies with good clinical outcome. However, the potential superiority of moderate dose escalation to 74 Gy has not been shown in phase III randomized studies. In this review, the limitations in target volume definition in previous studies; and the factors that may be critical to safe dose escalation in the treatment of locally advanced NSCLC, such as respiratory motion management, image guidance, intensity modulation, FDG-positron emission tomography incorporation in the treatment planning process, and adaptive radiotherapy, are discussed. These factors, along with novel treatment approaches that have emerged in recent years, are proposed to warrant further investigation in future trials in a more comprehensive and integrated fashion.

A phase I and pharmacokinetic study of oral perifosine with different loading schedules in patients with refractory neoplasms.

PURPOSE: To determine the maximum tolerated dose (MTD) of perifosine (NSC 639966), an alkylphospholipid modulator of signal transduction, using different oral loading and maintenance regimens in an effort to avoid gastrointestinal toxicity while seeking maximal sustained plasma concentrations. METHODS: Thirty-one patients with advanced neoplasms were treated with monthly cycles of perifosine loading doses of 300, 600, 900, 1,200 and 1,500 mg (dose levels 1 through 5, respectively) on days 1-2 depending on the actual dose of the initial cycle. For subsequent cycles, perifosine loading doses were reduced to 100, 200, 300, 400 and 1,000 mg at the respective corresponding dose levels. Daily perifosine "maintenance" doses of 50, 100, 150, 200 and 250 mg for levels 1 through 5, respectively, commenced on days 2 or 3 and continued for a total of 21 days. No treatment was given for days 22-27. The pharmacokinetics of perifosine with these schedules was characterized. RESULTS: Dose-limiting diarrhea developed at or above dose level 4. The MTD and recommended phase II dose was dose level 3B, with a loading dose of 900 mg on day 1 divided into two doses of 450 mg administered 6 h apart and a maintenance dose of 150 mg on day 2 through 21. On subsequent cycles, the loading dose was reduced to 300 mg. Non-gastrointestinal toxicities included three episodes of gout or gout-like syndromes observed at doses above the MTD. The median peak plasma concentration of perifosine achieved at the MTD was approximately 8.3 µg/mL. Four patients had stable disease ranging from 167 to 735 days. CONCLUSIONS: Perifosine given according to a loading and maintenance schedule can safely sustain concentrations of drug, approaching concentrations achieved in preclinical models with evidence of anti-tumor effect.

Signal transduction--directed cancer treatments.

The pathogenic mechanisms giving rise to cancer frequently involve altered signal transduction pathways. Therefore therapeutic agents that directly address signal transduction molecules are being explored as cancer treatments. Inhibitors of protein tyrosine and threonine kinases including STI-571, ZD-1839, OSI-774, and flavopiridol are ATP-site antagonists that have completed initial phase I and phase II evaluations. Herceptin and C225 are monoclonal antibodies also directed against signaling targets. Numerous other kinase antagonists are in clinical evaluation, including UCN-01 and PD184352. Alternative strategies to downmodulate kinase-driven signaling include 17-allyl-amino-17-demethoxygeldanamycin and rapamycin derivatives, and phospholipase-directed signaling may be modulated by alkylphospholipids. Farnesyltransferase inhibitors were originally developed as inhibitors of ras-driven signals but may have activity by affecting other or additional targets. Signal transduction will remain a fertile basis for suggesting cancer treatments of the future, the evaluation of which should include monitoring effects of the drugs on their intended target signaling molecules in preclinical and early clinical studies.