Paul H. Gumerlock

Increased Epidermal Growth Factor Receptor Gene Copy Number Detected by Fluorescence In Situ Hybridization Associates With Increased Sensitivity to Gefitinib in Patients With Bronchioloalveolar Carcinoma Subtypes: A Southwest Oncology Group Study

PURPOSE Bronchioloalveolar carcinoma (BAC) and adenocarcinomas with BAC features seem to be increasing in incidence, particularly in younger, never-smoking women. Epidermal growth factor receptor (EGFR) inhibitors demonstrated response rates of 20% to 30% in patients with advanced BAC subtypes, but selection methods for patient therapy are not established. PATIENTS AND METHODS EGFR and HER2 gene copy numbers were assessed by fluorescence in situ hybridization (FISH) in 81 patients treated with gefitinib 500 mg/d (Southwest Oncology Group protocol S0126) and were correlated to treatment outcome. Tumors were classified into two main strata: FISH-positive (high polysomy/gene amplification) and FISH-negative (disomy/low polysomy). RESULTS In 81 patients, the median survival time for EGFR/FISH-negative patients was 8 months and not yet reached for FISH-positive patients (but approaching 18 months; hazard ratio [HR] = 2.02; P = .042). Median progression-free survival time for EGFR/FISH-positive patients was 9 months versus 4 months for the FISH-negative patients (HR = 1.67; P = .072). In multivariate analysis, EGFR copy number by FISH remained a significant predictive factor for survival after accounting for smoking status, sex, histology, and performance status. Fifty-five patients were evaluated for response using Response Evaluation Criteria in Solid Tumors Group, and 12 of 19 EGFR/FISH-positive patients (63%) demonstrated disease control versus 14 (39%) of 36 patients in the FISH-negative group (P = .087). No association was found between HER2 gene copy number and response (n = 39 patients) or survival (n = 56 patients; P > .10). CONCLUSION Increased EGFR gene copy number detected by FISH is associated with improved survival after gefitinib therapy in patients with advanced BAC, suggesting FISH methodology can be used to assess survival potential in patients treated with EGFR tyrosine kinase inhibitors.

Consolidation Docetaxel After Concurrent Chemoradiotherapy in Stage IIIB Non–Small-Cell Lung Cancer: Phase II Southwest Oncology Group Study S9504

PURPOSE To test the concept of taxane sequencing in combined-modality therapy, this phase II trial (S9504) evaluated consolidation docetaxel after concurrent chemoradiotherapy in patients with pathologically documented stage IIIB non-small-cell lung cancer (NSCLC). Results were compared with those of the predecessor study (S9019) with identical eligibility, staging criteria, and treatment, excepting docetaxel consolidation. PATIENTS AND METHODS Treatment consisted of cisplatin 50 mg/m2 on days 1, 8, 29, and 36, etoposide 50 mg/m2 on days 1 through 5 and 29 through 33, and concurrent thoracic radiotherapy (total dose of 61 Gy). Consolidation docetaxel started 4 to 6 weeks after chemoradiotherapy at an initial dose of 75 mg/m2. RESULTS Stage subsets (tumor-node-metastasis system) in 83 eligible patients were as follows: T4N0/1, 31 patients (37%); T4N2, 22 patients (27%), and T1-3N3, 30 patients (36%). Concurrent chemoradiotherapy was generally well tolerated, but two patients died from probable radiation-associated pneumonitis. Neutropenia during consolidation docetaxel was common (57% with grade 4) and most frequent during escalation to 100 mg/m2. Median progression-free survival was 16 months, median survival was 26 months, and 1-, 2-, and 3-year survival rates were 76%, 54%, and 37%, respectively. Brain metastasis was the most common site of failure. In S9019, median survival was 15 months and 1-, 2-, and 3-year survival rates were 58%, 34%, and 17%, respectively. CONCLUSION Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB NSCLC is feasible and generally tolerable, and results compare favorably with the predecessor trial S9019. Nevertheless, this study remains hypothesis-generating and does not provide definitive evidence of the benefit of this approach. Phase III trials evaluating the S9504 regimen have been initiated to validate these results.

Gefitinib therapy in advanced bronchioloalveolar carcinoma: Southwest Oncology Group Study S0126.

PURPOSE Advanced bronchioloalveolar carcinoma (BAC) is a distinct subtype of non-small-cell lung cancer (NSCLC) for which there is currently no optimal therapy. Based on preclinical and clinical data suggesting relevance of the epidermal growth factor receptor (EGFR) axis in BAC, the Southwest Oncology Group initiated a phase II trial (S0126) to evaluate the EGFR tyrosine kinase inhibitor gefitinib in chemotherapy-naïve and chemotherapy-pretreated patients with advanced BAC. METHODS A total of 136 eligible and assessable patients (101 untreated, 35 previously treated) received gefitinib 500 mg daily until progression or prohibitive toxicity. RESULTS The median age was 68.0 years (range, 34.3 to 88.6); 51% were female; 89% had a performance status (PS) of 0% or 1% and 11% had a PS of 2. The Response Evaluation Criteria in Solid Tumors response rate was 17%, with 6% complete responses (CRs) among 69 previously untreated patients with measurable disease, and 9% with no CRs among 22 pretreated patients. Median survival was 13 months for both chemo-naïve (95% CI, 8 to 18) and previously treated patients (95% CI, 6 to 17). Overall survival at 3 years was 23% (95% CI, 14% to 32%). Toxicity consisted mainly of rash and diarrhea, but 2% of patients died of presumed interstitial lung disease. Exploratory subset analyses revealed improved survival among women (P = .031), patients developing a rash (P = .003), never-smokers (P = .061), and patients with a PS of 0 or 1 (P = .015). CONCLUSION Gefitinib is an active agent in advanced stage BAC. Several subsets demonstrate significantly improved clinical outcomes.

Trastuzumab Plus Docetaxel in HER-2/neu-Positive Prostate Carcinoma Final Results from the California Cancer Consortium Screening and Phase II Trial

Overexpression of the HER‐2/neu oncoprotein has been reported to occur in ≤ 60% of patients with prostate carcinoma and to correlate with shortened survival. Trastuzumab is a humanized monoclonal antibody to the HER‐2 receptor and has activity against HER‐2–positive breast carcinoma, more so when combined with a taxane. The authors screened for HER‐2 overexpression in patients developing hormone‐refractory prostate carcinoma (HRPC) and conducted a Phase II trial of trastuzumab plus docetaxel in HER‐2–positive patients.

The Cyclin-Dependent Kinase Inhibitor UCN-01 Plus Cisplatin in Advanced Solid Tumors: A California Cancer Consortium Phase I Pharmacokinetic and Molecular Correlative Trial

Background: UCN-01 (7-hydroxy-staurosporine) is a novel antineoplastic agent targeting cyclin-dependent kinases, which shows potent in vitro and in vivo activity against a broad range of tumor types. Our group has previously shown that UCN-01 potentiates the apoptotic response of agents such as cisplatin in vitro by preventing sequence-specific abrogation of G2 arrest caused by DNA-damaging chemotherapies. Patients and Methods: This National Cancer Institute–sponsored phase I trial was designed to determine the safety, maximum tolerated dose, and pharmacokinetics of escalating doses of cisplatin in combination with UCN-01 in patients with advanced malignant solid tumors, as well as to do molecular correlative studies on tumor specimens. Cisplatin was infused over 1 hour before UCN-01 (45 mg/m2/d) given as a 72-hour continuous infusion. Escalation of cisplatin was planned through five dose levels at 20, 30, 45, 60, and 75 mg/m2. Results: Ten patients were accrued. Accrual was halted at dose level 2 (cisplatin, 30 mg/m2) due to dose-limiting toxicities consisting of grade 5 sepsis with respiratory failure associated with grade 3 creatinine (one patient) and grade 3 atrial fibrillation (one patient). Plasma and salivary pharmacokinetics of UCN-01 were unaffected by cisplatin. Pretreatment and posttreatment tumor biopsies showed that UCN-01 was active against a key molecular target, the checkpoint kinase Chk1. Conclusions: This phase I trial failed to achieve targeted therapeutic dose levels of cisplatin when combined with prolonged infusion UCN-01. However, because preclinical data indicate that UCN-01 potentiates response to platinum, further studies with alternative dose schedules of the combination, or with other platinum analogues, are warranted.

Human androgen receptor expression in prostate cancer following androgen ablation

OBJECTIVE Metastatic prostate cancer kills patients because their tumor cells fail to respond to combined androgen blockade (CAB) or respond and then relapse. To understand the molecular basis of androgen-insensitive growth of prostate tumor cells, we evaluated changes in human androgen receptor gene (hAR) mRNA levels in patients with prostate cancer treated with CAB. METHODS The study was carried out using quantitative reverse-transcriptase polymerase chain reaction analysis. The level of hAR mRNA were compared to serum prostate-specific antigen and the mutant status of p53 in the tumor. RESULTS hAR was expressed in 44 of 46 tumors from untreated patients, as opposed to 30 of 45 from those who had received CAB (p = 0.001). These 30 were from 8 of 9 stage D patients and from 22 of 36 patients on downsizing CAB therapy prior to radical prostatectomy. Expression was most often seen in high stages (56% of stage B vs. 89% of stage D) and high grades (52% of Gleason 3-7 vs. 92% of Gleason 8-10, p = 0.015). No tumor with a missense p53 mutation had hAR expression following CAB. Twenty-two patients following CAB were found to have undetectable serum prostate-specific antigen levels, while their tumor expressed hAR. CONCLUSIONS hAR expression after CAB is seen preferentially in high-grade, high-stage tumors, the type of prostate carcinomas that fail to have a durable remission. Undetectable serum prostate-specific antigen from tumors that remain hAR positive may predict relapse after hormonal ablative therapy.

Apparent Outbreaks of Clostridium Difficile-Associated Diarrhea in Horses in a Veterinary Medical Teaching Hospital

Intestinal colonization with toxigenic strains of Clostridium difficile was documented in 9 of 10 horses with acute onset diarrhea in a veterinary medical teaching hospital, whereas a similar isolate was detected in only 1 of 23 other horses without diarrhea in the hospital. One horse with diarrhea was infected simultaneously with both C. difficile and Salmonella krefeld. Clostridium difficile was detected by fecal culture on selective medium, confirmed with a latex particle agglutination test, and identified as toxigenic by polymerase chain reaction amplification of toxin A and toxin B gene sequences. Using an arbitrarily-primed polymerase chain reaction, 6 distinct C. difficile isolates were detected in the feces of the 9 affected horses at the time of the outbreak of diarrhea.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Plus Chemotherapy: Case Closed or Is the Jury Still Out?

The cases for and against giving combinations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib concurrently with chemotherapy for first-line treatment of advancedstage non–small-cell lung cancer (NSCLC) have just become even more complex. In this issue of the Journal of Clinical Oncology are two additional pieces of evidence— one favoring the prosecution’s case (EGFR TKIs plus concurrent chemotherapy is a bad idea: “guilty as charged”) and one for the defense (the evidence against the combination is all “circumstantial”: this is a case of the defendant, erlotinib, being “in the wrong place at the wrong time”). Let’s examine the evidence from these two studies. Herbst et al present data from the TRIBUTE trial of paclitaxel/carboplatin plus concurrent erlotinib or placebo, showing that erlotinib added nothing to chemotherapy for any outcome measure in the overall study population. These data are strikingly reminiscent of those published previously in the gefitinib-based INTACT (Iressa NSCLC Trial Assessing Combination Treatment) trials and the similarly designed TALENT trial of gemcitabine/cisplatin plus or minus erlotinib. Altogether, these four trials testing the concept of chemotherapy plus concurrent EGFR TKI account for 4,421 patients, a substantial investment of patient resources. While erlotinib added nothing to efficacy, it did contribute to toxicity. The authors report 48 deaths attributable to an adverse event: 32 (10.2%) of 322 deaths in the erlotinib arm versus 15 (4.4%) of 340 in the placebo arm. So the question at hand is why were TRIBUTE and TALENT negative studies? Similarly, why did gefitinib not add benefit to chemotherapy in INTACT 1 and INTACT 2? After all, we know that chemotherapy by itself produces objective responses and prolongs survival in NSCLC when compared with supportive care alone. In a recently reported trial in patients with NSCLC failing chemotherapy (BR21) erlotinib monotherapy resulted in objective responses and prolonged survival when compared with placebo. Thus, it is logical to conclude that the antitumor activity of these agents should be at least additive (ie, 1 1 should equal 2). (Personal communication, Alisha and Zachary Stickney, April 18, 2005.) However, in the four large clinical trials cited above, 1 1 appears to equal only 1. How could this be? Although there are a number of possible explanations, two hypotheses that seem most likely have been proposed: (1) Lack of patient selection for the target (EGFR) explains the results; or (2) Chemotherapy and EGFR TKIs, given concurrently, result in a negative interaction (antagonism?) in at least a subset of patients treated. The first hypothesis, that negative results are explained by failure to “enrich” the study population(s) by a biomarker predictive of response, clearly has merit. One need only look back to the clinical trials of trastuzumab plus chemotherapy in breast cancer to see the rationale for predetermining a sensitive population most likely to benefit from such a combination. Mathematical probability suggests that if trastuzumab plus chemotherapy had been tested in a nonselected population, no benefit of trastuzumab would have been discernable. In favor of this explanation, the authors of TRIBUTE report a survival benefit for the combination in patients categorized as “never-smokers,” a group previously reported to have a higher response rate to erlotinib or gefitinib as single agents, and as noted below, a group with a higher likelihood of harboring an EGFR-activating mutation. It is here that the study by Eberhard et al describing EGFR and KRAS mutations in a subset of 274 patient tumors from TRIBUTE becomes relevant. A large number of potential biomarkers for sensitivity or resistance to EGFR TKIs have been proposed, including protein expression of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 25 SEPTEMBER 1 2005

Bortezomib Plus Gemcitabine/Carboplatin as First-Line Treatment of Advanced Non-small Cell Lung Cancer: A Phase II Southwest Oncology Group Study (S0339)

Introduction: Bortezomib is a small-molecule proteasome inhibitor with single-agent activity in patients with non-small cell lung carcinoma (NSCLC) and synergy with gemcitabine in preclinical studies. This phase II study of bortezomib in combination with gemcitabine/carboplatin was conducted in chemotherapy-naive advanced NSCLC patients to assess efficacy and safety. Methods: Patients with selected stage IIIB/IV NSCLC, performance status 0–1, and no history of brain metastasis received up to six 21-day cycles of gemcitabine 1000 mg/m2, days 1 and 8, carboplatin area under curve 5.0, day 1, and bortezomib 1.0 mg/m2, days 1, 4, 8, and 11. Results: One-hundred-fourteen patients (52% adenocarcinoma, 85% stage IV) received a median of 3.6 treatment cycles. Median follow-up was >3 years. Median overall survival was 11 months; 1-year and 2-year survival rates were 47% and 19%, respectively. Median progression-free survival was 5 months; 1-year progression-free survival rate was 7%. Response rate was 23%, and disease control rate (responses + stable disease) was 68%. The most common grade 3/4 toxicities were thrombocytopenia (63%) and neutropenia (52%). One patient experienced febrile neutropenia. Grade 3/4 neuropathy occurred in 4%, and a further 6% experienced grade 2 sensory neuropathy. Conclusions: Bortezomib plus gemcitabine/carboplatin resulted in a notable survival benefit in patients with advanced NSCLC, with the anticipated primary toxicity of myelosuppression. Further studies designed to investigate the role of bortezomib in advanced NSCLC are warranted.

Integration of the proteasome inhibitor PS-341 (Velcade) into the therapeutic approach to lung cancer.

PS-341, a potent and selective proteasome inhibitor, is the prototype for a new class of therapeutics that targets the ubiquitin-proteasome pathway. It is active as a single agent and potentiates chemotherapy and radiation in pre-clinical models. Early phase clinical studies have demonstrated tolerability and activity in multiple myeloma, lymphoma, prostate cancer and lung cancer. By its mechanism of inhibiting protein degradation, PS-341 targets a wide-range of pathways that are relevant to tumor progression and therapy resistance, and can directly modulate expression of cyclins, p27(Kip1), p53, NF-kappaB, Bcl-2 and Bax. PS-341 is currently in phase I/II clinical development in lung cancer. This paper will review the pre-clinical and clinical experience with PS-341 as it relates to lung cancer.