Single-Agent Docetaxel in Patients With Refractory Non-Small-Cell Lung

ABSTRACT: There are few options availablefor the patient with advanced non-small-cell lung cancer in whom first-linechemotherapy has failed. Docetaxel (Taxotere), a semisynthetic taxoid,is one of the few drugs that has been systematically investigated as asecond-line option for patients with advanced non-small-cell lung cancer.Four phase II studies have now demonstrated that 100 mg/m² of docetaxel,administered over 1 hour once every 3 weeks, offers some activity againstplatinum-resistant or platinum-refractory non-small-cell lung cancer. Partialresponses have ranged from 14% to 22%, and the median survival durationranges from 30 to 42 weeks. A comparison of survival data from a phaseII trial with historical controls suggests that there also may be a clinicallymeaningful survival advantage afforded by docetaxel, 100 mg/m², inthe second-line setting, with improvement in median survival from 16 to42 weeks, and 1-year survival improvement from 16% to 41%. Two large, randomizedtrials are currently ongoing to better define the role of docetaxel inthe second-line setting. [ONCOLOGY 11(Suppl 7):11-15, 1997]

Introduction

Advanced non-small-cell lung cancer remains relatively chemotherapy-resistantto first-line treatment.[1,2] The relative benefits of chemotherapy vspalliative treatment only are debatable. Randomized studies comparing platinum-basedcombination therapy to best supportive care for advanced disease have shownonly a minor, although statistically significant, impact on survival.[3-6]Median survival has been reported to improve from 17 to 27 weeks, and 1-yearsurvival rate from 5% to 15% in patients who receive platinum-based chemotherapy,as compared with palliative care only.[1]

Despite the marginal benefit associated with chemotherapy, most oncologistsagree that it is reasonable to at least offer a trial of front-line systemicchemotherapy, usually with platinum-based combination regimens, to patientswith advanced non-small-cell lung cancer who have an acceptable performancestatus.

Given the fact that the benefits of first-line platinum-based chemotherapymay be minimal in patients with non-small-cell lung cancer, the indicationsfor second-line treatment in the patient who has not responded to initialchemotherapy are even more debatable.[3-6] Not only would these patientsgenerally have a worse performance status than chemotherapy-naive patients,but one might expect that they would have tumors refractory to all chemotherapydue to acquired or inherent resistance. This underscores the importanceof developing rational, cost-effective guidelines for the use of chemotherapyin patients with advanced non-small-cell lung cancer who have not respondedto front-line therapy.

Docetaxel (Taxotere), a semisynthetic taxoid, is one of the few drugsthat have been systematically investigated as a second-line option forpatients with advanced non-small-cell lung cancer.[7] This paper will reviewthe results of several phase II studies supporting the potential benefitof docetaxel in patients with advanced non-small-cell lung cancer in whomprevious chemotherapy has failed. It will also discuss the implicationsof these data as they relate to historical controls and will describe ongoingphase III trials of docetaxel in the second-line setting.

Phase IIStudies of Docetaxel in Previously Treated Patients

A total of 88 patients participated in two phase II studies[7-9] conductedat the M.D. Anderson Cancer Center[8] (44 patients) and at the Universityof Texas Health Sciences Center at San Antonio[9] (44 patients accruedfrom three sites).

Eligibility

Eligible patients had stage IV or unresectable stage III non-small-celllung cancer, a performance status of 2 or less (Zubrod scale), and hadnot responded to at least one prior platinum-containing regimen, eithercisplatin (Platinol) or carboplatin (Paraplatin). Patients who had receivedmore than two prior chemotherapy regimens were excluded. Platinum-resistantpatients were defined as those who had an initial response to platinumbut subsequently progressed. Platinum-refractory patients were those whonever showed a response to platinum therapy.

Treatment Plan

Docetaxel was administered at a dosage of 100 mg/m², as a 1-hourintravenous (IV) infusion, once every 3 weeks. In addition, most patientswere premedicated with IV diphenhydramine, 50 mg, 30 minutes prior to theadministration of docetaxel.

For patients who experienced a hypersensitivity reaction, a second 50-mgdose of IV diphenhydramine was administered along with 10 mg of IV dexamethasone.Premedication for

patients with hypersensitivity reactions for subsequent docetaxel infusionsincluded 4 mg of oral dexamethasone every 6 hours and 10 mg of IV dexamethasoneplus 50 mg of IV diphenhydramine, 30 minutes before receiving docetaxel.Antiemetics and growth factors were not used.

Results

The characteristics of the 88 patients are shown in Table1.[7-9] There were 46 men and 42 women, most of whom had a Zubrod performancescore of 1 or less. The median age was 57 years (range, 29 to 71 years).The majority (84%) of patients had stage IV disease, two-thirds had adenocarcinoma,and over half had received prior radiation therapy.

In platinum-refractory/resistant patients treated with docetaxel, 100mg/m², once every 3 weeks, 20% of the 71 evaluable patients achieveda partial response (Table 2).[7-9] Asubset analysis of response rates based on the presence of adenocarcinomarevealed a trend toward higher response rates among patients with otherhistologies. This trend was not statistically significant, however.

The median time to response was 6 weeks, with a median response durationof 29 weeks (Table 2). The projectedmedian survival (all patients, both studies) was 39 weeks, and the 1-yearsurvival rate was 40% (Figure 1).

Response rates and median survival did differ between the two studies.[7-9]Patients from the M.D. Anderson Cancer Center study achieved higher responserates (21%) and longer median survival times (42 weeks) than patients participatingin the University of Texas Health Sciences Center study (14% and 25 weeks,respectively) (Table 2). These differencesmay be related to patient selection factors during the enrollment phaseof the study. At the M.D. Anderson Cancer Center, only 5% of patients werein the poor-performance status category, as compared with 23% of patientsfrom the San Antonio site.

Safety

The toxicity profile reported from the phase II trials[8,9] was comparablewith that seen in companion trials conducted in previously untreated patientswith advanced non-small-cell lung cancer. The primary dose-limiting toxicitywas neutropenia. At the M.D. Anderson Cancer Center, 75% of patients developedgrade 3 or 4 neutropenia, with febrile neutropenia occurring in 7% of thefirst cycle and 16% overall.[7]

Similarly, there was not much difference in the incidence of nonhematologicside effects between the chemotherapy-naive patients and the previouslytreated patients, with the exception of peripheral neuropathy.[7] A greaterincidence of peripheral neuropathy was noted in patients who had receivedprior chemotherapy, which may have been due to their prior exposure tocisplatin.[7]

AdditionalPhase II Studies in Platinum-Refractory Patients

Preliminary data are available from two other recently reported phaseII trials on the use of docetaxel in patients with platinum-refractorynon-small-cell lung cancer.[10,11] In both trials, patients were treatedwith 100 mg/m² of docetaxel, administered as a 1-hour IV infusion,once every 3 weeks. In addition, all patients received routine premedicationwith dexamethasone.

One multicenter trial, reported by Gandara and colleagues,[10] showeda response rate of 16% in 77 patients with non-small-cell lung cancer whowere refractory to platinum treatment. The median survival duration and1-year survival rates noted by these authors were 7 months and 25%, respectively.The most commonly reported serious adverse event was neutropenia (19%).

Kleisbauer and coworkers[11] conducted a multicenter phase II studyin 18 platinum-refractory patients with advanced non-small-cell lung cancer.This study, which is currently ongoing, reports a preliminary responserate of 22% to 100 mg/m² of docetaxel. Information on median survivaland 1-year survival rates is not yet available.

Second-Line Docetaxel Therapy vs Historical Controls

Recently, the investigators from the M.D. Anderson Cancer Center performeda retrospective analysis comparing data from the 44 patients who receiveddocetaxel, 100 mg/m², in the second-line phase II study with a comparablehistorical-control patient

population. The objective was to determine whether the favorable survivalseen in the M.D. Anderson Cancer Center trial was truly due to the efficacyof docetaxel in that setting or simply reflected selection bias, giventhat 95% of patients in that trial had a good performance status and mightbe expected to do well regardless of second-line therapy.

Using a computerized protocol database, a cohort of 36 non-small-celllung cancer patients who matched the entry criteria for the docetaxel studywere identified for the historical-control group. These patients had receivedfirst-line chemotherapy from one of 18 different phase I protocols conductedat the M.D. Anderson Cancer Center between 1988 and 1991. Thus, patientsselected for the historical-control cohort had stage IV or unresectablestage III non-small-cell lung cancer, had not responded to at least oneprior chemotherapy regimen (which was platinum-based in all but one patient),and were taxoid-naive.

Both groups were well balanced with regard to age, gender, stage, histology,number of prior chemotherapy cycles, and their response to front-line combinationchemotherapy. One important difference between the two groups was performancestatus. There were significantly fewer patients (5%) with a performancestatus of 2 in the docetaxel group than in the control group (19%).

The partial response rate was 21% in the patients who participated inthe docetaxel phase II study at the M.D. Anderson Cancer Center, as comparedwith 0% in the historical-control group (Table3). Median survival was 42 weeks for the docetaxel-treated patientsvs 16 weeks for the historical-control group, and the 1-year survival ratewas 41% vs 16% (P = .003).

Because the control group had more patients with a performance statusof 2 (which might have skewed the survival in favor of the docetaxel arm),we calculated survival for patients with good performance status (ie, 0to 1). The analysis of patients with good performance status also showeda significant improvement in survival for docetaxel: for the 42 patientsin this group, median survival duration and 1-year survival rates were43 weeks and 42%, respectively, as compared with 16 weeks and 16%, respectively,for the 29 historical-control group patients with good performance status(P = .018).

Although there are limitations to this type of retrospective analysis,it does provide some insight into the relative advantage of using 100 mg/m²of docetaxel (infused over 1 hour, once every 3 weeks) as a second-linetreatment in patients with non-small-cell lung cancer in whom platinum-basedchemotherapy has failed.

OngoingStudies After First-Line Platinum-Based Chemotherapy Failure

Two large, randomized phase III studies are currently evaluating theuse of docetaxel in patients with good performance status and advanceddisease who have not responded to at least one prior platinum-containingregimen. The first study is comparing the efficacy of docetaxel at dosesof 75 and 100 mg/m² administered as an IV infusion over 1 hour, onceevery 3 weeks, with best supportive care.

In the second study, patients are being randomized to receive either75 mg/m² of docetaxel, 100 mg/m² of docetaxel, or in the controlarm, vinorelbine (Navelbine) or ifosfamide (Ifex). The primary end pointof both studies is survival, with secondary end points being quality oflife and response rate. Preliminary results from these studies are anticipatedby the end of 1997.

Conclusions

Four phase II studies have now demonstrated that docetaxel at a doseof 100 mg/m², administered over 1 hour, once every 3 weeks, has activityin platinum-resistant or platinum-refractory non-small-cell lung cancer.Partial responses have ranged from 14% to 22%, and median survival durationis in the range of 30 to 42 weeks.

A retrospective analysis conducted at the M.D. Anderson Cancer Center[8]suggests that there may be a clinically meaningful survival advantage ofdocetaxel, 100 mg/m², in the second-line setting as well, with animprovement in median survival from 16 to 42 weeks and an increase in 1-yearsurvival rate from 16% to 41%. It should be noted, however, that most ofthe patients from the M.D. Anderson Cancer Center had excellent performancestatus, despite the fact that they had already received extensive priortherapy. Two large, randomized trials are currently ongoing to better definethe role of docetaxel as a second-line therapy.

The related taxoid, paclitaxel (Taxol), has not been studied as systematicallyin the second-line setting. Data from the six studies that have been conductedare conflicting.[12-17] One trial suggests that paclitaxel--at a dose of200 mg/m², administered over 1 hour--may have activity in platinum-resistantpatients. However, the results are of limited value because the cohortof patients studied was small and survival data were not reported.[17]In contrast, five other small studies have reported no or minimal activityof paclitaxel in this setting.[12-16] Finally, available data on otherdrugs--including vinorelbine,[18-20] irinotecan (Camptosar),[21,22] andothers--have been similarly disappointing.

Based on available clinical data, it would be reasonable to offer atrial of second-line docetaxel therapy in patients with advanced non-small-celllung cancer who have failed first-line, platinum-based therapy. However,because most of the data are derived from patients with good performancestatus, such treatment should generally used in patients who have a performancestatus of 0 to 1. Additional prospective randomized trials are underwayto further define the role of docetaxel as second-line therapy for previouslytreated non-small-cell lung cancer patients.

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