Treatment of Non-Small-Cell Lung Cancer in North America: The Emerging Role of Irinotecan

ABSTRACT: Topoisomerase I inhibitors have demonstrated significantactivity in non-small-cell lung cancer. In phase II studies, particularly inJapan, single-agent irinotecan (Camptosar, CPT-11) has produced response ratesas high as 35%. In combinations with cisplatin (Platinol), it has also resultedin overall response rates of 41% to 52%, with median survival of 10.2 to 13months, and 1-year survival rates of 33% and 58%. A Japanese phase IIIrandomized trial of irinotecan, either alone or in combination with cisplatin vsvindesine/cisplatin in previously untreated stage IIIB/IV non-small-cell lungcancer, demonstrated that survival among stage IV patients was significantlybetter in the irinotecan arms compared to the vindesine/cisplatin group.However, another Japanese phase III study comparing irinotecan/cisplatin tovindesine/cisplatin failed to show a survival difference. Initial North Americanefforts recapitulated this work, while a follow-up study incorporated weeklyirinotecan with weekly cisplatin, yielding a response rate of 36%, mediansurvival of 11.6 months, and a 1-year survival rate of 46%. Irinotecan/taxanecombinations have also shown promise. Phase I/II studies in advanced non-small-celllung cancer with paclitaxel (Taxol), irinotecan, and carboplatin (Paraplatin)produced a response rate of 38%, median survival of 11 months, and a 1-yearsurvival rate of 47%; other trials with irinotecan and paclitaxel are ongoing.Phase I data for irinotecan/docetaxel (Taxotere) have indicated an overallresponse rate of 32%, median survival of 39 weeks, and a 1-year survival rate of38%; subsequent phase II trials used either cisplatin or irinotecan incombination with docetaxel and yielded a promising median survival of 45.6weeks, comparable to the standard cisplatin/docetaxel combination. Phase Itrials with irinotecan and gemcitabine (Gemzar) have also yielded promisingresults. Follow-up efforts include phase II studies in both chemonaive advancednon-small-cell lung cancer and progressive small-cell lung cancer (salvagetherapy). Clearly, clinical trial data have demonstrated the utility ofirinotecan in the treatment of advanced non-small-cell lung cancer. Plannedcombinations with new chemotherapeutic agents and biological response modifiersmay provide additional treatment options. [ONCOLOGY 15(Suppl 1):19-24, 2001]

Introduction

Even though its annual incidenceis eclipsed by breast cancer andprostate cancer, lung cancer remains the leading cause of cancer death in NorthAmerica. Although the incidence of lung cancer is starting to plateau in NorthAmerican males, it continues to rise in American women and in both gendersoutside the United States, particularly in Europe and Asia. The 5-year survivalrate in the United States is only 14% overall, and 50% more women die of lungcancer than breast cancer.[1] Generally, the disease is either systemic atdiagnosis, or manifests distant spread after local regional therapy. Hence, newagents with improved systemic activity are desperately needed. This article willreview the activity of irinotecan (Camptosar, CPT-11), both alone and incombination with cisplatin (Platinol) and other agents in advanced non-small-celllung cancer. It will also touch on planned and ongoing phase III trialsestablishing its utility in non-small-cell lung cancer.

Single-Agent Therapy

Multiple phase II studies, particularly in Japan, haveestablished the utility of irinotecan in the treatment of advanced non-small-celllung cancer. Response rates have ranged as high as 30% to 35%, usingconventional schedules of 100 to 125 mg/m²/wk ´ 4 weeksfollowed by a 2-weekrest every6 weeks,[2-4] or doses of 300 to 350 mg/m² every 3 weeks with or withouthematopoietic growth factor support.[5] In one US study evaluating single-agentirinotecan, the response rate was disappointing at only 15% using a conventionalschedule of 100 mg/m²/wk ´ 4 every 6 weeks, and the median survival was only6.2 months.[6] Toxicities have generally included myelosuppression and diarrhea.The results from these studies are summarized in Table1.

Cisplatin/Irinotecan Combinations

Cisplatin remains the cornerstone of combination therapy inadvanced non-small-cell lung cancer, and meta-analyses have demonstrated astatistically significant survival benefit for cisplatin-based regimens vs bestsupportive care.[7,8] Consequently, investigators have sought to assess theactivity of irinotecan in combination with cisplatin, with the earliest effortsemanating from Japan. Masuda and colleagues evaluated cisplatin at 80 mg/m² day1 every 4 weeks in combination with irinotecan at 60 mg/m² days 1, 8, and 15.[9]The overall response rate was 52%; time to progression was 4.4 months, mediansurvival 10.2 months, and the 1-year survival rate was 33%. In an attempt tocapitalize on their putative therapeutic synergy, Ueoka and collaboratorsassessed the irinotecan and cisplatin combination at doses of 50 and 60 mg/m²,respectively, days 1 and 8 every 4 weeks.[10] The overall response rate wasslightly lower at 41%, but median survival was 13 months and the 1-year survivalrate was 58%.

Phase III Randomized Trials

Masuda and colleagues conducted a phase III trial of irinotecan,either alone or in combination with cisplatin, vs vindesine/cisplatin, thereference arm.[11] Eligible patients were those with previously untreated stageIIIB or IV measurable non-small-cell lung cancer, an Eastern CooperativeOncology Group (ECOG) performance status of 0 to 2, and adequate marrow,hepatic, renal, and pulmonary function; patients older than 75 were excluded. Atotal of 385 evaluable patients were enrolled, 246 of whom had stage IV disease.Demographics with respect to age, performance status, prior weight loss,albumin, and lactate dehydrogenase were well matched for each arm. Patients wererandomized to one of three arms: (A) irinotecan at 60 mg/m² days 1, 8, and 15and cisplatin at 80 mg/m² day 1 every 4 weeks; (B) vindesine at3 mg/m² days 1, 8, and 15 and cisplatin at 80mg/m² day 1 every 4 weeks; or (C)irinotecan at 100 mg/m² days 1, 8, and 15 every 4 weeks. The results are shownin Table 2.

Leukopenia was much more pronounced in the vindesine/cisplatincombination, while thrombocytopenia was more common in the irinotecan/cisplatincombination. Both irinotecan arms resulted in substantially more grade 3 and 4diarrhea; the cisplatin arms yielded considerably more nausea and vomiting. Theincidence of anemia was driven by cisplatin: 39% grade ³ 3 foririnotecan/cisplatin, compared to 23% for vindesine/cisplatin, vs 6% foririnotecan alone. Survival among stage IV patients was significantly better forthose receiving irinotecan (arms A or C) compared to those receivingvindesine/cisplatin (Figure 1). This established irinotecan, along withvinorelbine (Navelbine) and paclitaxel (Taxol),[12,13] as one of three"new" agents which, in combination with cisplatin, has proven superiorto "standard" older cisplatin combinations.

However, a separate phase III study comparingirinotecan/cisplatin to vindesine/cisplatin in 210 patients with advanced non-small-celllung cancer failed to show a survival difference.[14] The median survival foririnotecan/cisplatin was 44.7 weeks, with respective 1- and 2-year survivalrates of 36.4% and 8.7% in stage IV patients. The median survival in thevindesine/cisplatin arm was 45.3 weeks, with 1- and 2-year survival rates of41.4% and 10.3%, respectively (P = .668).

North American Trials

The initial combination effort in North America reported byDeVore and colleagues recapitulated the Japanese study of Masuda and coworkers:cisplatin at 80 mg/m² day 1 and irinotecan at 60mg/m² weekly × 3 every 4weeks.[15] In the 52 patients enrolled, the overall response rate was 29%, witha median time to progression of 5.1 months, median survival of 9.9 months, and a1-year survival rate of 37%. Grade ³ 3 neutropenia occurred in 46% of patients,with an overall 11.5% incidence of febrile neutropenia. Nausea/vomiting andasthenia were driven by cisplatin; grade ³ 3 incidences were 32.7%/5.8% and23.1%, respectively, and grade 3 or 4 diarrhea occurred in 17.3% and 11.5% ofpatients, respectively. The relative dose intensity of irinotecan was 75.5%.Seventy-three percent of the patients required dose reductions of irinotecan;most patients ultimately had their irinotecan dose reduced to ≤ 40mg/m².

Consequently, a follow-up study, in which Vanderbilt CancerCenter, its affiliated network (VCCAN), and Fox Chase Cancer Center (FCCC)joined forces, combined weekly irinotecan with weekly cisplatin.[16] There werethree rationales behind this move: (1) in vitro preclinical models haddemonstrated the putative synergy of these two agents, which could be betterexploited by same-day administration, (2) improved sequencing of irinotecan andcisplatin might potentially improve efficacy, and (3) attenuation of thecisplatin dose with each administration could reduce toxicity and preserve doseintensity. The regimen was modeled after the phase I data of Saltz andcolleagues.[17]

Eligible patients received irinotecan at 65 mg/m² and cisplatinat 30 mg/m², each given weekly × 4 weeks followed by a 2-week rest, andtreatment was repeated at 6-week intervals. Fifty patients were enrolled. Theoverall response rate was 36%, which was slightly higher than that observed inthe previous North American study. Median time to progression was 6.9 months,median survival 11.6 months, and the 1-year survival rate 46%—the best resultsever observed at the VCCAN in advanced non-small-cell lung cancer patients,and comparable to previous results observed at Fox Chase and in the FCCCnetwork.[18-20]

The overall incidence of grade ³ 3 neutropenia was 25.5%,febrile neutropenia occurred in 6% of patients, grade ³3 thrombocytopeniaoccurred in 12%, and grade ³ 3 nausea/vomiting occurred in 26%. The relativedose intensity of irinotecan in this combination was 89%, and the dose intensitywas fairly well maintained for both agents. A comparison of these two regimensis depicted in Table 3. Data to date would favor the approach employing weeklyas opposed to monthly cisplatin.

Taxane/Irinotecan Combinations

Burtness and colleagues mounted an open phase I trial ofirinotecan and paclitaxel, with both agents administered weekly × 4 weeks every6 weeks.[21] Twenty-one patients were enrolled in this phase I study, and atotal of 53 cycles were administered. The maximum tolerated dose in thisschedule was irinotecan at 50 mg/m² and paclitaxel at 75mg/m² weekly.Pharmacokinetics revealed no drug-drug interaction based on levels of irinotecanand its active metabolite SN-38 (7-ethyl-10-hydroxycamptothecin).

The same investigators are conducting a formal phase II study ofthis combination in advanced non-small-cell lung cancer patients with an ECOGperformance status of 0 to 2. It employs an abbreviated schedule: irinotecan at50 mg/m² in combination with paclitaxel at 75mg/m², both agents given weekly ´2 every 3 weeks. To date, seven patients have been accrued. No grade 4neutropenia has been observed. Two of six evaluable patients have sustainedpartial response (18+ weeks), three have had stable disease, and only one hasshown progressive disease (J. Murren, personal communication, July 2000).

Rosen and coworkers combined irinotecan with paclitaxel, withboth agents given once every 3 weeks.[22] This open phase I study included anumber of cancer diagnoses, including lung (n = 3), hepatobiliary (n = 4),pancreas (n = 2), gastric (n = 2), and other (n = 6). The maximum tolerated dosewas 225 mg/m² for irinotecan and 100 mg/m² for paclitaxel. Grade ³ 3 diarrheawas observed in only one of nine treatment courses at the maximum tolerateddose, whereas at higher doses, grade ³ 3 diarrhea occurred in 5 of 17 patients.Objective responses were seen in non-small-cell lung cancer and occult primarysquamous malignancy. Paclitaxel coadministration did not alter irinotecanpharmacokinetics, based on high-performance liquid chromatography quantificationof plasma concentrations of irinotecan, its active metaboliteSN-38, and glucuronide SN-38G in patients who were administered doses up to themaximum tolerated dose.

Socinski and colleagues have conducted phase I and II studies ofpaclitaxel, irinotecan, and carboplatin (Paraplatin) in patients with advancednon-small-cell lung cancer.[23] At the initial dose levels, irinotecan wasadministered on a day 1 and 8 schedule, and incorporated full-dose paclitaxel at225 mg/m² every 3 weeks and carboplatin at an area under the concentration-timecurve (AUC) of 6 every 3 weeks. But dose-limiting toxicity in three of the firstseven patients accrued led to dose reductions of paclitaxel and carboplatin andthe elimination of day 8 irinotecan. The maximum tolerated doses for these threeagents using an every-3-week schedule were paclitaxel at 175 mg/m², irinotecanat 100 mg/m², and carboplatin at an AUC of 5.

Thirty-three patients were enrolled in the phase I effort, andthe overall response rate in 31 evaluable patients was 39% (10% completeresponse rate). The most common grade ³ 3 toxicity was neutropenia, whichoccurred in 50% of patients. Five (16%) developed neutropenic fever. Median timeto progression was a promising 6.8 months, median survival 11 months, and the1-year survival rate 47%.

To date, 40 patients have been enrolled in the phase II effort.The response rate of 38% is comparable to the phase I effort and time toprogression at 6.2 months is similar, while median survival is somewhat lower at8.8 months (the 1-year survival rate has not yet been reached). Disappointingly,the incidence of neutropenic fever is 30%, higher than that observed in thephase I study. Future studies will either lower the carboplatin dose to an AUCof 4 or add a hematopoietic growth factor in an effort to mitigate thistoxicity.

Finally, a phase I effort assessed irinotecan in combinationwith docetaxel (Taxotere).[24] Twenty-six treatment-naive advanced non-small-celllung cancer patients (22 stage IV) received docetaxel day 2 and irinotecan days1, 8, and 15, with doses being escalated across sequential cohorts. The maximumtolerated dose was 50 mg/m² for docetaxel and 60mg/m² for irinotecan. Higherdoses led to dose-limiting toxicity, primarily neutropenia. The overall responserate was 32%, median survival 39 weeks, and the 1-year survival rate 38%.

In a subsequent randomized phase II effort that assessed eithercisplatin or irinotecan in combination with docetaxel,[25] 57 advanced non-small-celllung cancer patients received docetaxel at 60 mg/m² day 8 and irinotecan at 60mg/m² days 1 and 8. Median time to progression was 18.1 weeks, and mediansurvival was promising at 45.6 weeks. Grade ³ 3 neutropenia occurred in 82.5%,grade ³ 2 nausea/vomiting in 52.6%, and grade ³ 2 diarrhea in 43.9%. Resultswith this nonplatinum combination proved comparable to the standardcisplatin/docetaxel combination.

Irinotecan and Gemcitabine

Rocha-Lima and colleagues from the Medical University of SouthCarolina at Charleston have assessed irinotecan in combination with gemcitabine(Gemzar) (IrinoGem).[26] Preclinical data evaluating the combination ofirinotecan and gemcitabine have demonstrated dose-dependent interactions betweenthe two drugs. Combination index analyses have revealed antagonism at lowconcentrations, but synergism at concentrations of gemcitabine above 0.1 mM andirinotecan above 3.2 mM in the human SCOG small-cell lung cancer cellline.[27,28] Rocha-Lima and coworkers conducted a phase I trial using a days 1and 8 every-3-week schedule to determine the maximum tolerated dose ofirinotecan that could be administered as a 90-minute IV infusion immediatelyafter gemcitabine at a dose of 1,000 mg/m² by 30-minute IV infusion in patientswith solid tumors.[27] Nineteen patients were enrolled at four irinotecan doselevels of 50, 75, 100, and 115 mg/m².

Grade 4 diarrhea in two of seven patients constituted thedose-limiting toxicity at an irinotecan dose of 115 mg/m²; hematologic toxicitywas not dose-limiting. Three patients required omission of day 8 cycle 1chemotherapy due to grade 3 myelosuppression. Three out of four previouslytreated non-small-cell lung cancer patients who were treated with irinotecandoses of 50, 75, and 100 mg/m² had stable disease for more than 4 cycles; no non-small-celllung cancer patients were treated with irinotecan at 115 mg/m².[26]

The maximum tolerated dose of irinotecan in this combination was100 mg/m²—the recommended starting dose for phase II studies. Cancer andLeukemia Group B is spearheading a phase II trial of irinotecan and gemcitabinein advanced non-small-cell lung cancer and a similar trial as salvage therapyin progressive small-cell lung cancer (Figure2). Results should be available inthe next 12 to 18 months.

Future Efforts in Advanced Disease

A phase III trial comparing cisplatin/irinotecan andgemcitabine/cisplatin using a day 1 and 8 schedule every 3 weeks to thenoncisplatin constituents—irinotecan and gemcitabine—is being contemplated (Figure3), asis a phase III study comparing the weekly cisplatin/irinotecan × 4 every-6-week schedule to standard therapy. Proposed phase II studies will also assessthe role of angiogenesis inhibitors and proapoptotic agents introduced intoweekly schedules of cisplatin and irinotecan. Finally, the Japanese arespearheading a four-arm phase III trial comparing irinotecan/cisplatin, their new standard,to other state-of-the-art combinations, including vinorelbine/cisplatin,gemcitabine/cisplatin, and carboplatin/paclitaxel.

Conclusion

In summary, a survival advantage has been observed in stage IVnon-small-cell lung cancer patients in at least one randomized prospectivephase III trial using monthly cisplatin and weekly irinotecan compared tovindesine/cisplatin. On the other hand, weekly irinotecan and cisplatin appearsto be more active and better tolerated. Future studies will elucidate the statusof irinotecan combinations vis-à-vis other standard combinations. They willalso assess the role of irinotecan, either alone or in combination withgemcitabine, as salvage therapy in chemotherapy-exposed patients.

Irinotecan and Gemcitabine

Rocha-Lima and colleagues from the Medical University of SouthCarolina at Charleston have assessed irinotecan in combination with gemcitabine(Gemzar) (IrinoGem).[26] Preclinical data evaluating the combination ofirinotecan and gemcitabine have demonstrated dose-dependent interactions betweenthe two drugs. Combination index analyses have revealed antagonism at lowconcentrations, but synergism at concentrations of gemcitabine above 0.1 mM andirinotecan above 3.2 mM in the human SCOG small-cell lung cancer cellline.[27,28] Rocha-Lima and coworkers conducted a phase I trial using a days 1and 8 every-3-week schedule to determine the maximum tolerated dose ofirinotecan that could be administered as a 90-minute IV infusion immediatelyafter gemcitabine at a dose of 1,000 mg/m² by 30-minute IV infusion in patientswith solid tumors.[27] Nineteen patients were enrolled at four irinotecan doselevels of 50, 75, 100, and 115 mg/m².

Grade 4 diarrhea in two of seven patients constituted thedose-limiting toxicity at an irinotecan dose of 115 mg/m²; hematologic toxicitywas not dose-limiting. Three patients required omission of day 8 cycle 1chemotherapy due to grade 3 myelosuppression. Three out of four previouslytreated non-small-cell lung cancer patients who were treated with irinotecandoses of 50, 75, and 100 mg/m² had stable disease for more than 4 cycles; no non-small-celllung cancer patients were treated with irinotecan at 115 mg/m².[26]

The maximum tolerated dose of irinotecan in this combination was100 mg/m²—the recommended starting dose for phase II studies. Cancer andLeukemia Group B is spearheading a phase II trial of irinotecan and gemcitabinein advanced non-small-cell lung cancer and a similar trial as salvage therapyin progressive small-cell lung cancer (Figure2). Results should be available inthe next 12 to 18 months.

Future Efforts in Advanced Disease

A phase III trial comparing cisplatin/irinotecan andgemcitabine/cisplatin using a day 1 and 8 schedule every 3 weeks to thenoncisplatin constituents—irinotecan and gemcitabine—is being contemplated (Figure3), asis a phase III study comparing the weekly cisplatin/irinotecan × 4 every-6-week schedule to standard therapy. Proposed phase II studies will also assessthe role of angiogenesis inhibitors and proapoptotic agents introduced intoweekly schedules of cisplatin and irinotecan. Finally, the Japanese arespearheading a four-arm phase III trial comparing irinotecan/cisplatin, their new standard,to other state-of-the-art combinations, including vinorelbine/cisplatin,gemcitabine/cisplatin, and carboplatin/paclitaxel.

Conclusion

In summary, a survival advantage has been observed in stage IVnon-small-cell lung cancer patients in at least one randomized prospectivephase III trial using monthly cisplatin and weekly irinotecan compared tovindesine/cisplatin. On the other hand, weekly irinotecan and cisplatin appearsto be more active and better tolerated. Future studies will elucidate the statusof irinotecan combinations vis-à-vis other standard combinations. They willalso assess the role of irinotecan, either alone or in combination withgemcitabine, as salvage therapy in chemotherapy-exposed patients.

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