Current Role of Irinotecan in the Treatment of Non-Small-Cell Lung Cancer

The comprehensive review by Dr. Karen Kelly meticulously outlines therationale for the study of irinotecan in non-small-cell lung cancer (NSCLC),summarizes results of trials of this agent as monotherapy and as a component ofdoublet and triplet regimens in previously untreated NSCLC patients, and thenreviews its role in previously treated NSCLC patients.

Like the taxanes and gemcitabine, irinotecan is certainly an active drug inNSCLC. Unfortunately, however, it appears a therapeutic plateau has been reachedin the treatment of advanced NSCLC with these newer active drugs in combinationwith a platinum compound. Median survivals of approximately 8 months and 1-yearsurvival rates of approximately 35% are now widely reported in multiple phaseIII trials from a variety of cooperative groups.[1,2]

Strategies for Using Irinotecan

Despite attempts at varying the active agents studied, their schedules ofadministration, and sequences/doses of component agents, no recent trial hassuggested an appreciable move forward with any such approach. To that end, it isdifficult to foresee in what setting irinotecan might be routinely advantageouswhen used in the untreated NSCLC population. However, a burgeoning understandingof the molecular biology of common solid tumors may provide an opportunity foririnotecan and other agents to be used more creatively in this disease.

One such strategy would be to study drug combinations for tumor types inwhich the leading candidates for successful targeted therapies and irinotecanboth have activity. To date, the most promising classes of agents have beeneither small molecules (eg, erlotinib [OSI-774, Tarceva], gefitinib [ZD1839,Iressa]) or monoclonal antibodies targeting the HER family (trastuzumab [Herceptin],cetuximab [IMC-C225, Erbitux]).

Given the frequency of perturbations in this signaling pathway in commonsolid tumors and the activity profile of irinotecan, combination trials could beenvisioned in NSCLC as well as colorectal, ovarian, and cervical cancers.[3,4]Moreover, preclinical data suggest that epidermal growth factor receptor (EGFR)-tyrosinekinase (TK) inhibitors may be helpful in diseases that have little EGFRexpression—for example, small-cell lung cancer (SCLC), in which irinotecan ishighly active.[5]

Design of Future Trials

How should these trials be designed to allow expedient interpretable resultsthat could lead to advances in the treatment of common solid tumors? At aminimum, such trials would need to incorporate appropriate correlative studiesincluding pharmacokinetic assays—as both irinotecan and the most widelystudied EGFR-TK inhibitors are hepatically metabolized—and molecularassessments of EGFR pathway activation/inhibition. Since antibodies forphosphorylated (or activated) EGFR are not yet standardized, routine exclusionof patients based on the immunohistochemical profile of EGFR would be unwise.[6]

Trials involving this class of targeted agents would be a logical place tostart, but other leads should also be pursued clinically. For example,up-regulation of the nuclear transcription factor NFkB has been detected incancer cells exposed to irinotecan and could obviate chemotherapy-inducedapoptosis.[7] Inhibition of NFkB activation by a proteosome inhibitor such asPS-341 could thus enhance the effects of the cytotoxic agent.

Since randomized phase II designs do not test comparative efficacy profilesand because phase III trials are unwarranted in the absence of provocativeresults of a pilot trial, we might initially screen for some modicum of activitygreater than that seen historically with the chemotherapy agent under study.When possible, these historical cohorts should consist of patients treated in asimilar phase of study, perhaps studied by the same investigators, and withsimilar clinical characteristics. Such a trial should be undertaken with atwo-stage design and powered to detect a minimal level of increased activitythat would warrant further study.

Conclusions

Irinotecan stands as an active agent for both advanced NSCLC and SCLC.Ongoing phase III trials are attempting to confirm the results of a Japanesetrial, and if positive, would likely change the standard of care for extensive-stage SCLC.[8] However, in NSCLC, it will be difficult to identify a uniqueniche for irinotecan alone or as a component of cytotoxic combinations. Itspotential may lie in its suitability for rationally designed combination therapywith novel targeted agents. In this way, it might be successfully employed asthe backbone of true therapeutic advances.

References:

1. Schiller JH, Harrington D, Belani CP, et al: Comparison of fourchemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med346:92-98, 2002.

2. Kelly K, Crowley J, Bunn P, et al: A randomized phase III trial ofpaclitaxel plus carboplatin (PC) vs vinorelbine plus cisplatin (VC) in untreatedadvanced non-small cell lung cancer (NSCLC): A Southwest Oncology Group (SWOG)trial (abstract 1777). Proc Am Soc Clin Oncol 18:461a, 1999.

3. Garcia-Carbonero R, Supko JG: Current perspectives on the clinicalexperience, pharmacology, and continued development of the camptothecins. ClinCancer Res 8:641-661, 2002.

4. Arteaga C: The epidermal growth factor receptor: From mutant oncogene innonhuman cancers to therapeutic target in human neoplasia. J Clin Oncol19:32s-40s, 2001.

5. Sirotnak F, Zakowski M, Miller V, et al: Efficacy of cytotoxic agentsagainst human tumor xenografts is markedly enhanced by coadministration ofZD1839 (Iressa), an inhibitor of EGFR tyrosine kinase. Clin Cancer Res6:4885-4892, 2000.

6. Albanell J, Rojo F, Averbuch S, et al: Pharmacodynamic studies of the EGFreceptor inhibitor ZD1839 (Iressa) in skin from cancer patients:Histopathological and molecular consequences of receptor inhibition. J ClinOncol 20:110-124, 2001.

7. Lin ZP, Boller YC, Amser SM, et al: Prevention of brefeldin A-inducedresistance to teniposide by the proteasome inhibitor MG-132: Involvement of NF-kBactivation in drug resistance. Cancer Res 58:3059-3065, 1998.

8. Noda K, Nishiwaki Y, Kawahara M, et al: Irinotecan plus cisplatin comparedwith etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med346:85-91, 2002.