An Update from the Chemotherapy Foundation on Non-Small Cell Lung CancerNovember 12-15, 2003New York, New YorkFranca Lebow MA
Lung cancer is the number one cause of cancer-related deaths in the United States and in women, this malignancy has overtaken heart disease as the number one killer. Non-small cell lung cancer (NSCLC) accounts for 80 to 85% of all lung cancer cases and approximately one-third of NSCLC patients present with advanced disease. At the Chemotherapy Foundation Symposium XXI, several investigators updated the progress in the treatment of NSCLC with combination chemotherapy, radiation therapy, and with a variety of novel agents.
Combination Chemotherapy in Advanced Disease
Combination chemotherapy is the current standard of care for both stage III and stage IV patients. In his opening remarks, David S. Ettinger, MD, of Johns Hopkins University, summed up treatment for advanced disease this way: two-drug platinum-based chemotherapy has improved survival and quality of life in patients with good performance status; two drugs are more effective than one drug, but three drugs are not better than two; elderly patients can be treated safely with a Paraplatin® doublet; and the benefit of chemotherapy in poor performance status (PS) patients remains uncertain.
The ECOG 1594 trial1 assessed four doublets where the control arm was paclitaxel/Platinol®, and the experimental arms were paclitaxel/Paraplatin®, Gemzar®/Platinol®, and Taxotere®/Platinol®. All of the primary endpoints were similar across all four arms with the exception of median time to progression, which favored Gemzar®/Platinol® (4.2 months, P=0.001). Seven randomized, phase III studies since then, have reported an apparent advantage in median time to progression favoring the Gemzar®/Platinol® doublet with a range of 4.2 months to 6.9 months across these trials. Although this regimen has demonstrated consistent efficacy and superiority over older standards, the Platinol®-associated toxicity remains a serious concern, leading researchers to explore alternative combinations.< /SPAN>
Presented at ASCO 2002 was a phase III study2 comparing Gemzar®/Paraplatin® to Gemzar® alone in stage IIIB/IV patients. While there was only a two month difference in median time to progression between the two groups, there were marked differences in overall survival (29.6% vs. 11.5%, P=0.0001) and in 1-year survival (44% vs. 32%) favoring the doublet over single-agent Gemzar® (see Table 1). Moreover, Dr. Ettinger pointed out that many of these patients had poor prognostic factors. More than half the patients treated in either arm were stage IV, a third of patients experienced more than 5% weight loss, and 14% of patients were PS2.< /SPAN>
Table 1: Gemzar®/Paraplatin® vs. Gemzar® Alone: Efficacy
Greater efficacy with the combination regimen comes at a price and indeed grade 3/4 toxicities were notably higher in the doublet arm with nearly half the patients experiencing thrombocytopenia, a third with leucopenia, and a quarter of patients suffering other non-hematologic adverse effects.
Studies comparing platinum doublets to non-platinum doublets have had mixed results. One phase III trial3 comparing paclitaxel/Gemzar® to paclitaxel/Paraplatin® had similar results for all endpoints with response rates slightly higher in the Gemzar® arm. In an EORTC study4 of three doublets, the paclitaxel/Gemzar® combination had slightly lower response rates for all endpoints, whereas the Gemzar®/Platinol® arm had the highest responses overall (see Table 2). Yet another phase III trial,5 reported at the 2003 annual meeting of ASCO, yielded an overall response rate of 44% among patients on paclitaxel/Gemzar®, 35% of patients on paclitaxel/Paraplatin® and 28% of patients on Gemzar®/Paraplatin®. In addition, grade 3/4 neutropenia and thrombocytopenia were highest in the latter arm.
Table 2: EORTC Trial of Three Chemotherapy Regimens: Efficacy
Such data begs the question should platinum-based regimens remain the mainstay of chemotherapy for advanced disease. Interestingly, an international team of investigators recently completed a meta-analysis of survival outcomes to compare platinum-based comparator drugs versus Gemzar® plus Platinol® or Paraplatin®. At the 10th World Lung Cancer Conference in Vancouver this summer, Joan Schiller, MD, reported the meta-analysis. The team divided 13 studies into one subgroup comprised of those studies with Platinol® alone or a platinum-containing comparator such as etoposide or Ifex® (five trials with roughly 1900 patients) and a second subgroup comprised of those studies looking at a “third generation” agent plus a platinum agent (eight trials with roughly 2600 patients). The overall estimate is that Gemzar®-containing, platinum-based regimens are better than platinum comparators regarding progression-free survival, 5.1 months vs. 4.4 months, and an absolute benefit of 4.2% (year 1). The same is true for overall survival, 9.0 months vs. 8.2 months, and an absolute benefit of 3.9% (year 1).
Exploring New Agents
After years of clinical experience with Gemzar®, much is known about the pathway that it targets and about the sensitivity and resistance to this agent. The Gemzar®/Platinol® combination is a sound regimen to which novel agents can be added in order to enhance apoptosis or to reduce toxicity. Yet, Martin Edelman, MD, of the University of Maryland cautioned his colleagues not to get too excited about new agents until their efficacy is proven. He pointed to the INTACT 1 and 2 studies, which showed no true advantage of adding Iressa® (250 or 500 mg qd) to either Gemzar®/Platinol® or to paclitaxel/Paraplatin® in treating chemonaive patients. Nonetheless, a host of new agents including Affinitak, Velcade®, Bexarotene, and eicosanoid modulators have been combined with Gemzar®-containing regimens.
Velcade® inhibits the proteasome enzyme complex, which regulates a wide variety of protein functions including cell cycle, apoptosis and angiogenesis. Hence, blocking proteasome allows Velcade® to disrupt several pathways. This agent is the first FDA approved proteasome inhibitor and it is now authorized for the treatment of refractory multiple myeloma. Dr. Edelman noted that Velcade® has potential activity in lung cancer as well, but because of neurotoxicity associated with the drug, it would not combine well with taxanes. The California Cancer Consortium has accrued about a third of the 34 stage IIIB/IV NSCLC patients for its study evaluating the safety and feasibility of combining Velcade® with the Gemzar®/Paraplatin® doublet on a 21-day cycle, and to define the MTD for Velcade® in this setting.
Another enzyme pathway under investigation is that of 5-lipoxygenase, which becomes leukotriene, for which there are several inhibitors currently available. Interestingly, research has shown that 5-lipozygenase inhibition is chemopreventative and potentially therapeutic, but to date this pathway has never been tested in cancer. Enter zileuton (Zyflo®), an anti-asthma agent, which targets this enzyme pathway. Dr. Edelman is leading a trial that will not only be the first to target this pathway, but will also be the first to test a double pathway as the study will include another enzyme inhibitor, celecoxib (Celebrex®). This multi-center, randomized phase II trial, CALGB 30203, will add zileuton to Gemzar®/Paraplatin® in one arm; celecoxib to this doublet in the second arm; and both zileuton and celecoxib to this doublet in a third arm.
Predictive biochemical markers of response-specific cytotoxic drugs have become the focus of a great deal of research over the past few years. A randomized study in Spain6 analyzed the expression of several such markers and suggested that low levels of ribonucleotide reductase (RRM1) are associated with better response to Gemzar®/Platinol®. Triapene is an inhibitor of the RRM2 catalytic subunit of this enzyme and this agent has demonstrated in vitro synergy with Gemzar®. The Eastern Cooperative Oncology Group (ECOG) will begin accruing patients in early 2004 for a single arm, phase II trial experimenting with the addition of Triapene to the Gemzar®/Platinol® regimen.
The enzyme cyclooxydase-2 (COX-2) is upregulated in lung cancer and is associated with tumor proliferation and angiogenesis. Preclinical work has shown COX-2 inhibition to be synergistic with chemotherapeutics agents. Phase II trials with the COX-2 inhibitor, celecoxib, suggested that the drug is active in advanced NSCLC when combined with Taxotere®. Another team of researchers at the University of Maryland used this rationale to design a randomized, phase II trial adding celecoxib to either Taxotere®/Camptosar® or Gemzar®/Camptosar®.
Patients with stage IIIB or IV NSCLC with PS 0-1 were randomized to either chemotherapeutic regimen every three weeks, and then further divided to receive, or not receive, celecoxib (400 mg BID). The primary endpoint of the study was to attain a one-year survival rate of 35% or greater as the historical control in this patient population ranges between 32 and 37%. To provide 80% power to detect a 35% increase at the P=0.05 level (one-sided), 216 patients were enrolled. The 2×2 factorial design assumed that if celecoxib is beneficial, it is uniformly so.
The investigators did not observe any significant differences in response, with relatively small numbers of responders across the treatment arms. Clinical benefit (PR and SD) ranged between 23.5% and 34.8% and most notably, celecoxib did not appear to modify the toxicity of the chemotherapeutic agents. As expected, diarrhea and neutropenia were more common with Taxotere® while thrombocytopenia was more common with Gemzar®. These results failed to confirm previous studies, which suggested that celecoxib may mollify toxicities.
Perhaps the novel agent that has garnered the most attention recently is pemetrexed (Alimta®). Alimta® is a multi-targeted antifolate that inhibits at least three enzymes involved in DNA synthesis: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. An advantage of such a multi-targeted agent is the decreased likelihood that cancer cells can develop resistance to it, remarked Paul Bunn, MD, as he began his update.
The original phase II trials7,8 conducted with Alimta® as a single agent in untreated patients showed an overall response rate ranging from 18% to 23%, a medial survival ranging from 8.4 months to 9.6 months, and a one-year survival of 50% in both studies. Such results are similar to those seen with other active agents against NSCLC. Alimta® was evaluated as a second-line treatment in refractory patients in a study,9 which stratified patients by prior treatment (see Table 3) and again results were similar to Taxotere® in the second-line setting.
Table 3: Second-line Alimta® in NSCLC
The above study led to the phase III randomized trial10 comparing Alimta® to Taxotere® as second-line therapy, which made the headlines at ASCO 2003 as it demonstrated that Alimta® is as effective as Taxotere® but far less toxic. Here, 571 patients (the vast majority of whom had prior platinum-based chemotherapy) were randomized to receive 500 mg/m² I.V. Alimta® every three weeks or 75 mg/m² I.V. Taxotere®. Both groups of patients also received 8 mg bid dexamethasone, on the day before, day of, and day after chemotherapy, and the Alimta® patients had vitamin B12 and folic acid supplementation every nine weeks.
Both cohorts of patients received a median of four cycles and the planned dose intensity in each arm was 95%. The two drugs had very similar clinical efficacy with median progression-free survival of 2.9 months; and overall survival of 29.7%, in both arms. Median survival was 8.3 months in the Alimta® patients vs. 7.9 months in the Taxotere® patients. While all efficacy parameters were essentially equivalent between the two arms, the toxicity profile of Alimta® was markedly lower (see Table 4).
Table 4: Adverse Events in Phase III of Alimta® vs. Taxotere®
Dr. Bunn went on to review several studies combining Alimta® with chemotherapeutic agents including Platinol®, Gemzar®, and Paraplatin®, noting that such doublets appear to be as active as other two-drug combinations. When given with the proper supplementation, he concluded, Alimta® is active in both first-line and second-line treatment and offers symptom and survival benefit to the same extent as Taxotere® without the clinical toxicity.
Combined Modality Therapy
Approximately 40% of stage III NSCLC patients have locally advanced disease, not amenable to surgical resection. Radiotherapy plays an integral role as either curative treatment or for palliation and relief of symptoms including hemoptysis, dyspnea due to bronchial obstruction, or persistent pain. Despite undergoing radiation treatment, patients often experience local or distant recurrence. To counter this, studies were designed to assess the value of adding chemotherapy to radiation. Several chemotherapeutic agents have proven to be potent radiosensitizers thereby enhancing the cytotoxic effects of radiotherapy.
Today, chemotherapy and radiotherapy in combined modality treatment is the accepted standard of care for unresectable stage III NSCLC. Results of several trials verified that combining a platinum-based regimen with radiation yielded better response rates and overall survival relative to radiotherapy alone. Controversy lingers among oncologists as to the best way to deliver this combined modality therapy. As he reviewed the data supporting different approaches, Hak Choy, MD, of the University of Texas Southwestern proposed that concurrent chemoradiation should become the standard of care.
Six key studies, conducted in different countries, have compared sequential chemoradiation with concurrent chemoradiation. As expected, the median survival was consistent across the sequential arms of the six studies as was the median survival for the concurrent arms, with an overall median survival of 14 months and 17 months (P<0.05), respectively. The gain of three months in median survival comes with the price of added toxicity. The prevalence of grade 3/4 esophagitis is 23% in the concurrent group of patients relative to 4% in the sequential group across all six studies. However, Dr. Choy pointed out that this toxicity occurs within three months, and the incidence of late esophageal toxicity falls markedly in the concurrent group of patients (under 5%).
Differences in long-term survival between the two approaches are dramatic. In a Japanese study,11 two-, three-, four- and five-year survival rates in the concurrent group of chemoradiation patients were 34.6%, 22.3%, 16.9% and 15.8%, respectively; whereas those in the sequential group were 27.4%, 14.7%, 10.1%, and 8.9%, respectively. Moreover, the response rate for the concurrent arm was significantly higher, 84%, than in the sequential arm, 66% (P=0.0002). In the RTOG 9410 study,12 reported this year at ASCO, four-year survival was 12% for the sequential patients versus 21% for the concurrent patients (P= 0.046). While the benefit of concurrent chemoradiation to median survival is three months, the near doubling in long-term survival is much more significant, hence validating Dr. Choy’s suggestion that concurrent chemoradiation become the standard treatment for good PS stage III patients.< BR>
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