Second-Line Chemotherapy

40

Second-Line Chemotherapy

Chemotherapy trials for malignant pleural mesothelioma have almost exclusively focused on chemotherapy-naive patients. Until 2000, the literature generally consisted of a plethora of phase II studies (1,2) in which interpretation of efficacy has been hampered by small sample size and heterogeneity in reporting of response outcomes. A recent sys-tematic review of this literature indicated the most active single agent to be cisplatin (3).

In 2002 the report of the pivotal randomized phase III trial (peme-trexed and cisplatin compared with cisplatin alone), the largest clinical study in mesothelioma to date (n=456), confirmed an improvement in response rate, survival, quality of life, and lung function for this com-bination in the first-line setting (4). After setting a new standard of care for first-line therapy and confirming the value of palliative chemother-apy in malignant pleural mesothelioma, clinical research questions can now focus on second-line chemotherapy, previously not worthy of investigation. Indeed clinical trials in this patient population are rare. Recently, however, a dedicated second-line phase II study has been published, confirming the feasibility of conducting clinical trials in this setting (5). Furthermore, the literature, which contains anecdotal reports and a number of phase II studies that specifically allowed entry of patients with prior chemotherapy, suggests the potential efficacy of second-line chemotherapy (6,7). Last, Manegold et al (8) recently reported that post-study (second-line) chemotherapy in the above-mentioned phase III trial, usually with gemcitabine or doxorubicin, was identified as a significant predictor of extended survival (p<.01). This finding could not be explained by a retrospective analysis of pa-tient risk factors by Cox Multiple Regression analysis (8). This chapter reviews the use of second-line chemotherapy for malignant pleural mesothelioma and suggests future directions for clinical care and re-search activity in this area.

Review of the Literature

There have been at least 16 studies or reports published that describe the inclusion of patients with malignant mesothelioma treated in the second-line setting (Table 40.1). Only one of these, Giaccone et al (5), is a dedicated phase II study focusing solely on a second-line population. In most series, about 30% of patients were pretreated. While the inclu-sion of pretreated patients in clinical studies commenced as early as 1983, the efficacy reports of second-line treatment can only be con-sidered as anecdotal given the small number of patients included. Nonetheless, one can see that responses were consistently observed (Table 40.2), the most notable being of responses with carboplatin in the 1980s (9,10). Subsequently, with the emergence of new active agents

Table 40.1. Studies or reports of second-line chemotherapy in pretreated patients with malignant mesothelioma

Percent No. of receiving second-line second-line

Drug(s) Study design n patients therapy Reference Gemcitabine, Report of outcome 456 82 in 38–48 8 vinorelbine, of post-study pemetrexed

doxorubicin, chemotherapy in and cisplatin and others phase III study of arm; 104 in

Pemetrexed (Pem) cisplatin arm and cisplatin (cis) v

cis

Raltitrexed and Phase II, two centers 70 15 21 7 oxaliplatin

ZD0473 Phase II, multicenter 47 47 100 5

Ranpirnase Phase II, multicenter 105 39 37 16

Doxil Phase II, single center 15 5 33 19

Raltitrexed and Phase I, with expanded 17 10 59 8 oxaliplatin mesothelioma cohort

Doxil Phase II 24 12 50 20

Cisplatin and Letter NA 3 100 6

gemcitabine

Cisplatin, 5-FU, Phase II 45 10 22 21

leucovorin, mitomycin-C, etoposide

Ifosfamide Phase II, multicenter 30 8 27 22

Carboplatin Phase II, two centers 31 5 16 10

Diaziquone Phase II 20 4 20 23

Carboplatin Phase II 17 3 18 24

Carboplatin Phase II 16 6 37 9

Cisplatin Phase II 25 7 28 25

Vindesine Phase II 20 6 30 26

and drug combinations, the total number of patients reported as demonstrating drug activity in the second-line setting has increased.

The gemcitabine/cisplatin regimen is one such combination that has emerged as an active first-line therapy with reported response rates of 31% to 48%, with associated improvement in lung function and global quality of life, and a surprisingly low (<10%) progressive disease rate during the study treatment (11,12). The first report of potential second-line activity of the new cisplatin/gemcitabine regimen was in three patients previously treated within a randomized trial comparing the amphibian ribonuclease Onconase (Ranpirnase), to doxorubicin (6). All three patients had failed prior doxorubicin and were treated with cisplatin and gemcitabine. One patient demonstrated “radiological regression” of tumor and symptomatic improvement, while another obtained pain relief after commencement of chemotherapy. No sub-sequent trials of the gemcitabine/cisplatin as second-line therapy have been reported.

Table 40.2. Summary of reported clinical/efficacy outcomes in second-line treated patients (the outcomes reported are from the studies listed in Table 40.1)

No. Type of prior Median

Drug(s) treated chemotherapy Response Median TTP survival Reference Gemcitabine, 186 Pem/Cis ns ns Post-study 8 vinorelbine, or chemotherapy

doxorubicin, Cis (186) prolonged others survival

Raltitrexed and 15 Cisplatin (15) 3/15 27 weeks 44 weeks 7 Oxaliplatin (95% CI 13–31) (95% CI 24–40)

(18 weeks) (31 weeks)

ZD0473 47 Cisplatin (39) 5/43* 77 days 203 days 5 (95% CI 44–105) (95% CI 165–277) Ranpirnase 39 Platinum (24) 2** 102 days overall 61% overall 16

Doxorubicin (16) (95% CI 64–161) 1-year survival

Doxil 5 Doxorubicin (2) 1/5 ns ns 19 Raltitrexed and 10 ns 4/6 (all ns ns 13 Oxaliplatin platinum

refractory)

Doxil 12 Dox/Cis (9) 0/24 ns ns 20 Cisplatin and 3 Doxorubicin (3) 1/3 ns ns 6 gemcitabine

Cisplatin, 5-FU, 10 5-FU (3) ns ns ns 21 leucovorin, Immunotherapy (7) mitomycin-C, etoposide Ifosfamide 8 ns 1/8 ns ns 22 Carboplatin 5 Anthracyclines 1/5 ns ns 10 Diaziquone 4 ns 0/4 ns ns 23 Carboplatin 3 ns 0/3 ns ns 24 Carboplatin 6 ns 1/6 ns ns 9 Cisplatin 7 ns 0/7 ns ns 25 Vindesine 6 ns ns ns ns 26

* All minor responses in 43 evaluable patients. ** One partial, one minor response.

The next combination in which activity was seen in chemotherapy-pretreated patients was with the thymidilate synthase inhibitor raltitrexed (Tomudex) combined with oxaliplatin (7,13) (Tables 40.1 and 40.2). Oxaliplatin is a new platinum analogue demonstrating only partial cross-resistance with cisplatin or carboplatin, first demonstrated in platinum-resistant leukemia models (14). In a phase I study evalu-ating this new combination, impressive results were seen in an initial cluster of patients with mesothelioma (13). Therefore, the investigative team decided to recruit further mesothelioma patients into the phase I study in order to determine potential activity in this subset. Overall, six of the 17 patients [35%] with mesothelioma demonstrated an objec-tive partial response in that phase I trial. An even more interesting finding was that four of these six responding patients were considered “platinum refractory,” i.e., having disease progression during or within 6 months of cisplatin-based therapy. These responses were confirmed by independent radiologic review. Ten of the 17 patients had received prior chemotherapy; four were responders, three had stable disease, and only three patients had disease progression at the first assessment. These findings suggested activity with this combination, which was then explored in a phase II study specifically focused on mesothelioma (7) (Tables 40.1 and 40.2).

The phase II study evaluated the efficacy of raltitrexed and oxali-platin in 70 patients with diffuse malignant pleural mesothelioma, 15 of whom had received prior chemotherapy (7). Patients received raltitrexed 3 mg/m2 _{and oxaliplatin 130 mg/m}2 _{i.v. q21 days. All}

15 previously pretreated patients had received cisplatin. The overall response rate was 20%. The same response rate was observed in the pretreated patients. In pretreated patients, the median time to progres-sion was 27 weeks [95% confidence interval (CI), 13–31 weeks] com-pared with 17 weeks in the chemotherapy-naive population (95% CI, 11–21 weeks). Median survival from the start of treatment in pretreated patients was 44 weeks (95% CI, 24–40 weeks) and 226 weeks (95% CI, 63–292 weeks) from the diagnosis of mesothelioma. This compares with a median survival from the start of treatment in chemotherapy-naive patients of 31 weeks (95% CI, 23–40 weeks) and 49 weeks (95% CI, 40–52 weeks) from the diagnosis of mesothelioma. One-year sur-vival was 22% in chemotherapy-naive patients (95% CI, 10.9–33.2%) compared with 40% in the pretreated patients (95% CI, 15.2–64.8%). Toxicity was manageable, with the most common adverse events being asthenia, nausea/vomiting, and paresthesia. No toxic deaths occurred. Improvement in one or more symptom dimensions occurred in 13% to 40% of the 15 pretreated patients compared with 18% to 34% in the chemotherapy-naive patients.

In this post hoc subset analysis, the prolonged survival seen in the cisplatin-pretreated patients most likely represents a selection bias in favor of better prognosis in this group (i.e., those with more slowly growing tumors survive long enough to receive second-line therapy). An alternative hypothesis is that there are mesotheliomas that are inherently chemotherapy sensitive. Similar to patients with high-grade lymphomas and germ cell tumors, such patients owe their prolonged

survival to effective second- and third-line drug therapy, not to a slow growth rate of the tumor. Although detailed prognostic classification comparing pretreated and chemotherapy-naive patients was not pre-sented, overall, 66% of patients had epithelial histology and 81.4% had a World Health Organization (WHO) performance status of 0 or 1 (7). Still, it is remarkable to see tumor responses with a platinum analogue in cisplatin-pretreated patients. These data suggest the non–cross-resistance (or lack of non–cross-resistance) to the raltitrexed and oxaliplatin combination in mesothelioma. Non–cross-resistance or inherent drug sensitivity, apart from patient-based favorable prognostic characteris-tics, would appear to be a key factor in predicting second-line activity of chemotherapy combinations in many diseases where second-line chemotherapy is effective (non–small-cell lung cancer, lymphomas, ovarian and breast cancers, germ-cell tumors, etc.).

Another novel agent showing promise in mesothelioma is the antitumor ribonuclease Onconase (Bloomfield, NJ) (ranpirnase). It acts by binding to the cell surface and then penetrating through to the cytosol where it degrades transfer RNA (tRNA), which may result in cell death either through an apoptotic switch or by interruption of cell growth and proliferation through protein synthesis inhibition (15). Results from a multicenter phase II study, which included pretreated patients, have been published (16) (Tables 40.1 and 40.2). A random-ized trial comparing first-line doxorubicin with Onconase has also been completed (17). The phase II study enrolled 105 patients, 39 (37%) of whom had prior chemotherapy (16) (Table 40.2). In 11 of the 39 patients, a cisplatin-containing regimen was used, in three, a doxorubicin-containing regimen was used, and in 13, a doxorubicin/cisplatin com-bination was used. The remaining 12 patients were treated with a variety of other agents. All patients received Onconase 480mg/m2_i.v.

weekly. Survival was the primary end point, and outcomes were assessed according to their Cancer and Leukemia Group B (CALGB) prognostic group classification. Of the 81 patients evaluable for a response, four partial responses and two minor responses were seen, and 35 stabilizations of previously progressive disease were noted. In the 39 pretreated patients, one partial response, one minor response, and 11 stabilizations of previously progressive disease were seen. Overall median survival was 6 months (95% CI, 4.7–10 months), with 1- and 2-year survival of 34.3% and 21.6%, respectively. The breakdown of survival between previously treated and first-line–treated patients was not reported, so the true survival impact of Onconase in the second-line setting is not known. Survival was prolonged in patients with either tumor response or stable disease, even when analyzed by CALGB prognostic group. Furthermore, as 37% of patients were pre-viously treated, it is likely that chemotherapy-pretreated patients demonstrating nonprogressive disease had a survival gain, particularly given the 95% confidence limits around the median survival estimate. The only dedicated second-line study of chemotherapy in malignant mesothelioma investigated the activity and tolerability of a novel platinum analogue ZD0473 (5). This was an open-label, multicenter phase II study that recruited 47 patients from six different countries

with a median age of 59 (range 37–75). All patients had received prior chemotherapy, and 39 of 47 (83%) had received a prior platinum-based protocol. The WHO performance status was 0, 1 in 36 patients, and 2 in 11 patients; 80% of patients had advanced disease (International Mesothelioma Interest Group stages II to IV). All patients had relapsed or progressive disease at study enrollment. The mesothelioma histo-logic classification was not reported.

ZD0473 was administered at a starting dose of 120 mg/m2 _{in 14}

patients, six of whom tolerated subsequent escalation to 150 mg/m2_.

The remaining 33 patients received a starting dose of 150 mg/m2_.

Forty-three patients were evaluable for response using the revised WHO-RECIST criteria. No complete or partial responses were seen, but there were five minor responses (≥10% lesion shrinkage), and 19 patients had stable disease. Median time to progression was 77 days (95% CI, 44– 105 days) and median survival was 203 days (95% CI, 165–277 days). The median number of cycles received overall was 3.0 (range 1–6) and six patients received more than six cycles. All patients eventually withdrew from the study, five due to adverse events and 29 due to progressive disease. The main toxicity was hematologic (thrombocytopenia, 36% grade III) with no grade IV hematologic or nonhematologic toxicity observed. Quality of life was assessed using the Functional Assessment of Cancer Therapy–Lung (FACT-L) ques-tionnaire. Little change was reported in patient overall quality of life throughout the trial. Although no major responses were seen with ZD0473, this study was important in confirming the feasibility of clin-ical trials of second-line chemotherapy.

With over 40% of patients responding to pemetrexed/cisplatin as first-line treatment for malignant mesothelioma, patients and their treating physicians now have higher expectations for chemotherapy in this disease. These expectations have fueled a need for clinical trials in the second-line setting. A recent updated report on the pemetrexed/cis-platin phase III trial may shine some light and give impetus to answer the question of survival with second-line chemotherapy (8). In this report, the impact of second-line post-study chemotherapy on the survival of patients within the pemetrexed/cisplatin phase III trial was explored. The analysis of post-study chemotherapy was not a part of study design, occurred in selected patients, and should be considered a hypothesis-generating exercise. The percentage of patients receiving post-study chemotherapy was 48% in the cisplatin treatment arm compared with 38% in the pemetrexed/cisplatin arm. The majority of patients received gemcitabine, navelbine, or doxorubicin monotherapy. Multiple regression analysis indicated that post-study chemotherapy had a significant correlation with prolonged survival (p <0.01). One of the key findings of this report was the survival advantage observed in the pemetrexed/cisplatin treatment in spite of the imbalance in post-study chemotherapy favoring the cisplatin arm. This strengthens the argument further for the efficacy of first-line pemetrexed/cisplatin but also indicates the potential for improved survival with second-line treatment.

Future Directions

The value of second-line chemotherapy on patient survival and quality of life should be tested in a randomized controlled trial, ideally against a best supportive care control arm. Eli Lilly Inc. has embarked upon such a study comparing single-agent pemetrexed to best supportive care in the second-line setting. The trial is designed to accrue 240 patients but is accruing slowly and predominantly in the United Kingdom, Europe, and South Africa (Paolo Paoletti, M.D., personal communication, May 2003). Whether it will complete accrual is uncertain.

The question as to which agent or drug combination is best tested as second-line treatment depends to a great extent on which agents are used as first-line treatment. Gemcitabine alone was the most commonly used post-study chemotherapy agent in the context of prior cisplatin with or without pemetrexed, as reported in the Manegold et al (8) study (19.5% vs. 29.8%, pemetrexed/cisplatin vs. cisplatin arms, respectively). Gemcitabine in combination was the second most com-monly used regimen (15.9% vs. 14.4%), followed by single-agent vinorelbine (9.8% vs. 4.8%) and single doxorubicin (8.5% vs. 10.6%). The variable single agent activity of gemcitabine as a single agent in the first-line setting (0–31% response rate across three phase II studies) and its greater efficacy in combination with cisplatin would argue for a gemcitabine combination rather than a single-agent study (18). The potential efficacy of oxaliplatin in patients previously treated with cis-platin suggests it may be a suitable agent to explore in combination with gemcitabine after failure of pemetrexed/cisplatin. Furthermore, given the benefit of doublet chemotherapy shown with peme-trexed/cisplatin, other doublets would be easily studied. The gem-citabine/doxorubicin doublet has shown good efficacy in metastatic urothelial malignancy and would be expected to be relatively non–cross-resistant with the pemetrexed/cisplatin regimen. Other potential doublets include vinorelbine and a platinating agent. The oxaliplatin/raltitrexed combination is yet another that has demon-strated some second-line activity in a small cohort of patients. Most important, formal phase II studies of such second-line chemotherapy regimens are required before a phase III trial could be considered. For example, CALGB has undertaken a phase II study of the novel antian-giogenesis/tyrosine kinase receptor antagonist BAY43–9006 as second-line therapy (H. Kindler, personal communication, May 2003). If the study accrues well and shows activity, a phase III study could be planned using that agent alone compared to best supportive care.

This population of pretreated high-performance status mesothe-lioma patients is an ideal population in which to study new drugs. At the University of Chicago, for example, open phase II trials available in this population include imatinib (Gleevec) (27) and SDX-101 (l-alanosine). Planned trials include an m-TOR (mammalian target of rapamycin) inhibitor and an inhibitor of multiple tyrosine kinases.

Conclusion

The role of chemotherapy in malignant mesothelioma has changed since the late 1990s with the emergence of new active regimens, im-proved image reporting, and high-quality data from large multicenter randomized studies. A review of the literature indicates increasing reports of efficacy of second-line chemotherapy in selected fit patients. The activity of pemetrexed and cisplatin in the first-line setting and the apparent value of post-study chemotherapy within the context of that phase III study have confirmed the sensitivity of some mesotheliomas to chemotherapy. Those data, in turn, have opened the door for explo-ration of chemotherapy or other novel therapies in the second-line setting for malignant mesothelioma. Last, novel phase II studies are required, indeed vital, to determine active agents and combinations in this setting. Careful analysis of the results of such studies by risk/prog-nostic group assignment and prior response duration will need to be done. Ultimately the most promising agent(s) will need to be evaluated in a randomized comparison against the current standard of best sup-portive care.

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