Untreated Extensive-stage Small Cell Lung Research Articles

A study on oligo-progression after durvalumab plus platinum-etoposide for ES-SCLC.

e20642 Background: Chemotherapy plus immune-checkpoint inhibitor(ICI) therapy is the standard of care for untreated extensive-stage small cell lung cancer(ES-SCLC), but the pattern of progression has not been fully investigated. It is known that a certain percentage of patients with ES-SCLC have Oligo-Progression, and ICI treatment can be continued with the addition of local therapy. This is great significance in the current situation where post-treatment is limited. Methods: We performed a retrospective analysis of patients with ES-SCLC treated with durvalumab plus platinum–etoposide regimen from September 2020 to January 2023 in our institution. Results: Forty patients were included, median age was 68 years (range 45-89), 32 (80%) patients were male and 8 (20%) patients were female, ECOG-PS was 0 or 1 in 25 (63%) patients, 2 or 3 in 15 (38%) patients, 38 (95%) patients had a smoking history, 39 (98%) patients were Stage IV, and the regimens were durvalumab plus cisplatin–etoposide in 15 (38%) patients and durvalumab plus carboplatin–etoposide in 25 (63%) patients. The median PFS was 5.9 months (95% CI: 3.8-8.0) and the median OS was 25.4 months (95% CI: 6.0-44.8). 14(35%) patients were still on treatment. Of the 17 (43%) patients with confirmed RECIST-PD, 4 patients had Oligo-Progression. All of them continued ICI treatment with additional radiation therapy. Two patients are continuing ICI treatment. Two patients with second recurrence, and the time from RECIST-PD to second recurrence was 5 months and 18 months, respectively. Conclusions: Among patients with RECIST-PD after durvalumab plus Platinum–Etoposide for ES-SCLC, Oligo-Progression was observed in 24%, and the strategy of continued ICI treatment in addition to local therapy may be promising.

1533P Atezolizumab (ATZ) plus carboplatin (Cb) and etoposide (eto) in patients with untreated extensive-stage small cell lung cancer (ES-SCLC): Results from the interim analysis of MAURIS trial

MAURIS is a multicenter, open label, single arm, phase IIIb trial conducted in 25 Italian centers, that evaluates the safety and efficacy of ATZ + Cb-Eto in patients with newly diagnosed ES-SCLC, according to the new standard of care from the pivotal trial IMpower133. Patients (pts) with ECOG PS2, untreated asymptomatic brain metastases (BM) were eligible for this study and consolidative and palliative radiotherapy was also allowed. An interim analysis (IA) has been conducted roughly one year from the end of enrolment with a median follow-up of 10.5 months. Patients enrolled in the study received ATZ 1200 mg + Cb-Eto every 3 weeks for 4–6 cycles in the induction phase, followed by ATZ maintenance every 3 weeks up to disease progression, unacceptable toxicity or clinical deterioration. The primary endpoints were the incidence of serious adverse events (SAE) and immune-mediated AEs (imAE). The secondary endpoints were 1 year survival, overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). 154 patients (95 males, mean age 65.1 years, 6 pts with PS2, 19 pts with BM) were treated. At data cut-off 28 oct 2021, 139 pts (90.3%) discontinued the treatment: 97 pts (63.0%) due to progressive disease, 17 pts (11.0%) due to AE. Safety data related to the induction phase and efficacy data at data cut-off were analysed overall and by the number of induction cycles.Table: 1533PInduction PhaseTotal n=154≤3 cycles n=224 cycles n=43≥5 cycles n=89Safety n (%)SAEs46 (29.9)14 (63.6)15 (34.9)17 (19.1)Treatment related SAE28 (18.2)6 (27.3)12 (27.9)10 (11.2)imAE23 (14.9)4 (18.2)5 (11.6)14 (15.7)Treatment related AE117 (76.0)13 (59.1)35 (81.4)69 (77.5)Treatment AE leading to death7 (4.5)6 (27.3)0 (0.0)1(1.1)Efficacy1 year survival, n (%)65 (41.9)0 (0.0)18 (41.9)47 (52.8)OS (mo), median (95% CI)10.7 (9.9-13.7)2.7 (1.0-7.6)10.4 (8.6-14.2)13.8 (10.7-18.2)PFS (mo), median (95% CI)5.5 (5.3-5.8)1.8 (1.0-3.9)4.5 (4.1-5.5)5.8 (5.5-6.5)ORR, n (%)111 (71.6)5 (21.7)31 (72.1)75 (84.3) Open table in a new tab In this interim analysis, safety data observed in the induction phase seem consistent with IMpower133 results considering a patient population closer to clinical practice both for baseline patient characteristics and co-treatments allowed. In terms of efficacy data, we found that PFS and ORR were also aligned. Survival data in relation to the number of cycles in the induction phase, according to the investigator’s choice, might reflect a biased population and they should be confirmed.

SKYSCRAPER-02: Primary results of a phase III, randomized, double-blind, placebo-controlled study of atezolizumab (atezo) + carboplatin + etoposide (CE) with or without tiragolumab (tira) in patients (pts) with untreated extensive-stage small cell lung cancer (ES-SCLC).

LBA8507 Background: Atezo, in combination with CE, was the first cancer immunotherapy approved for 1L treatment of ES-SCLC. However, most pts eventually experience disease progression. TIGIT is a novel inhibitory immune checkpoint present on activated T cells and NK cells. Tira (anti-TIGIT) may synergise with other immunotherapies, such as PD-L1/PD-1 inhibitors, and further amplify the immune response to improve clinical outcomes. SKYSCRAPER-02 (NCT04256421) evaluates whether the antitumor effect and survival benefits of the combination of atezo + CE could be enhanced by adding tira in pts with ES-SCLC. Methods: Eligible pts with untreated ES-SCLC (asymptomatic treated or untreated brain metastases [BM] permitted) were randomized 1:1 to receive induction tira 600 mg IV or placebo (pbo) combined with atezo 1200 mg IV + CE for 4 x 21-day cycles followed by maintenance tira or placebo combined with atezo every 3 weeks until disease progression or loss of clinical benefit. Stratification factors include ECOG PS (0 vs 1); presence/history of BM (yes vs no); LDH (≤upper limit of normal [ULN] vs >ULN). Co-primary endpoints were investigator-assessed PFS and OS in all randomized pts without the history/presence of BM at baseline (primary analysis set [PAS]). Additional endpoints include PFS and OS in all randomized pts regardless of BM status (full analysis set [FAS]), objective response rate, duration of response, and safety. Results: A total of 490 patients were randomized (tira + atezo + CE, n=243; pbo + atezo + CE, n=247). As of 6 Feb 2022, median duration of follow-up was 13.9 months (mo); data represent final analysis for PFS and interim analysis for OS. In the PAS, no additional benefit was seen for tira + atezo + CE in PFS or OS compared with pbo + atezo + CE (Table). PFS and OS in the FAS were consistent with those observed in the PAS (Table). Grade 3/4 TRAEs occurred in 52.3% (tira + atezo + CE) and 55.7% (pbo + atezo + CE) and Grade 5 TRAEs occurred in 0.4% (tira + atezo + CE) and 2.0% (pbo + atezo + CE). TRAEs leading to any treatment discontinuation occurred in 5.0% and 5.3% with tira + atezo + CE and pbo + atezo + CE, respectively. Conclusions: The addition of tira to atezo + CE did not provide benefit over atezo + CE in pts with untreated ES-SCLC with or without BM. The combination was well tolerated, and no new safety signals were identified. The study will continue to planned final OS analysis. Clinical trial information: NCT04256421. [Table: see text]

Phase I study of entinostat (Ent), atezolizumab (A), carboplatin (C), and etoposide (E) in previously untreated extensive-stage small cell lung cancer (ES-SCLC), ETCTN 10399.

e20606 Background: A-CE has demonstrated improved overall survival in ES-SCLC, but there are currently no approved therapies targeting genomic alterations in SCLC. Mutations in acetyltransferases CREBBP and EP300 occur at a frequency of 15% and 13%, respectively, in SCLC, and PDX models with CREBBP mutations were demonstrated to be susceptible to targeting with HDAC inhibitors. Ent, a class I selective HDAC inhibitor, has also demonstrated clinical activity in a combination with pembrolizumab in patients with NSCLC and uveal melanoma with minimal hematologic toxicity at RP2D of 5 mg PO weekly. We conducted a phase I trial to evaluate the combination of Ent with A-CE for ES-SCLC, NCI ETCTN 10399. Methods: Patients (pts) with treatment-naïve ES-SCLC, stable or treated brain metastases, ECOG ≤2 were enrolled and treated on up to 4 dose levels of Ent. Allocation to cohorts was determined using Bayesian optimal interval (BOIN) design targeting a MTD with a DLT rate of 20%. Dose levels (DL) included Ent 2 mg, 3 mg, or 5 mg PO weekly on day (d) 1 in addition to 4 cycles of A-CE (A 1200 mg, C AUC 5, E 100 mg/m2 d 1-3) followed E+A for 1 year. Pre-treatment tissue and plasma collected for WES. Results: 3 pts were enrolled and treated at DL1 with Ent 2 mg. Pts were age 69-83, 2 male, 1 female, 2 were ECOG 1, 1 was ECOG 0, and 1 with prior SRS radiation for brain metastases. 2 of 3 experienced DLTs during cycle 1: (1) Grade (Gr) 4 febrile neutropenia after 2 doses of Ent and (1) Gr 5 sepsis after 1 dose of Ent. BOIN design required stopping accrual to dose level 1 and the trial was closed to further accrual. The pt without DLT experienced grade 3 thrombocytopenia after 2 doses of Ent, but recovered after holding cycle 1, day 15 Ent. This patient experienced Gr 3 neutropenia during cycle 2. The most common adverse events were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), hypocalcemia (2). Of these, most were Gr 3-4: anemia (1), neutropenia (3), thrombocytopenia (2), leukopenia (1), hypocalcemia (1). Conclusions: The combination of low dose Ent 2 mg PO weekly + AC-E is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia in the first 1-2 weeks and ≥Gr 3 neutropenia and thrombocytopenia prior to completing 2 cycles of treatment for all pts. There is no role for further exploration of entinostat with carboplatin, etoposide, and atezolizumab. Clinical trial information: NCT04631029.

Imfirst: A phase IIIb, safety, single arm study of carboplatin (CB) or cisplatin (CP) plus etoposide (ET) with atezolizumab (ATZ) in patients with untreated extensive-stage small cell lung cancer (ES-SCLC) in Spain—Primary safety results of the induction phase.

8567 Background: Clinical trial (CT) IMpower133 met both primary endpoints and is the first CT to show significant clinical improvement over standard chemotherapy (C) with a good safety profile in first line (1L) ES-SCLC. The addition of ATZ to CB + ET resulted in an OS landmark of 34% and 22% compared to 21% and 16.8% of patients alive at 18 and 24 months respectively versus C. IMfirst evaluates ATZ + CB or CP + ET in a broader patient population than the pivotal study. ECOG Performance status (PS) 2, asymptomatic untreated brain metastases, underlying stable autoimmune diseases and HIV+ pts are eligible. IMfirst also includes the possibility of 6 C induction cycles according to investigator´s choice and consolidation radiotherapy. Methods: To evaluate the safety and efficacy of ATZ added to CB or CP + ET as 1L treatment in an interventional real world setting of ES-SCLC. Exploratory endpoints include tumor biomarker analysis related to ATZ. Results: As of Oct 2020, 117 pts had been enrolled, 105 treated with ATZ + CB + ET and 12 with ATZ + CP + ET. The median age was 65 years (Y) (range 35-89); 84 males; 14 pts (12%) had CNS metastases and 66 pts were current smokers and 50 former smokers, one had never smoked. The PS was 0 in 28 pts (24%), 1 in 75 (64%) and 2 in 14 (12%). The median of cycles of ATZ received was 4 for all the pts (range 1-12) and 2 for the pts (40) in maintenance phase (range 1-8). Number of pts with adverse events (AEs) was 109, 36 with Serious Adverse Events (SAEs) and 63 with AEs. 8 pts had SAEs related to treatment, 4 had adverse events of special interest and 13 pts discontinued the treatment due to AEs: 6 to ATZ, 12 to CB or CP and 10 to ET, 1 patient discontinued ATZ due to a related AE. Table shows the treatment related AEs (TRAEs). No grade 5 TRAEs were reported. Conclusions: IMfirst induction phase analysis confirms the safety profile of ATZ plus C in a broader population of patients. Efficacy, biomarker and further safety analyses will be presented in the future with longer follow up.[Table: see text]

Comparative Efficacy and Safety of Immunotherapeutic Regimens with PD-1/PD-L1 Inhibitors for Previously Untreated Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis.

Improving therapeutic strategies for extensive-stage small cell lung cancer (ES-SCLC) remains a challenge. To date, no reports have directly compared the efficacy and safety of immune checkpoint inhibitors plus platinum–etoposide (ICIs+EP) with platinum–irinotecan (IP) or directly compared different ICIs+EP for previously untreated ES-SCLC. This study used a Bayesian approach for network meta-analysis to compare efficacy and safety between ICIs+EP and IP and between each pair of three ICIs+EP. The six treatment arms were: pembrolizumab plus platinum–etoposide (Pem+EP), durvalumab plus platinum–etoposide (Dur+EP), atezolizumab plus platinum–etoposide (Atz+EP), platinum–amrubicin (AP), IP, and platinum–etoposide (EP). No significant differences in overall survival were observed between ICIs+EP and IP and between each pair of three ICIs+EP. The incidence of ≥grade 3 adverse events (G3-AEs) was significantly higher in ICIs+EP than IP, whereas no significant difference was found in G3-AEs between each pair of three ICIs+EP. The incidence of ≥grade 3 neutropenia and thrombocytopenia was significantly higher in ICIs+EP than IP, whereas the incidence of ≥grade 3 diarrhea was significantly lower in ICIs+EP than IP. These findings will help clinicians better select treatment strategies for ES-SCLC.

Cost-effectiveness analysis of durvalumab plus etoposide: platinum in the first-line therapy of extensive stage small-cell lung cancer from the Chinese payers' perspective.

Results from the CASPIAN trial (Durvalumab ± Tremelimumab in Combination With Platinum Based Chemotherapy in Untreated Extensive-Stage Small Cell Lung Cancer) trial demonstrated the clinical benefit of durvalumab plus etoposide-platinum (EP) chemotherapy as first-line treatment for patients with extensive stage small-cell lung cancer (ES-SCLC). However, considering the high price of durvalumab, it is unclear whether addition of durvalumab to EP chemotherapy has economic value compared with EP alone. In this study, we aimed to evaluate the cost-effectiveness of durvalumab plus EP chemotherapy as a first-line treatment for patients with ES-SCLC. A Markov model comprising three health states (stable, progressive, and dead) was developed to simulate the process of small-cell lung cancer. Utility and costs were obtained from published resources. Health outcomes were derived from the CASPIAN trial. Costs were calculated based on the standard medical fees in Zhejiang Province from Chinese patients' perspective. Utility values were obtained from published data. One-way and probabilistic sensitivity analyses were applied to verify model robustness. The addition of durvalumab to EP chemotherapy costs more than $32,220, with a gain of 0.14 quality-adjusted life years (QALYs) compared with EP alone. The incremental cost-effective ratio was $230,142.9 per QALY, which exceeds the willingness to pay threshold of $28,527 per QALY. In the sensitivity analysis, the utility values for the progressive state, costs of durvalumab and EP chemotherapy, and costs for the progressive state were considered to be the three most sensitive factors in the model. The addition of durvalumab to EP chemotherapy is not a cost-effective strategy in the first-line therapy of ES-SCLC from the Chinese payers' perspective.

PCN89 A Cost-Effectiveness Analysis of Atezolizumab in Combination with Carboplatin and Etoposide in Patients with Untreated Extensive-Stage Small Cell Lung Cancer

To assess the cost-effectiveness of atezolizumab in combination with carboplatin and etoposide (CE) compared to CE in the treatment of patients with untreated extensive-stage small cell lung cancer (ES-SCLC), in the Portuguese setting. A partitioned survival model including progression-free survival, post-progression survival and death health states was used to estimate the cost-effectiveness of atezolizumab in combination with CE, using data from the IMpower133, a phase III, randomized, double-blind, placebo-controlled trial. Utility weights were estimated using the proximity to death approach separately for on/off treatment and applying the EQ-5D-5L Portuguese value set to the patient reported outcomes from the IMpower133 trial. Portuguese-specific disease management resource use was based on a panel of clinical experts and on Portuguese diagnosis-related group microdata. The main sources for unit costs were national legislation and official drug cost databases. The analysis was conducted from NHS’s perspective, assuming a lifetime horizon and a 5% discount rate for both costs and effects. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of results. Atezolizumab increases average life expectancy by 0.24 undiscounted life years (LY) or 0.22 undiscounted quality adjusted life years (QALY), enabling a discounted gain of 0.22 LY or 0.20 QALY. Economic analysis shows that the higher cost of the atezolizumab option is mainly due to higher treatment costs. The estimated incremental cost-effectiveness ratios are 124,218€/LY and 138.494€/QALY. Deterministic sensitivity analyses show that results are robust to most scenarios but sensitive to the parametric extrapolation options of the treatment duration and overall survival. Treatment with atezolizumab in combination with CE showed an incremental effectiveness both in terms of LY and QALY compared to CE alone. The cost-effectiveness model of atezolizumab in combination with CE in patients with untreated ES-SCLC was considered valid to support a reimbursement decision in the Portuguese setting.

1808TiP Atezolizumab (ATZ) in combination with carboplatin (Cb) and etoposide (Eto) in the treatment of patients with previously untreated extensive-stage small cell lung cancer (ES-SCLC): A multicenter, phase IIIb, single arm, safety study (MAURIS trial)

1808TiP Atezolizumab (ATZ) in combination with carboplatin (Cb) and etoposide (Eto) in the treatment of patients with previously untreated extensive-stage small cell lung cancer (ES-SCLC): A multicenter, phase IIIb, single arm, safety study (MAURIS trial)

A Study of Atezolizumab Plus Carboplatin and Etoposide With or Without Tiragolumab in Patients With Untreated Extensive-Stage Small Cell Lung Cancer

A Study of Atezolizumab Plus Carboplatin and Etoposide With or Without Tiragolumab in Patients With Untreated Extensive-Stage Small Cell Lung Cancer

A Study of Atezolizumab in Combination With Carboplatin Plus Etoposide to Investigate Safety and Efficacy in Patients With Untreated Extensive-Stage Small Cell Lung Cancer

A Study of Atezolizumab in Combination With Carboplatin Plus Etoposide to Investigate Safety and Efficacy in Patients With Untreated Extensive-Stage Small Cell Lung Cancer

Irinotecan-platinum combination therapy for previously untreated extensive-stage small cell lung cancer patients: a meta-analysis

BackgroundThere is still a debate regarding whether regimens combining irinotecan with platinum could replace regimens combining etoposide with platinum, as first-line chemotherapy for extensive-stage small cell lung cancer (ES-SCLC). We performed a meta-analysis to compare these regimens as first-line chemotherapy for ES-SCLC.MethodsA literature search for randomized controlled trials was performed using the Cochrane Library, PubMed, and Embase. The inverse variance method was used to estimate summary hazard ratios and their 95% confidence intervals for overall survival and progression free survival. Relative risk was used to estimate the overall response rate, disease control rate, 1-year survival, 2-year survival, and adverse event data.ResultNine randomized controlled trials (2451 patients) were included. Regimens combining irinotecan and platinum improved overall survival, progression-free survival and overall response rate compared to combination etoposide and platinum regimens. Meanwhile, superior progression-free survival and overall response rate outcomes were observed in the Asian subgroup of patients. These patients receiving a combination irinotecan and platinum regimen experienced grade 3–4 diarrhea more frequently and experienced less hematologic toxic events than the non-Asian groups.ConclusionsOur data suggest that a combination irinotecan and platinum regimen can prolong overall survival, progression-free survival and overall response rate for patients with ES-SCLC as compared to a combination etoposide and platinum regimen. And the Asian patients could benefit from irinotecan combined with platinum easier.

Carfilzomib (CFZ), carboplatin and etoposide for previously untreated extensive-stage small cell lung cancer (ES-SCLC): Phase 1b results from a phase 1b/2 study.

e20092Background: Studies have suggested proteasome inhibitors can be combined with topoisomerase inhibitors to treat ES-SCLC. CFZ has previously demonstrated activity in relapsed SCLC. Results fro...

Positive Interaction between Prophylactic Cranial Irradiation and Maintenance Sunitinib for Untreated Extensive-Stage Small Cell Lung Cancer Patients After Standard Chemotherapy: A Secondary Analysis of CALGB 30504 (ALLIANCE)

BackgroundProphylactic cranial irradiation (PCI) has become a standard option for patients with extensive-stage small cell lung cancer (ES-SCLC). The Cancer and Leukemia Group B 30504 trial was a randomized phase II study of the effect of sunitinib versus placebo in ES-SCLC patients responding to platinum-based systemic therapy. The study required preenrollment brain imaging. PCI was provided at the discretion of treating physicians. We performed a secondary analysis of the Cancer and Leukemia Group B trial to determine the impact of PCI on patients with ES-SCLC. MethodsFisher’s exact test and the Wilcoxon rank-sum test were conducted to identify the differences between patients receiving PCI and patients not receiving PCI. Kaplan-Meier analyses described progression-free survival (PFS) and overall survival (OS) for patients in the PCI and non-PCI groups. ResultsA total of 85 patients received maintenance therapy (41 received placebo and 44 received sunitinib). Patient characteristics were balanced between the PCI and non-PCI groups. The patients receiving PCI plus sunitinib had a nonsignificant 2.7-month improvement in PFS (5.0 months versus 2.3 months, p = 0.14, hazard risk [HR] = 0.62, 95% confidence interval [CI]: 0.33–1.18) trending toward improved OS (8.9 months versus 5.4 months, p = 0.053, HR = 0.47, 95% CI: 0.22–1.03). PCI was associated with a trend toward improved median PFS (2.9 months versus 2.2 months, p = 0.096, HR = 0.69, 95% CI: 0.45–1.07) but not median OS (8.3 months in the PCI group versus 8.7 months in the non-PCI group, p = 0.76, HR = 1.07, 95% CI: 0.67–1.71). The patients receiving placebo had no improvement in PFS or OS with PCI. ConclusionsTrends toward improved PFS and OS were seen in patients receiving PCI and sunitinib, thus supporting the need for further prospective research evaluating the integration of maintenance systemic therapy and PCI for patients with ES-SCLC. Improved outcomes for patients with ES-SCLC after induction chemotherapy may require PCI, thoracic radiotherapy, and maintenance systemic therapy to achieve control of both intracranial and extracranial disease.

A randomized double-blind phase II trial of platinum (P) plus etoposide (E) with or without concurrent ZD6474 (Z) in patients (pts) with previously untreated extensive-stage (ES) small cell lung cancer (SCLC): Hoosier Oncology Group LUN06-113.

7506 Background: Standard treatment with P + E results in median survival for ES SCLC 10 months. Dose escalation, addition of third cytotoxic agents, and maintenance therapy have failed to improve ...

Multitrial evaluation of progression-free survival (PFS) as a surrogate endpoint for overall survival (OS) in previously untreated extensive-stage small cell lung cancer (ES-SCLC): An Alliance-led analysis.

7510 Background: We previously demonstrated that PFS may be a candidate surrogate endpoint for OS in ES-SCLC using data from 3 randomized trials (Foster, Cancer 2011). Here, we sought to formally assess the patient- and trial-level surrogacy of PFS using data from 9 additional randomized phase II and III trials conducted by the NCI-funded cancer cooperative groups since 1986. Methods: Individual patient data from all 12 trials (3178 patients: 9 phase III and 3 phase II) were pooled. OS was the primary endpoint in all phase III trials; 3 phase III and 1 phase II trial were positive per protocol. Patient-level surrogacy (Kendall’s tau) was assessed using the Clayton copula bivariate survival model. Trial-level surrogacy was assessed via association of the log hazard ratios on OS and PFS across trials, including: weighted (by trial size) least squares regression of Cox model effects (R² WLS) and weighted (by trial size) correlation of the copula effects (R² Copula). One trial had 4 treatment arms thus 14 total two-arm comparisons were made. Results: With a median follow-up of 41.8 months in the 106 patients still alive, the median OS and PFS across trials were 9.7 months (95% CI: 9.5, 9.9) and 5.7 months (95% CI: 5.5, 5.8), respectively. There were 3120 PFS events in total (2564 disease progressions and 556 deaths without progression). The median time from progression to death was 4.1 months (95% CI: 3.9, 4.3). PFS showed modest association with OS at the patient-level (tau= 0.56) and at the trial-level (R² WLS = 0.58; R² Copula (standard error) = 0.55 (0.29)). The 95% CIs for the predicted HR for OS given observed HR on PFS under a weighted leave-one-out prediction always included the observed HR for OS; however such intervals were wide, suggesting uncertainty on the practical use of PFS as a surrogate for OS in this setting. Conclusions: PFS failed to demonstrate surrogacy for OS in ES-SCLC based on this large pooled analysis. Given that the difference in the median PFS and OS is less than 6 months, we recommend using OS as the primary endpoint in phase III trials of previously untreated ES-SCLC.

Chemotherapy with or without maintenance sunitinib for untreated extensive-stage small cell lung cancer: A randomized, placebo controlled phase II study CALGB 30504 (ALLIANCE).

7506 Background: Sunitinib (S) inhibits small cell lung cancer (SCLC) targets VEGFR1-3, PDGFR, and KIT. We tested whether giving S after chemotherapy (C) for extensive stage SCLC improves progression free survival (PFS). Methods: CALGB 30504 was a randomized, double-blind, placebo (P) controlled phase II study for untreated SCLC, performance status 0-2, adequate organ function, and no S risk factors: bleeding, hypertension, or brain metastases. Enrollment was prior to C: cisplatin 80 mg/m2 or carboplatin AUC5 day 1 plus etoposide 100 mg/m2days 1-3 every 21 days 4-6 cycles. Patients without progression after C were stratified cisplatin vs carboplatin, and 4-5 vs 6 cycles C, and randomized 1:1 to P or S 37.5 mg daily until progression assessed every 6 weeks. Prophylactic cranial irradiation was offered to responders (CR or PR) to start about 4-6 weeks after C. S was held during radiation. Crossover from P to S was allowed at progression. Primary endpoint was PFS (from time of randomization) for maintenance (M) P vs S using a 1-sided log rank test with a=0.15; 80 randomized and treated patients provide »89% power to detect a hazard ratio (HR) of 1.67. Results: Between 5/09 and 12/11, 144 enrolled and 138 received C. Ninety five were randomized to P vs S; 10 did not receive M due to progression, refusal, and AE (5 each arm). Eighty five received M, 41 P and 44 S. Demographics were balanced. M toxicities grade > 3 and incidence > 5% included (%): grade 3 (S: fatigue 19, neutrophils 10, leukocytes 7, platelets 7) (P: fatigue 5); grade 4 (S: 1case GI hemorrhage, 1case lipase) P zero; grade 5 zero both arms. Efficacy (90% CI): PFS on maintenance after C was P 2.3 mo (CI: 1.7-2.6) and S 3.8 mo (2.7-4.4) (HR=1.54, CI 1.03-2.32, p=0.04). Overall survival (OS) was P 6.7 mo (5.5-9.5) and S 8.8 mo (8.0-9.8) (HR=1.10, CI 0.71-1.70, p=0.36). At progression on P, 17 received S and among 14 evaluable 10 (71%) had stable disease receiving 2-9 cycles S. Conclusions: The primary objective was met showing improved PFS for maintenance S. There was a non-significant trend toward improved OS despite crossover design. S was well tolerated. Further study of sunitinib after chemotherapy for SCLC is justified. Clinical trial information: NCT00453154.

Complement and Correction for Meta-Analysis of Patients with Extensive-Stage Small Cell Lung Cancer Managed with Irinotecan/Cisplatin versus Etoposide/Cisplatin as First-Line Chemotherapy

We thank Guo et al. for their comment on our article entitled “A Meta-Analysis of Randomized Controlled Trials Comparing Irinotecan/Platinum with Etoposide/Platinum in Patients with Previously Untreated Extensive-Stage Small Cell Lung Cancer.”1 The meta-analysis was completely accepted for publication in February 2010, and the new clinical trial reported by Zatloukal et al.2 was published online in March 2010; therefore, we were unable to add the new trial to the meta-analysis. Both trials given carboplatin or cisplatin were included into the meta-analysis.

Tumor response and progression‐free survival as potential surrogate endpoints for overall survival in extensive stage small‐cell lung cancer

AbstractBACKGROUND:The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression‐free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS.METHODS:Individual patient data from 870 untreated extensive stage small‐cell lung cancer patients participating in 6 single‐arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient‐level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial‐level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial‐level surrogacy measures included: R2 from weighted least squares regression model, Spearman correlation coefficient, and R2 from bivariate survival model (Copula R2).RESULTS:Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1‐10.0) and 5.5 (95% CI, 5.2‐5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient‐level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35‐0.51; concordance index 0.63; P < .01), with 6‐month PFS being the strongest (HR, 0.41; 95% CI, 0.35‐0.49; concordance index, 0.66, P < .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R2 = 0.79; Copula R2 = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R2≤0.48).CONCLUSIONS:PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials. Cancer 2011. © 2010 American Cancer Society.

A Meta-Analysis of Randomized Controlled Trials Comparing Irinotecan/Platinum with Etoposide/Platinum in Patients with Previously Untreated Extensive-Stage Small Cell Lung Cancer

To compare the efficacy and toxicities of irinotecan/ platinum (IP) with etoposide/platinum (EP) in patients with previously untreated extensive-stage small cell lung cancer (E-SCLC). The PubMed database, the Cochrane Library, conference proceedings, databases of ongoing trials, and references of published trials and review articles were searched. Two reviewers independently assessed the quality of the trials and extracted data. The relative risk for overall response to treatment, hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and odds ratios for the different types of toxicity were pooled by STATA package. Six trials involving 1476 patients with previously untreated E-SCLC were ultimately analyzed. The intention-to-treatment analysis indicated that IP regimens could acquire more overall response than EP regimens (relative risk = 1.10, 95% confidence interval [CI]: 1.00 -1.21, p = 0.043). The pooled HR showed that IP could prolong OS (HR = 0.81, 95% CI: 0.66 -0.99, p = 0.044). Nevertheless, the pooled HR failed to show a favorable PFS in IP regimens (HR = 0.82, 95% CI: 0.64 -1.06, p = 0.139). IP regimens led to less grade 3 to 4 anemia, neutropenia, and thrombocytopenia but more grade 3 to 4 vomiting and diarrhea than EP regimens. Treatment-related deaths were comparable between the two groups. Although the PFS was similar from this meta-analysis, our results suggest that IP might have an advantage in overall response and OS compared with EP with less hematological toxicities. The IP regimens may be an alternative of EP regimens in the first-line treatment of E-SCLC.