Gain In Progression-free Survival Research Articles

Equal censoring but still informative: When the reasons for censoring differ between treatment arms

In randomized controlled trials, informative censoring has been described as a potential bias, mainly affecting time-to-event composite endpoints, like progression-free survival (PFS). It is usually suspected in the presence of unequal attrition rates between arms. Early censoring occurs for different reasons: patients may withdraw from a trial because of toxicity, or because of disappointment with their allocation arm. If censoring is more frequent in one arm due to increased toxicity, this removes the frailest individuals and introduces a bias favoring this arm. Conversely, patients who withdraw because of disappointment of their allocation arm may be more affluent and healthy patients, who will seek treatment options outside the protocol. In trials with one treatment arm presenting higher toxicity rates, and the other arm potentially leading to patient disappointment, censoring can occur for different reasons in each arm however with the same rates. We modeled this hypothesis in a randomized controlled trial where modifying only 15% of censored patients' fate in each arm at early time-points made the PFS gain fade. Equal censoring but for different reasons is a hitherto unexplored form of informative censoring with potentially large implications across the cancer clinical trials landscape.

‘Inner world’ of luminal HER 2-negative metastatic breast cancer: Efficacy of ribociclib in different intrinsic subtypes

The heterogeneity of breast cancer (BC), which determines various clinical scenarios of the disease, is still inaccessible to our understanding. Heterogeneity is based primarily on intrinsic subtypes of breast cancer, determined using genomic tests. Currently, four intrinsic subtypes are generally recognized: luminal A and B, HER-enriched (HER2-E) and basal-like. HER2-E subtype in luminal HER-negative (ER+HER–) breast cancer accounts for 11–22 per cent of cases. The efficacy of a combination of hormone therapy (HT) and the CDK4/6 inhibitor ribociclib in the HER2-E subtype was evaluated in a large exploratory analysis of MONALEESA-2, -3, and -7 trials. The gain in progression-free survival (PFS) and overall survival (OS) from the addition of ribociclib to HT was observed in all intrinsic subtypes, except for basal-like, and reached maximum in HER2-E subtype: Ribociclib increased the median PFS to 16.4 months from 5.5 months on HT (HR = 0.389; p < 0.0001) and median OS to 40.3 months from 29.4 months (HR = 0.600; p = 0.0180). The significant frequency of occurrence of the HER2-E subtype in ER+HER-BC, the low efficiency of monoHT in this subtype is another argument in favor of prescribing combination therapy in early lines. Information about the intrinsic subtype not only brings us closer to understanding tumor heterogeneity, but may also become a significant factor in determining treatment tactics in the future.

Exploring the significance of PARP inhibitor therapy after first-line chemotherapy in patients with homologous recombination proficient ovarian cancer: An extracted individual patient data and trial-level meta-analysis.

5580 Background: The use of poly (ADP-ribose) polymerase inhibitors (PARPi) as maintenance therapy in advanced epithelial ovarian cancer (EOC) patients (pts) has shown to delay cancer progression among patients with mutated BRCA (mBRCA) or homologous recombination deficiency (HRD), with debatable and divergent benefit among the subgroup of patients with homologous recombination proficiency (HRP). We aimed to further clarify the efficacy of PARPi after first-line chemotherapy (1L CT) in patients with HRP EOC. Methods: A systematic literature search of PubMed, Embase, The Cochrane Library until February 9th was conducted to identify articles or presentations of phase III clinical trials (P3CT) evaluating PARPi maintenance therapy after 1L CT in ovarian cancer. Individual patient data was reconstructed from Kaplan-Meier plots of progression-free survival (PFS) among pts with mBRCA, HRD and HRP through WebPlotDigitizer and R package IPDfromKM and futher combined. We also performed trial-level meta-analysis with a random effects model. Comparisons were made with Cox proportional hazards. Clinical benefit for each sub-group was accessed with the ESMO Magnitude of Clinical Benefit Formulary 2b (ESMO MBCS). Results: The literature search resulted in 513 items. After screening, 6 P3CT (SOLO1, PRIMA, VELIA, PAOLA, PRIME, and ATHENA-MONO) were selected, and the longer follow-up data of each trial was used. A total of 3205 pts were included in the analysis (2090 in PARPi arms, 1115 in control arms). HRP was associated with worse PFS regardless of the treatment arm (HRP vs mBRCA in PARPi arms: HR 1.92, 95% CI 1.62 – 2.21, P < 0.001). Compared to control treatment arm, PARPi therapy was associated with a improved PFS in all subgroups, although the magnitude of benefit decreased from mBRCA to HRD and HRP (Table). Trial-level meta-analysis yielded similar results. PARPi therapy summed 4 out of 4 possible points at ESMO MBCS for mBRCA and HRD, but only 2 points among HRP pts, confirming a lower clinical benefit in this subgroup. Conclusions: This meta-analysis included additional P3CT recently presented and new data of subgroup analysis of previous studies. Results confirm a statistically significant benefit of PARPi maintenance after 1L CT for HRP EOC. Nevertheless, the relative and absolute gain in PFS is modest (9% in 2 years), while mBRCA and HRD subgroups have a substantial benefit. The worse prognosis of HRP pts, in addition to the small clinical benefit of PARPi therapy, highlights the need for new treatment strategies for this subgroup. [Table: see text]

Impact of immunotherapy on intracranial progression-free survival in patients with advanced lung cancer and melanoma with brain metastasis: A single-center retrospective study and comparison of the pre- and post-immunotherapy era.

e14005 Background: Brain metastasis is associated with considerable morbidity and mortality. Limited systemic therapeutic options were available pre-immunotherapy era for CNS metastasis. However, with the advancement of therapeutics development and understanding of tumor immunology, the role of immunotherapy, particularly checkpoint inhibitors, has expanded and demonstrated optimistic results in multiple studies, notably in metastatic non-small cell lung cancer, small cell lung cancer, and melanoma. This study aims to investigate the efficacy of checkpoint inhibitors on the progression-free survival of patients with CNS metastasis in NSCLC, SCLC, and melanoma. Methods: A retrospective IRB-approved single institute study was conducted on 18 years or older patients with the diagnosis of NSCLC, SCLC, and melanoma who received chemotherapy-only (CT) from January 1, 2014 to December 31, 2017 versus immunotherapy-only (IO) from January 1, 2018 to December 31, 2021. Study parameters included the first diagnosis of CNS metastasis till the subsequent progression, evidenced by imaging studies for progression-free survival (PFS), and the last clinical records for survival month. Mann-Whitney test was performed via software R to identify if there was a difference in the median between the two groups for each response. Results: A total of 66 patient charts, consisting of 30 CT and 36 IO, were evaluated. The median PFS for CT and IO are 3.5 and 7.5 months, respectively. There is a statistical significance that the median PFS for the IO is greater than the CT group (p = 0.0005065, 95% CI [1-7]). The median survival month for the CT and IO are 6 and 9.5 months, respectively. Statistical evidence shows that the median survival for the IO is greater than the CT group (p = 0.0117, 95% CI [0.000075-10]). When the data is extrapolated for the survival analysis with the minimum sample size of 75 for each group, the survival time for CT and IO are 8 and 16 months, respectively (p = 0.008, test statistic 6.9) based on a log-rank test for PFS; the survival time for CT and IO are 13 and 23 months respectively (p = 0.02, test statistics 5.6) based on a log-rank test for survival month. Conclusions: Our retrospective single institutional study supported by statistical evidence provides an additional opportunity to understand better clinical implications of immunotherapy in improved CNS disease control and potentially improved survival months, at least in metastatic NSCLC, SCLC, and melanoma, similar to that of already observed efficacy in extracranial metastasis. In clinical practice, a significant gain in PFS will likely result in improved overall survival with preserved quality of life due to the ability to control CNS metastatic disease with systemic immunotherapy beyond palliative radiation.

Savings associated with therapeutic appropriateness for patients with relapsed refractory multiple myeloma and high cytogenetic risk diagnosed by FISH test

Background: Approximately 23% of myeloma patients have cytogenetic abnormalities which confer a significantly poorer prognosis, and therefore they are defined as “high-risk myeloma” (HRC+) patients. Objective: To estimate the economic impact of a large-scale use of the fluorescence in situ hybridization (FISH) test for the identification of HRC+ patients. Methods: The comparison between the total costs of two scenarios, the first one where patients are not tested for cytogenetic abnormalities, the second one where FISH test is used to identify HRC+ patients and to treat them with the most appropriate therapies, was conducted. The Italian National Healthcare Service (NHS) perspective was adopted. The cost of each treatment was estimated by multiplying Italian unit ex-factory prices by median progression-free survival (PFS). For each scenario, the cost per month of PFS gained was calculated. Sensitivity analysis was conducted to evaluate the impact on the results. Results: N = 777 patients are expected to be HRC+ in Italy. If they were all identified through FISH test and treated with the most appropriate therapies, this would result into savings of € 552,000 and a PFS gain of 419 months, compared with a scenario with no identification. The cost per patient per month of PFS gained is lower in the scenario where FISH test was available (€ 9,921 vs € 10,229 in the scenario without testing). Sensitivity analyses confirmed the robustness of the base case results. Conclusions: A larger adoption of FISH test to identify HRC+ patients is expected to improve clinical outcomes in relapsed refractory multiple myeloma.

Prognostic Significance of Clinical Factors Including BRCA Mutation in Epithelial Ovarian, Peritoneal, Fallopian Tube Cancer.

We analyzed the survival outcomes of patients with epithelial ovarian, peritoneal, or fallopian tube cancer with BRCA1/2 mutations and the clinical factors associated with the prognosis of these cancers. We included patients who had been diagnosed with and treated for epithelial ovarian, peritoneal, or fallopian tube cancer and had undergone germline BRCA testing in six hospitals between January 2012 and December 2019. Of the 378 identified patients, 76 (20.1%) carried a BRCA1/2 mutation. Progression-free survival (PFS) and overall survival (OS) did not differ between patients with and without BRCA1/2 mutation. Multivariate analysis for 18 months after the primary treatment showed higher PFS in the BRCA1/2 mutation group (p=0.024). Subgroup analysis in patients with high-grade serous carcinoma showed that BRCA1/2 mutation was an independent favorable prognostic factor for PFS (p=0.035). Subgroup analysis of patients with stage III or IV disease demonstrated an independent gain in PFS in patients with BRCA1/2 mutation (p=0.015). Neoadjuvant chemotherapy as a primary treatment was related to poor PFS (p<0.001) and reduced OS (p=0.005). Having a germline BRCA1/2 mutation improved short-term PFS in patients with epithelial ovarian, peritoneal, or fallopian tube cancer. Elevated initial CA125 level and primary neoadjuvant chemotherapy were related to poor prognosis.

Patient preferences for features of HER2-targeted treatment of advanced or metastatic breast cancer: a discrete-choice experiment study

BackgroundWe aimed to quantify patients’ benefit-risk preferences for attributes associated with human epidermal growth factor receptor 2 (HER2)-targeted breast cancer treatments and estimate minimum acceptable benefits (MABs), denominated in additional months of progression-free survival (PFS), for given treatment-related adverse events (AEs).MethodsWe conducted an online discrete-choice experiment (DCE) among patients with self-reported advanced/metastatic breast cancer in the United States, United Kingdom, and Japan (N = 302). In a series of nine DCE questions, respondents chose between two hypothetical treatment profiles created by an experimental design. Profiles were defined by six attributes with varying levels: PFS, nausea/vomiting, diarrhea, liver function problems, risk of heart failure, and risk of serious lung damage and infections. Data were analyzed using an error component random-parameters logit model.ResultsAmong the attributes, patients placed the most importance on a change in PFS from 5 to 26 months; change from no diarrhea to severe diarrhea was the least important. Avoiding a 15% risk of heart failure had the largest MAB (5.8 additional months of PFS), followed by avoiding a 15% risk of serious lung damage and infections (4.6 months), possible severe liver function problems (4.2 months), severe nausea/vomiting (3.7 months), and severe diarrhea (2.3 months) compared with having none of the AEs. The relative importance of 21 additional months of PFS (increasing from 5 to 26 months) increased for women with HER2-negative disease and those with children.ConclusionsPatients valued PFS gain higher than the potential risk of AEs when deciding between hypothetical breast cancer treatments.

The Overall Survival and Progression-Free Survival in Patients with Advanced Adrenocortical Cancer Is Increased after the Multidisciplinary Team Evaluation.

Simple SummaryAdrenocortical carcinoma (ACC) is a rare and malignant disease with a poor prognosis in advanced disease. The complexity of ACC management requires a multidisciplinary approach, an emerging model of treatment, suitable for oncological diseases. Our study aims to determine the role of multidisciplinary team evaluation in affecting the overall survival and progression-free survival in ACC patients. We perform a retrospective analysis of ACC patients treated in Padova, with particular reference to their discussion in the multidisciplinary group of adrenal disease, definitively established in 2013 and defined as a collegial meeting between physicians involved in adrenal diseases. We describe a positive impact on survival rates in ACC patients after the multidisciplinary meeting.We aimed to evaluate the role of adrenal multidisciplinary team evaluation (MTE) in affecting the overall survival (OS) and progression-free survival (PFS) in patients with adrenocortical carcinoma (ACC). We included in a retrospective monocentric study 47 patients with ACC. We divided our cohort into group 1 (without adrenal-MTE discussion, ACC diagnosis from 2004 to 2012, n = 14) and group 2 (diagnosis and beginning of treatments after 2013, all discussed in the adrenal MTE, n = 33). OS was defined by the survival between the first and the last visit, while PFS as the time from the first visit to the progression of the disease. Kaplan–Meier curves were used to compare OS and PFS between Group 1 and Group 2. Group 1stages III–IV (n = 10) presented a shorter median OS than Group 2stages III–IV (25 patients, 4 vs. 31 months, p = 0.023). Likewise, the median PFS was lower in Group 1 as compared to Group 2 (2.9 vs. 17.2 months, p < 0.001). The gain in PFS (6 months) was also confirmed in stage III-IV patients (2.9 vs. 8.7 months, respectively, for Group 1 and Group 2, p = 0.02). Group 1 presented a median PFS of 4 months, while the median PFS of Group 2 was 14.7 months (p = 0.128). In conclusion, we found a significant gain in terms of survival in patients after the MTE discussion in 2013. Therefore, ACC patients should be referred to a tertiary center, ideally from the time of diagnosis, to promptly apply all available treatments, according to the single patient’s clinical history and based on multidisciplinary management.

Association between control group therapy and magnitude of clinical benefit of cancer drugs.

e18604 Background: Oncology societies have developed tools to quantify the magnitude of clinical benefit. These include the American Society of Clinical Oncology Value Framework (ASCO-VF) version 2, the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) version 1.1, the National Comprehensive Cancer Network (NCCN) Evidence Blocks and the ASCO Cancer Research Committee criteria (ASCO-CRC). Associations between the characteristics of approved drugs and magnitude of clinical benefit have been explored in depth. Here, we assess the association between characteristics of control group therapy and magnitude of clinical benefit. Methods: We searched Drugs@FDA to identify new solid tumor cancer drugs approved based on randomized trials (RCTs) between January 2012 and December 2021. Substantial clinical benefit was defined as: overall survival gain ≥ 2.5 months and progression-free survival gain ≥ 3 months for the ASCO-CRC (palliative setting only); ASCO-VF threshold score ≥45 (palliative and curative setting); NCCN Evidence Blocks threshold score ≥16 (palliative and curative setting); and grade A or B for trials of curative intent and 4 or 5 for those of non-curative intent using ESMO-MCBS. Associations between characteristics of control group therapy (e.g. type of active therapy, use of matched placebo and overlap between experimental and control therapy) and substantial clinical benefit scores were explored using logistic regression. Results: We identified 174 RCTs supporting the approval of 76 drugs for 164 indications. Of these, 47% (82/174) were placebo-controlled trials among which 42% (34/82) comprised active treatment with a matched placebo. Substantial clinical benefit was observed in 45%, 46%, 72% and 73% using the ESMO-MCBS, ASCO-VF, NCCN Evidence Blocks and ASCO-CRC, respectively. These low proportions resulted in an inability to fit multivariable models adequately. RCTs with a control group comprising of active treatment with a matched placebo were associated with significantly lower odds of substantial benefit with ESMO-MCBS (OR 0.27, P = .003) and ASCO-VF (OR 0.30, P = .008) but not with NCCN Evidence Blocks (OR 0.74, P = .55) or ASCO-CRC criteria (OR 1.36, P = .54). Similar results were observed when excluding trials in the curative setting. There was a non-significant association with higher odds of substantial benefit with ESMO-MCBS with trials in which the control group was chemotherapy (OR 1.97, P = .07). For ASCO-CRC a non-significant association in the opposite direction was observed (OR 0.40, P = .06). Conclusions: Clinical benefit scales can be sensitive to the type of control group therapy. RCTs with an active treatment and matched placebo in the control group were less likely to be scored as providing substantial clinical benefit using the ESMO-MCBS and the ASCO-VF scales. Control group therapy did not influence NCCN Evidence Blocks or ASCO-CRC scores.

84P Predicting longer-term progression-free survival (PFS) with durvalumab after chemoradiotherapy (CRT) in unresectable stage III NSCLC using a mixture cure model (MCM)

Five-year results from the placebo-controlled phase 3 PACIFIC trial (NCT02125461) demonstrated robust and sustained overall survival (OS) and durable PFS benefit with durvalumab (given every 2 weeks up to 12 months) in pts with unresectable Stage III non-small-cell lung cancer (NSCLC) and no disease progression after platinum-based concurrent CRT. Given the potential for longer-term PFS gain in this curative-intent setting, we used MCM analysis, a common statistical model in such settings, to predict the potential longer-term PFS benefit with durvalumab.

Crizotinib Versus Conventional Chemotherapy in First-Line Treatment for ALK-Positive Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis.

IntroductionLung cancer is the most frequently diagnosed type of cancer and the main cause of death from malignant neoplasms worldwide. One of the most recent discoveries in the context of non-small cell lung cancer (NSCLC) was the mutation of the anaplastic lymphoma kinase receptor (ALK). This genetic alteration is found in approximately 2–5% of NSCLC patients, and crizotinib was the first targeted therapy discovered for its first-line treatment.ObjectiveTo conduct a systematic review and meta-analysis to estimate the magnitude of the overall survival (OS) and progression-free survival (PFS) from using crizotinib as treatment compared to traditional chemotherapy to guide future decision making.MethodsPRISMA and Cochrane recommendations were followed using the findings based on studies published in the main international electronic databases. Selection criteria included the following: randomized clinical trials (RCT) or cohort studies that had assessed the efficacy and effectiveness of crizotinib as monotherapy in patients with NSCLC with ALK fusions.ResultsFrom 2504 publications identified in the literature, only eight publications referring to seven studies met the selection criteria, with high heterogeneity identified between the studies. Overall, there was a significant gain in PFS (HR 0.38; 95% CI 0.30–0.49; p < 0.00001); however, there was no significant gain in OS (HR 0.68; 95% CI 0.43–1.08; p = 0.10).ConclusionThe study highlighted and confirmed that treatment with crizotinib led to clinical improvement in PFS among patients with advanced NSCLC with ALK fusion, as previously reported. However, there was no increase in overall survival in patients with NSCLC with genetic alterations of ALK. This must be considered when reviewing and funding treatments for NSCLC patients with this mutation.

Prognostic and predictive value of vessels encapsulating tumor clusters (VETC) in renal cell carcinoma (RCC).

e16554 Background: VETC has been described as an epithelial-to-mesenchymal-transition independent process of metastasis in hepatocellular carcinoma (HCC): endothelium covers small clusters of neoplastic cells allowing tumor dissemination. It has also been noted that VETC-positive HCCs benefit more from tyrosine kinase inhibitors (TKI) therapy. Interestingly, this type of angiogenesis was also found in RCC - and other cancers - and associated with poor prognosis. The objectives of the present study are: 1) to investigate the prognostic role of VETC in a cohort of primary consecutive RCC. 2) to model the predictive role VETC to TKI response in a cohort of metastatic RCC patients treated with sunitinib or pazopanib. Methods: The study was observational and retrospective. To evaluate the VETC effect on overall survival (OS) for Cox regression, with power .8, Hazard Ratio 2.35, proportion of subject VETC+ .4, proportion of events .6, correlation among covariates .4 and a type I error rate .5, the estimated sample size was n=89. We included consecutive patients undergoing surgery at our institution for primary RCC from 2005 to 2007, (Surgical Series; n=92 cases). Moreover, to investigate the possible role of VETC in predicting TKIs benefit, we considered all RCC patients treated with first line TKIs at our center (TKI Series; sunitinib, n = 39; pazopanib n = 17), and recorded the progression free survival (PFS). VETC was assessed with CD34 immunohistochemistry and defined as a continuous endothelial lining around tumor clusters. We used Bayesian probabilistic modeling to detect small effects and multilevel hierarchical modeling to reduce overfitting. Models were fit using Stan and R. The study was approved by institutional review board (n. 865/20) and registered on ClinicalTrials.gov. Results: VETC+ RCC had a worse prognosis in the Surgical Series, with a posterior probability density (PPD) of median OS of 88 months (mo) (standard deviation, SD: 16 mo) for VETC positive Vs 136 mo (SD: 26 mo) for VETC-; the expected loss of median OS was 48 mo (SD: 31 mo) for patients having a VETC + RCC. Conversely in the TKI Series, VETC+ RCC showed longer PFS compared to VETC- ones: with sunitinib a PPD of median PFS of 35 mo (SD:11 mo) for VETC+ Vs 19 mo (SD: 5 mo) for VETC-. Under Pazopanib a PPD of median PFS of 20 mo (SD: 8 mo) for VETC+ Vs 11 mo (SD: 7 mo) for VETC-. The expected gain of median PFS for of VETC+ cases, was 17 and 9 mo (SD: 12 and 11 mo), respectively in sunitinib and pazopanib treated cases. Conclusions: Our results confirmed the general adverse prognostic role of VETC in RCC, however this phenotype gave a substantial PFS gain for patients treated with TKI, similarly to what have been observed in HCC. VETC could be a new predictive bio-marker that allows the delivery of a personalized treatment: patients affected by RCC might directly benefit from a better selection of already approved drugs.

Dendritic cell vaccine (DCVAC) combined with chemotherapy (CMT) in patients with newly diagnosed epithelial ovarian carcinoma (EOC) after primary debulking surgery (PDS): Biomarker exploratory analysis of a phase 2, open-label, randomized, multicenter trial.

5521 Background: Most patients with EOC relapse despite PDS and CMT. Autologous DCVAC can present tumor antigens to elicit a durable immune response. We hypothesized that adding DCVAC to CMT stimulates antitumor immunity and improves clinical outcomes. Methods: Key eligibility criteria were FIGO stage III EOC (serous, endometrioid, or mucinous), post-PDS with &lt; 1 cm maximal residuum, no prior systemic therapy, and ECOG 0-2. In part 1, patients were randomized up to 6 weeks after PDS, 1:1:1, into arm A (A; DCVAC concomitant with CMT), arm B (B; DCVAC sequential after CMT), and arm C (C; CMT). Patients were stratified by tumor residuum (0 or &lt; 1 cm). CMT consisted of 6 cycles of carboplatin (AUC 5-7) and paclitaxel (175 mg/m2). Patients in A and B received up to 10 doses of DCVAC (1×107 DCs/dose). The primary endpoint was radiologically assessed progression-free survival (PFS). The key secondary endpoint was overall survival (OS). Results presented refer to a protocol-defined modified intention-to-treat population (mITT) including patients who received ≥1 CMT dose in C or ≥1 DCVAC dose in A and B. Results: Between November 2013 and March 2016, 99 patients were randomized. At the final analysis, the mITT included 31 patients in A, 29 patients in B, and 30 patients in C. Key baseline characteristics and DCVAC exposure were comparable across treatment arms. Median PFS was 20.3 months in A, not reached in B, and 21.4 months in C, with corresponding HRs (95% CI) compared to C of 0.98 (0.48-2.00) in A and 0.39 (0.16-0.96) in B. The PFS benefit in B was statistically significant (p = 0.034) This was supported by a non-significant trend in OS in A and B. Median OS was not reached in any arm at the time of median follow-up of 66 months (34% of events). Patients with low CD8+ T-cell counts (CD8Lo) in tumor samples in A and B had significantly improved clinical outcomes compared to patients in C with CD8Lo: median PFS gain of 6 months (19 vs 13 months) and a more robust OS gain (median not reached vs 31 months), with minimal difference between A and B. This effect could not be attributed to statistical differences in high CD8+ T-cell counts (CD8Hi) density patients. These findings indicated the best clinical outcome in DCVAC patients with immunologically “cold” tumors in both DCVAC arms. DCVAC showed a good safety profile with only 8 DCVAC-related adverse events (Grade 1-2). Conclusions: DCVAC improved PFS and OS outcomes in patients with newly diagnosed EOC, predominantly in patients with immunologically “cold” tumors, thus representing a promising treatment option in this patient population. Clinical trial information: NCT02107937.

A Survey of Survival Outcomes for Targeted Cancer Drugs Approved by the US Food and Drug Administration.

The last two decades have witnessed the vigorous development of targeted cancer drugs and the potent therapeutic effects of these drugs have been validated by various true and surrogate end points. Overall survival (OS) and progression-free survival (PFS) outcomes were two important end points used in targeted cancer drugs clinical trials but investigation on which was rare as a consequence of inherent heterogeneity and complexity. Here, we present the review and analysis of OS and PFS outcomes of all targeted cancer drugs approved by the U.S. Food and Drug Administration (FDA) through December 31, 2019, in the setting of clinical studies. The targeted cancer drug directory was accessed via NCI website. The survival outcomes of those drugs in the setting of clinical trials were collected from publicly available Package Inserts and ClinicalTrials.gov. Median overall (OS) and progression-free survival (PFS) outcomes were summarized for targeted cancer drugs that were evaluated as monotherapies in clinical trials, contributions of targeted drugs to combination therapies in terms of survival benefit were analyzed, survival outcomes of FDA-approved first-line targeted therapies in different cancers were investigated, and the correlation between the absolute OS gain (ΔOS) and PFS gain (ΔPFS) as well as the hazard ratios for PFS (HRPFS) and OS (HROS) between comparative arms of available randomized clinical trials was evaluated. A total of 223 indications for 126 targeted cancer drugs have been approved by the FDA through December 31, 2019, among which 28 indications of 23 drugs have been approved for first-line therapies. Eighty indications for leukemia, lymphoma, and rare cancer types without survival data were excluded in the investigation of survival outcomes. For the remaining 143 indications, 99 were approved as monotherapies and 72 were approved as combination therapies. Among monotherapy subset, 18 of 72 (25%) indications with available OS outcomes have maximum median OS less than 12months, 55 of 72 (76%) drug indications have maximum median OS less than 24months, and 67 of 72 (93%) have maximum median OS less than 36months. Regarding PFS, 38 of 88 (43%) drug indications have maximum median PFS less than 6months, 69 of 88 (78%) drug indications have maximum median PFS less than 12months, and 84 of 88 (95%) drug indications have maximum median PFS less than 24months. The addition of targeted drugs to combination regimens under FDA's approval provided notable survival benefit, but the median value of OS gain rate of the available combination regimens was lower than that of PFS. The univariate Spearman Rank correlation coefficient suggested a significant positive correlation between ΔOS and ΔPFS (R = 0.62) but a weak correlation between HROS and HRPFS (R = 0.11) in 46 randomized clinical trials that investigated contributions of targeted cancer drugs to combination therapies with available data. A moderate correlation between ΔOS and ΔPFS (R = 0.43) and a rather weak correlation between HROS and HRPFS (R = 0.07) were also found in other randomized clinical trials that included in our study with available data. The survival benefit provided by targeted cancer drugs varied a lot among cancer types. Though targeted cancer drugs showed improvements in both OS and PFS in approved combination regimens, the median value of OS gain rate was lower than that of PFS. As only weak correlation was found between HRPFS and HROS, the evidence supporting the use of PFS as a surrogate to OS in the setting of targeted cancer drugs might also be limited.

PCN69 Cost-Effectiveness Analysis of NOVEL Therapies for HER2+ Metastatic Breast Cancer: [FAM-] Trastuzumab Deruxtecan Versus Tucatinib Trastuzumab and Capecitabine Combination

To construct a cost-effectiveness model reflective of the evolving treatment paradigm in HER2+ metastatic breast cancer (mBC) and assess the cost effectiveness of trastuzumab deruxtecan (T-DXd), a HER2-targeting antibody–drug conjugate, versus tucatinib+trastuzumab+capecitabine in patients with HER2+ mBC who are resistant or refractory to [ado-] trastuzumab emtansine, from a US third-party payer’s perspective. A partitioned-survival model was created to compare the cost-effectiveness of T-DXd versus tucatinib+trastuzumab+capecitabine over a 20-year time horizon. Efficacy and safety data for T-DXd and tucatinib+trastuzumab+capecitabine were derived from the single-arm DESTINY-BREAST01 and placebo-controlled HER2CLIMB phase 2 trials, respectively. A matching-adjusted indirect comparison (MAIC) was conducted to derive the relative effect of T-DXd on progression-free survival (PFS). Overall survival (OS) gain for T-DXd was estimated using an assumed surrogacy relationship between mean PFS and OS gain. Health state utility values, resource use and costs were based on published sources. T-DXd dominated tucatinib+trastuzumab+capecitabine with an incremental gain of 0.49 quality-adjusted life-years (QALYs) and a negative incremental cost (decrement) of $83,784, when assuming a 1:1.5 incremental PFS:OS surrogacy relationship. T-DXd remained dominant when the estimated PFS gain without OS gain was assumed in scenario analyses. Results were robust in one-way sensitivity and scenario analyses, with all scenarios tested resulting in a positive incremental QALY gain and negative incremental cost This analysis is subject to inherent uncertainty due to the use of single-arm trial data and the immaturity of currently available OS data for T-DXd. Differences in key baseline characteristics between the trial populations resulted in low effective sample size and wide confidence interval in the MAIC. T-DXd may be an economically dominant treatment strategy when compared to tucatinib+trastuzumab+capecitabine as a 3L option in patients with HER2+ mBC from a US third-party payer perspective. Further data from ongoing trials will help reduce uncertainty in this finding.

Patient preferences for maintenance therapy versus routine surveillance: Gain in progression-free survival and risks of adverse effects

Objective: Maintenance therapy offers improved progression-free survival (PFS) for women with ovarian cancer. Patients face a tradeoff between potential gain in PFS and the risk of experiencing adverse effects. We assessed patient preferences for maintenance therapy using direct elicitation methods.

Biomarker Analyses of Response to Cyclin-Dependent Kinase 4/6 Inhibition and Endocrine Therapy in Women with Treatment-Naïve Metastatic Breast Cancer.

Preclinical data identified the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib as synergistic with antiestrogens in inhibiting growth of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) human breast cancer models. This observation was validated clinically in the randomized, placebo-controlled, phase III PALOMA-2 study. To determine markers of sensitivity and resistance to palbociclib plus letrozole, we performed comprehensive biomarker analyses, investigating the correlation with progression-free survival (PFS), on baseline tumor tissues from PALOMA-2. Despite a broad biomarker search, palbociclib plus letrozole demonstrated consistent PFS gains versus placebo plus letrozole, with no single biomarker or cassette of markers associated with lack of benefit from combination treatment. Palbociclib plus letrozole confers efficacy on both luminal A and B patients. Higher CDK4 levels were associated with endocrine resistance which was mitigated by the addition of palbociclib, whereas lower PD-1 levels were associated with greater palbociclib plus letrozole benefit. Tumors with more active growth factor signaling, as exemplified by increased expression of FGFR2 and ERBB3 mRNA, appeared to be associated with greater PFS gain from the addition of palbociclib. These data underscore the importance of CDK4/6 signaling in HR+/HER2- breast cancer and suggest that the interplay between steroid hormone and peptide growth factor signaling could drive dependence on CDK4/6 signaling.See related commentary by Anurag et al., p. 3.

Impact of retrospective data verification to prepare the ICON6 trial for use in a marketing authorization application.

Background:The ICON6 trial (ISRCTN68510403) is a phase III academic-led, international, randomized, three-arm, double-blind, placebo-controlled trial of the addition of cediranib to chemotherapy in recurrent ovarian cancer. It investigated the use of placebo during chemotherapy and maintenance (arm A), cediranib alongside chemotherapy followed by placebo maintenance (arm B) and cediranib throughout both periods (arm C). Results of the primary comparison showed a meaningful gain in progression-free survival (time to progression or death from any cause) when comparing arm A (placebo) with arm C (cediranib). As a consequence of the positive results, AstraZeneca was engaged with the Medical Research Council trials unit to discuss regulatory submission using ICON6 as the single pivotal trial.Methods:A relatively limited level of on-site monitoring, single data entry and investigator’s local evaluation of progression were used on trial. In order to submit a license application, it was decided that (a) extensive retrospective source data verification of medical records against case report forms should be performed, (b) further quality control checks for accuracy of data entry should be performed and (c) blinded independent central review of images used to define progression should be undertaken. To assess the value of these extra activities, we summarize the impact on both efficacy and safety outcomes.Results:Data point changes were minimal; those key to the primary results had a 0.47% error rate (36/7686), and supporting data points had a 0.18% error rate (109/59,261). The impact of the source data verification and quality control processes were analyzed jointly. The conclusion drawn for the primary outcome measure of progression-free survival between arm A and arm C was unchanged. The log-rank test p-value changed only at the sixth decimal place, the hazard ratio does not change from 0.57 with the exception of a marginal change in its upper bound (0.74–0.73) and the median progression-free survival benefit from arm C remained at 2.4 months. Separately, the blinded independent central review of progression scans was performed as a sensitivity analysis. Estimates and p values varied slightly but overall demonstrated a difference in arms, which is consistent with the initial result. Some increases in toxicity were observed, though these were generally minor, with the exception of hypertension. However, none of these increases were systematically biased toward one arm.Conclusion:The conduct of this pragmatic, academic-sponsored trial was sufficient given the robustness of the results, shown by the results remaining largely unchanged following retrospective verification despite not being designed for use in a marketing authorization. The burden of such comprehensive retrospective effort required to ensure the results of ICON6 were acceptable to regulators is difficult to justify.

Progression free survival (PFS) benefits of immuno-oncology agents (IOs) and implications for market cost-sharing inefficiencies.

6643 Background: Cancer care expense has high financial toxicity with 6 in 10 patients reporting distress about finances. System wide cost has also increased with new treatment approvals; from 2011 to 2016 FDA approved 52 cancer treatments. During this time, US healthcare spending increased from $26.8 billion to $42.1 billion. Lung cancer has high mortality- in 2018 American Cancer Society estimated 234,030 new cases with 50% likely to die from the disease. Hence new treatments are important societal need but costs are concerning. Methods: We selected Phase 3 trials of IO based regimens for non-small cell lung cancer (NSCLC) in first line setting, approved by FDA in 2018. Median PFS was compared between intervention and no-intervention group (NIG). Total costs were evaluated using 2018 Medicare reimbursements rates. Cost and PFS were converted to represent expenditures accrued for 12 months (mths) PFS gain. Results: Study 1 (NCT02125461) for stage 3 NSCLC; looked at maintenance Durvalumab after platinum doublet chemoradiation induction. Median PFS 17.2 vs 5.6 mths in NIG. 1 year PFS cost $155,391 vs $27,477. Study 2 (NCT02578680) for stage 4 NSCLC; looked at maintenance Pembrolizumab, Pemetrexed or Pemetrexed alone after platinum doublet induction. Median PFS 8.8 vs 4.9 mths in NIG. 1 year PFS cost $283,949 vs $116,159. Study 3 (NCT02775435) for stage 4 NSCLC (squamous); looked at maintenance Pembrolizumab after platinum doublet induction. Median PFS 6.4 vs 4.8 mths in NIG. 1 year PFS cost $195,820 vs $119,146. Study 4 (NCT02366143) for stage 4 NSCLC; looked at maintenance Atezolizumab, Bevacizumab or Bevacizumab alone after platinum doublet induction. Median PFS 8.3 vs 6.8 mths in NIG. 1 year PFS cost $316,499 vs $199,278. Conclusions: Median PFS doubled from IOs in NSCLC but costs accrued, more than doubled. The expense has to be quantified in relation to per capita GNP in US- $53,128 in 2017. Accepting even a higher threshold of $100,000 for 1 quality adjusted life year gained, costs appear economically unsustainable. But PFS gains are significant indicating need to enable IOs utilization, by making innovative cost sharing platforms.

Bevacizumab or PARP-inhibitors maintenance therapy for platinum-sensitive (PS) recurrent ovarian cancer (rOC)? A network meta-analysis (NMA).

5564 Background: Patients (pts) experiencing a PS rOC are generally re-exposed to a platinum based-chemotherapy (CT). In this setting, the addition of a targeted agent like bevacizumab (BEV) or PARP inhibitors (PARPi) as concomitant and/or maintenance therapy has shown to improve progression free survival (PFS). In the absence of direct comparison in randomized trials (RCTs), we have performed a NMA to evaluate differences in terms of efficacy between BEV and PARPi in pts with PS rOC, according to BRCA status. Methods: We searched PubMed, Embase and Medline for RCTs involving pts with PS rOC treated with BEV (n = 3, 1563 pts) or PARPi (n = 5, 1839 pts). Only trials with PFS as primary endpoint were included. Trials in first line setting were excluded. Analyses have been done pooling pts who had received PARPi in three groups, according to the available data on BRCA genes status: all comers (AC), BRCA mutated pts (BRCAm) and BRCA wild-type pts (BRCAwt). A frequentist approach has been used with R statistical software. To rank the effect size of treatments, surface under the cumulative ranking value (SUCRA) has been applied. Results: In AC pts, PARPi improved PFS compared to BEV (hazard ratio [HR] = 0.70, 95% CI 0.54-0.91, test of heterogeneity [I2] = 40.5%). In BRCAm pts the gain in PFS for PARPi was even higher compared to BEV (HR = 0.46, 95% CI 0.36-0.59, I2= 17.2%). In BRCAwt pts the benefit of PARPi over BEV was not statistically significant (HR = 0.87, 95% CI 0.63-1.20, I2= 35.7%) but PARPi had the highest likelihood of being ranked as the best treatment in terms of efficacy according to SUCRA (90% and 60%, respectively for PARPi and BEV). Hazard ratio for PFS between PARPi, BEV and CT in the three cohorts are reported in the table. Conclusions: According to indirect comparisons, PARPi performed the best for the treatment of PS rOC, especially in BRCAm pts who had not previously received PARPi. BEV could be still an option in BRCAwt pts. [Table: see text]