Estimands for overall survival in clinical trials with treatment switching in oncology.

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention-to-treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment-policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross-industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation.

INTELLANCE 2/EORTC 1410 randomized phase II study of Depatux-M alone and with temozolomide vs temozolomide or lomustine in recurrent EGFR amplified glioblastoma.

BACKGROUND: Depatuxizumab mafodotin (Depatux-M) is a tumor-specific antibody-drug conjugate consisting of an antibody (ABT-806) directed against activated epidermal growth factor receptor (EGFR) and the toxin monomethylauristatin-F. We investigated Depatux-M in combination with temozolomide or as a single agent in a randomized controlled phase II trial in recurrent EGFR amplified glioblastoma. METHODS: Eligible were patients with centrally confirmed EGFR amplified glioblastoma at first recurrence after chemo-irradiation with temozolomide. Patients were randomized to either Depatux-M 1.25 mg/kg every 2 weeks intravenously, or this treatment combined with temozolomide 150-200 mg/m2 day 1-5 every 4 weeks, or either lomustine or temozolomide. The primary endpoint of the study was overall survival. RESULTS: Two hundred sixty patients were randomized. In the primary efficacy analysis with 199 events (median follow-up 15.0 mo), the hazard ratio (HR) for the combination arm compared with the control arm was 0.71 (95% CI = 0.50, 1.02; P = 0.062). The efficacy of Depatux-M monotherapy was comparable to that of the control arm (HR = 1.04, 95% CI = 0.73, 1.48; P = 0.83). The most frequent toxicity in Depatux-M treated patients was a reversible corneal epitheliopathy, occurring as grades 3-4 adverse events in 25-30% of patients. In the long-term follow-up analysis with median follow-up of 28.7 months, the HR for the comparison of the combination arm versus the control arm was 0.66 (95% CI = 0.48, 0.93). CONCLUSION: This trial suggests a possible role for the use of Depatux-M in combination with temozolomide in EGFR amplified recurrent glioblastoma, especially in patients relapsing well after the end of first-line adjuvant temozolomide treatment. (NCT02343406).

Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia.

Lucatumumab is a fully humanized anti-CD40 antibody that blocks interaction of CD40L with CD40 and also mediates antibody-dependent cell-mediated cytotoxicity (ADCC). We evaluated lucatumumab in a phase I clinical trial in chronic lymphocytic leukemia (CLL). Twenty-six patients with relapsed CLL were enrolled on five different dose cohorts administered weekly for 4 weeks. The maximally tolerated dose (MTD) of lucatumumab was 3.0 mg/kg. Four patients at doses of 4.5 mg/kg and 6.0 mg/kg experienced grade 3 or 4 asymptomatic elevated amylase and lipase levels. Of the 26 patients enrolled, 17 patients had stable disease (mean duration of 76 days, range 29-504 days) and one patient had a nodular partial response for 230 days. Saturation of CD40 receptor on CLL cells was uniform at all doses post-treatment but also persisted at trough time points in the 3.0 mg/kg or greater cohorts. At the MTD, the median half-life of lucatumumab was 50 h following the first infusion, and 124 h following the fourth infusion. In summary, lucatumumab had acceptable tolerability, pharmacokinetics that supported chronic dosing and pharmacodynamic target antagonism at doses of 3.0 mg/kg, but demonstrated minimal single-agent activity. Future efforts with lucatumumab in CLL should focus on combination-based therapy.

High frequency of allelic losses in high-grade prostate cancer is associated with biochemical progression after radical prostatectomy.

Loss of heterozygosity (LOH) is the most consistent genetic change in prostate cancer (CaP). We aimed, to correlate specific LOH and the overall LOH frequency, to disease progression after radical prostatectomy (RP) in high-grade CaP. Between January 1990 through December 1998, 126 patients who underwent RP (cT1-T2), Gleason 8-10, were pT3, or pN1, or SM(+) (surgical margins). Nine were lost of follow-up, 39/117 (33%) had no biochemical progression (mean follow-up: 45 months). After exclusion for preoperative PSA >50 ng/mL, a case-control study was designed by matching 26 of these cases with 26 similar patients without biochemical progression (criteria: pT, pN, year of surgery). Using microsatellite markers, LOH were assessed on six chromosomal regions (7q31, 8p22, 12p13, 13q14, 16q23.2, 18q21). No prognostic value was associated with LOH at any one specific locus. However, the overall LOH frequency (five classes, cutoff of 60%), was significantly higher if progression (P = 0.02; P = 0.03) in SM(+) patients, and was near statistical significance (P = 0.08; P = 0.07) for the overall case-control population. In multivariate analysis (overall population), the overall LOH rate > or =60% was independently associated with progression [P = 0.035; Odds Ratio (OR) = 5.54]. An overall LOH rate > or =60% predicted poor outcome in 85% of SM(+) patients and 69% of the whole population. Our results suggest that the overall rate of LOH at chromosomal "hot spots" is more likely to be predictive of recurrence than the presence of LOH at any one particular locus. Moreover, the identification of a threshold of LOH could help in predicting patients with poor outcome who may be candidates for local or systemic adjuvant therapies.

The impact of CAG repeats in exon 1 of the androgen receptor on disease progression after prostatectomy.

BACKGROUND: The authors examined the impact of the number of CAG repeats in exon 1 of the androgen receptor on disease progression among men with prostate carcinoma after prostatectomy. This polymorphism has been associated with alterations in activity of the androgen receptor in in vitro systems and with the risk of clinically diagnosed prostate carcinoma in some epidemiologic studies. An earlier series found that, among men at low risk of progressive disease, a small number of CAG repeats predicted a high risk of recurrence, and the impact of CAG repeats varied among men with different risks of progressive disease. METHODS: The authors analyzed specimens from a large clinical series of fixed tissue specimens from men who underwent prostatectomy at a single institution, including 413 American white men (WM) and 298 African-American men (AAM), with 5-10 years of available clinical follow-up. RESULTS: There was little association between the number of CAG repeats and extent of disease, Gleason score, and preoperative PSA level at diagnosis. Overall, patients who had > 18 CAG repeats had a greater risk of recurrence compared with patients who had 18 CAG repeats had an estimated 52% increased risk of disease recurrence. The increased risk could be attributed to men who were at high risk of recurrence.

The effect of race/ethnicity on prostate cancer treatment outcome is conditional: a review of Wayne State University data.

PURPOSE: The mortality rate for prostate cancer in black American men (AAMs) is 2 times greater than that in other ethnic groups. However, there is considerable controversy as to whether race/ethnicity is an independent predictor of survival outcome. We present conditions in which race/ethnicity is and is not an independent predictor of survival outcomes. MATERIALS AND METHODS: We examined the conditions of age, stage and year of diagnosis, and the role of race/ethnicity on disease-free survival in men who underwent consecutive radical prostatectomy as monotherapy from 1990 to 1999. Data were collected from 229 AAMs and 562 white American men prospectively in the Karmanos Cancer Institute Prostate cancer data bases. RESULTS: When the majority of the cohort had pathologically organ confined disease, race/ethnicity was not an independent predictor of disease-free survival. When the majority of the cohort had a mean age of 70 years or greater, race/ethnicity was not an independent predictor. In studies done in the late 1990s, when the stage of radical prostatectomy cases had shifted toward pathologically organ confined disease as the dominant stage, race/ethnicity was not an independent predictor. However, if the cohort was diagnosed at younger age and/or with more advanced prostate cancer, race/ethnicity became an independent predictor. In the early 1990s there was pathologically advanced disease in the majority of our cohort. CONCLUSIONS: Race/ethnicity as an independent predictor of prostate cancer is conditional and dependent on age, stage and year of diagnosis. Year of diagnosis is associated with a stage shift to earlier staged prostate cancer from the early to late 1990s. In general, study cohorts are often subranges of the entire spectrum of prostate cancer that are limited by these factors, especially stage at diagnosis and treatment. If diagnosed and treated early enough, although there is evidence suggesting that AAMs have more aggressive disease biologically, the role of race as a factor in outcome is significantly decreased. The age factor is more complex and must be discussed in more detail.

Competition between Heterodera glycines and Meloidogyne incognita or Pratylenchus penetrans: Independent Infection Rate Measurements.

Competition on soybean between Heterodera glycines (race 3) and Meloidogyne incognita or H. glycines and Pratylenchus penetrans were investigated in greenhouse experiments. Each pair of nematode species was mixed in 3-ml suspensions at ratios of 1,000:0, 750:250, 500:500, 250:750, and 0:1,000 second-stage juveniles or mixed stages for P. penetrans. Nematodes from a whole root system were counted and infection rates standardized per 1,000 nematodes (per replication) prior to testing the null hypothesis through a lack-of-fit F-test. Although the effect of increasing H. glycines proportions on the infection rate of M. incognita was generally adverse, the rate deviated significantly from a trend of linear decline at the 75% H. glycines level in one of two experiments. All lack-of-fit F-tests for the H. glycines and P. penetrans mix were significant, indicating that infection rates for both nematodes varied considerably across inocula. The infection rate of H. glycines decreased with increasing P. penetrans proportions. The rate of P. penetrans infection increased with increasing H. glycines proportions up to the 50% level, but declined at the 75% level. Competition had no effect on nematode development. The general adverse relationships between M. incognita and H. glycines and those between P. penetrans and H. glycines showed a linear trend. The relationship between H. glycines and P. penetrans indicates that the former may be competitive when present at higher proportions than the latter. In this study we have evaluated nematode competition under controlled conditions and provide results that can form a basis for understanding the physical and physiological trends of multiple nematode interactions. Methods critical to data analyses also are outlined.

Maspin is up-regulated in premalignant prostate epithelia.

BACKGROUND: Maspin, a novel serine protease inhibitor, has been shown to inhibit prostate tumor cell motility and invasion in vitro and to inhibit prostate tumor growth and metastasis in vivo. Maspin expression in high-grade prostate carcinoma (PC) is reduced compared with that in low-grade PC. Interestingly, however, compared with low-grade PC, benign secretory prostate epithelial cells express significantly less maspin. This observation appears paradoxical to a putative tumor suppressive role of maspin in prostate carcinogenesis, and this finding issue needs to be clarified. METHODS: We examined maspin expression simultaneously in benign basal cells, benign secretory cells, high-grade prostate intraepithelial neoplasia (HGPIN), low-grade PC, and high-grade PC in 46 radical prostatectomy specimens plus 51 autopsy prostate glands by a combination of immunohistochemistry and in situ hybridization. RESULTS: Benign basal cells consistently expressed maspin at a high level. In PC, the loss of basolateral maspin expression coincides with loss of the basal cell layer. Maspin expression in secretory cells, on the other hand, appears to undergo a biphasic differential regulation, i.e., essentially absent in benign secretory cells, dramatically up-regulated in HGPIN, then progressively down-regulated through low-grade PC to high-grade PC. Maspin expression in PC is inversely correlated with tumor grade. Furthermore, maspin expression in HGPIN is inversely correlated with the Gleason's grade of the adjacent PC. CONCLUSIONS: An up-regulation of maspin expression precedes, rather than occurs at, the critical transition from premalignant prostate lesion of HGPIN to PC. Our data suggest maspin may mark an important transitional phase and play an important role in the premalignancy of the prostate gland.

Disease-free survival difference between African Americans and whites after radical prostatectomy for local prostate cancer: a multivariable analysis.

OBJECTIVES: Age-adjusted mortality rates (per 100,000) for men with prostate cancer from 1991 through 1997 reported by the Surveillance, Epidemiology, and End Results national registry have consistently demonstrated that African-American men (AAM) have twice the death rate of white men (WM). However, there has been considerable controversy as to how this relates to progression-free survival among these men. In an attempt to address this controversy of localized prostate cancer, we report on a multivariable analysis of survival data of a large number of AAM and WM who underwent radical prostatectomy. METHODS: The study cohort was composed of 791 men whose only prostate cancer treatment was radical prostatectomy performed between July 1990 and December 1999. The variables analyzed were age, preoperative prostate-specific antigen level, pathologic grade and stage, and race/ethnicity. Pathologic examination of all specimens was performed in a uniform manner according to an established protocol. Multivariable analysis based on Cox's proportional hazards regression model was performed to assess whether a significant difference in progression-free survival time between AAM and WM persisted after controlling for the main effects of other prognostic factors. RESULTS: The study cohort consisted of 229 AAM and 562 WM. Our results indicated that all variables, except age, had highly significant effects on progression-free survival, even in the presence of other predictors. CONCLUSIONS: The effects of age, preoperative serum prostate-specific antigen level, and pathologic grade and stage did not account for the racial disparity in progression-free survival among men diagnosed with clinically localized prostate cancer and treated with radical prostatectomy.

Pathologic analysis of tumor size and lymph node status in multifocal/multicentric breast carcinoma.

BACKGROUND: For unifocal invasive breast carcinoma, increasing tumor diameter predictably correlates with a greater frequency of lymph node involvement, thereby facilitating treatment decisions. In invasive breast tumors presenting with multiple nodules, however, it is unclear whether tumor size correlates with lymph node dissemination in a similar manner. METHODS: The authors analyzed a series of 101 invasive breast carcinomas presenting with multiple macroscopically apparent lesions (2 foci: n = 77; 3: n = 20; 4: n = 4). Two different assessments of the tumor size (diameter of largest focus and combined diameter of all the foci) were then correlated with the status of axillary lymph nodes. For comparison with unifocal tumors, the authors used both external and internal control series (the latter consisting of 469 patients from their institution). The associations between lymph node status, tumor size, and multifocality were modeled using univariate and multivariate logistic regression, for each modality of tumor size assessment. RESULTS: The logistic curves for multifocal and unifocal tumors were significantly different when the largest diameter was used as a tumor size estimate. Multifocal cases had higher frequencies of lymph node involvement than unifocal lesions of similar size category. In a multivariate logistic regression, the odds ratio of positive lymph node status in multifocal versus unifocal cases was 2.8 using largest diameter as a tumor size estimate (P < 0.0001). When the combined diameter assessment was used, however, the regression curve of multifocal cases was similar to that of unifocal cases, and the frequency of lymph node positivity was not significantly different in multifocal versus unifocal cases of the same size (odds ratio, 1.4; P = 0.13). CONCLUSIONS: The authors' results show that, if aggregate diameters are used, unifocal and multifocal breast carcinomas are similar with respect to frequency of regional lymph node metastasis. Currently used algorithms, which use the diameter of the largest nodule, result in understaging of multifocal breast carcinomas due to underestimation of actual tumor size.