OS In Phase Research Articles

CTIM-11. PHASE I/II STUDY TO EVALUATE THE SAFETY AND CLINICAL EFFICACY OF ATEZOLIZUMAB (ATEZO) IN COMBINATION WITH TEMOZOLOMIDE (TMZ) AND RADIATION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)

Abstract BACKGROUND Immunotherapy strategies such as PD-1/PD-L1 inhibition may work synergistically with radiation, which is known to increase antigen presentation and promote a pro-inflammatory tumor microenvironment. This trial evaluated the safety and clinical efficacy of concurrent atezo (anti-PD-L1) with radiation therapy and TMZ followed by adjuvant atezo and TMZ in patients with newly diagnosed GBM, unselected for MGMT status. METHODS Eligibility criteria included patients age > 18 yrs who had undergone only surgery. The primary endpoint was safety in Phase I (n = 10) and OS in Phase II (n = 50). Secondary endpoints included progression free survival (PFS), overall response rate (ORR), and duration of response. All 60 patients were evaluated for efficacy. Correlative endpoints include profiling tumor immune cell populations, peripheral blood for circulating chemokines/cytokines, and stool for gut microbiome. RESULTS 60 patients were enrolled. With a median follow-up time of 17.1 months (data cutoff = 15 April 2020), 37 patients have progressed, of which 30 patients have died. Median OS was 19 months (95% CI: 14.9, not reached). Median PFS was 10.6 months (95% CI: 8.2–16.7). Median OS in MGMT methylated patients (n = 18) was 29.9 months (95% CI: 11.4, not reached) and 16.3 months (95% CI: 13.9, not reached) in MGMT unmethylated patients (n = 33). Treatment-related adverse events with maximum CTCAE grade > 3 occurred in 33 patients; the most common were LFT elevation (n = 5) and lymphopenia (n = 23). To date, 20 of the enrolled 60 patients underwent re-resection post atezo treatment. The matched paired tumor analysis of pre and post treatment tissue will provide valuable insights into mechanisms of anti-PD-L1 therapy resistance. Tumor immunocorrelative studies are pending. CONCLUSIONS Concurrent use of atezo with radiation and TMZ was tolerable and demonstrated efficacy in line with published trials for newly diagnosed GBM.

Phase I/II study to evaluate the safety and clinical efficacy of atezolizumab (atezo; aPDL1) in combination with temozolomide (TMZ) and radiation in patients with newly diagnosed glioblastoma (GBM).

2511 Background: Immunotherapy strategies such as PD-1/PD-L1 inhibition may work synergistically with radiation, which is known to increase antigen presentation and promote a pro-inflammatory tumor microenvironment. This trial evaluated the safety and clinical efficacy of concurrent atezo with radiation therapy and TMZ followed by adjuvant atezo and TMZ in patients with newly diagnosed GBM, unselected for MGMT status. Methods: Eligibility criteria included patients with newly diagnosed GBM age > 18 yrs who had undergone only surgery. The primary endpoint was safety in Phase I (n = 10) and OS in Phase II (n = 50). Secondary endpoints included progression free survival (PFS), overall response rate (ORR), and duration of response. All 60 patients were evaluated for efficacy. Correlative endpoints include profiling of tumor immune cell populations and peripheral blood for evaluation of circulating chemokines/cytokines. Results: 60 patients were enrolled. With median follow-up time of 16.7 months (data cutoff = 30 Dec 2019), 24 patients had died and 32 had progressed. Median OS was 17.1 months (95% CI: 13.9, not reached). Median PFS was 9.7 months (95% CI: 7.6-15). Median PFS in MGMT methylated patients (n = 18) was 16.7 months (95% CI: 7.85, not reached) and 7.9 months (95% CI: 6.70-12.4) in MGMT unmethylated patients (n = 33). Treatment-related adverse events with maximum CTCAE grade > 3 occurred in 33 patients; the most common were LFT elevation (n = 5) and lymphopenia (n = 23). To date, 17 of the enrolled 60 patients underwent re-resection post treatment with atezo. The matched paired tumor analysis of pre and post treatment tissue will provide valuable insights into mechanisms of anti-PD-L1 therapy resistance. Tumor immunocorrelative studies are pending. Conclusions: Concurrent use of atezo with radiation and TMZ was tolerable and demonstrated modest efficacy. Clinical trial information: NCT03174197 .

NIMG-47. VOLUMETRIC ANALYSIS OF PHASE 2 AND 3 TRIALS IN RECURRENT GLIOBLASTOMA TREATED WITH VB-111 WITH OR WITHOUT BEVACIZUMAB OR BEVACIZUMAB MONOTHERAPY

Abstract VB-111 is a non-replicating adenovirus carrying a pro-apoptotic transgene for TNFR1/Fas under the control of a modified murine promoter to pre-proendothelin 1. The transgene is expressed only in angiogenic endothelial cells, and therefore VB-111 results in targeted apoptosis of neovascular vessels. The current study characterizes the quantitative radiographic results and impact on OS in phase 2 and 3 trials of recurrent glioblastoma (GBM) patients treated with VB-111 with or without bevacizumab (BV) or BV monotherapy. MRI data from a phase 2 (NCT01260506) and randomized, double arm, controlled phase 3 (GLOBE; NCT02511405) trial of VB-111 in recurrent GBM were used in current study: Arm A) VB-111 monotherapy until progression followed by combination VB-111 and bevacizumab (BV) (“Primed Combination”; Phase 2; N=24); Arm B) VB-111 in combination with BV (“Unprimed Combination”; Phase 3; N=124); Arm C) BV monotherapy (“Control”; Phase 3; N=120). Contrast enhanced T1-weighted digital subtraction was used to quantify tumor volume at all time points. Baseline tumor volume was prognostic for OS in all treatment groups when controlling for therapy and age (Cox, P< 0.001, HR=1.02). In patients with smaller tumors (< 25mL), the “primed combination” cohort (Arm A) from the phase 2 trial had a significant OS advantage compared to both upfront combination of VB-111 and BV (Arm B; P=0.0094, HR=0.53; median OS = 7 vs. 15mo) as well as BV alone (Arm C; P=0.025, HR=0.58; median OS=8.5 vs. 15mo). Patients with a radiographic response (>65% reduction) had a significant survival difference from non-responders when controlling for age, baseline tumor volume, and treatment arm (P=0.0014, HR=0.58). Responders to VB-111 monotherapy or combination therapy after priming with VB-111 exhibited characteristic, expansive areas of necrosis in areas of initial disease.

Optimizing biologic sequencing in metastatic colorectal cancer: first line and beyond.

Significant advances in the treatment of metastatic colorectal cancer (mcrc) since the early 2000s have led to improved clinical outcomes, including overall survival (os). When fluorouracil was the sole treatment agent for mcrc, os in phase iii studies was approximately 12 months. Now, in 2019, the median os (mos) in the most recent mcrc clinical trials has been approaching 3 years. The biologic agents that target the vascular endothelial growth factor (vegf), epithelial growth factor receptor (egfr), human epidermal growth factor receptor 2 (her2), PD-1, ctla-4, ntrk, and braf pathways play important roles in the mcrc treatment algorithm, given their significant-sometimes dramatic-activity. Emerging data indicate that the choice of a specific biologic at a particular time (line of treatment) for specific patient populations (based on tumour characteristics) is critical. In the present review, we discuss the available evidence for optimal biologic sequencing in the management of mcrc.

Quantitative radiographic analysis of phase II and III trials in recurrent glioblastoma treated with VB-111 with or without bevacizumab or bevacizumab monotherapy.

2018 Background: VB-111 is a non-replicating adenovirus carrying a pro-apoptotic transgene for TNFR1/Fas under the control of a modified murine promoter to pre-proendothelin 1. The transgene is expressed only in angiogenic endothelial cells, and therefore VB-111 results in targeted apoptosis of neovascular vessels. The current study characterizes the quantitative radiographic results and impact on OS in phase 2 and 3 trials of recurrent glioblastoma (GBM) patients treated with VB-111 with or without bevacizumab (BV) or BV monotherapy. Methods: MRI data from a phase 2 (NCT01260506) and randomized, double arm, controlled phase 3 (GLOBE; NCT02511405) trial of VB-111 in recurrent GBM were used in current study: Arm A) VB-111 monotherapy until progression followed by combination VB-111 and bevacizumab (BV) (“Primed Combination”; Phase 2; N = 24); Arm B) VB-111 in combination with BV (“Unprimed Combination”; Phase 3; N = 124) and Arm C) BV monotherapy (“Control”; Phase 3; N = 120). Contrast enhanced T1-weighted digital subtraction was used to quantify tumor volume at all time points. Results: Baseline tumor volume was not significantly different between patient cohorts (Kruskal-Wallis; P = 0.1482; median~20mL). Continuous measures of baseline tumor volume were prognostic for OS in all treatment groups when controlling for therapy and age (Cox, P < 0.001, HR = 1.02). In patients with small tumors ( < 25mL), the “primed combination” cohort (Arm A) from the phase 2 trial had a significant OS advantage compared to both upfront combination of VB-111 and BV (Arm B; P = 0.0094, HR = 0.5328; median OS = 7mo vs. 15mo) as well as BV alone (Arm C; P = 0.0248, HR = 0.5776; median OS = 8.5mo vs. 15mo). Patients with a radiographic response ( > 65% reduction) had a significant survival difference from non-responders when controlling for age, baseline tumor volume, and treatment arm ( P = 0.0014, HR = 0.5822). Notably, in responders to VB-111 monotherapy or combination therapy after priming with VB-111 exhibited characteristic, expansive areas of necrosis in areas of initial disease. Conclusions: Small recurrent tumors have a significant OS advantage when “priming” with VB-111 monotherapy prior to combination VB-111 and BV at recurrence. Patients responding to VB-111 exhibit specific imaging characteristics related to the drug mechanism of action. Clinical trial information: NCT02511405; NCT01260506.

1127P - Four-Year Survival Update for Metastatic Melanoma (MM) Patients (PTS) Treated with Ipilimumab (IPI) + Dacarbazine (DTIC) on Phase 3 Study CA184-024

ABSTRACT Background Data from clinical trials suggest a long-term survival effect (beyond 4 yrs) of IPI therapy in some pts with MM. An analysis of 177 pts from 3 phase I/II IPI studies conducted at NCI demonstrated 5-yr survival rates of 13-25% (Prieto, et al., CCR 2012). In other phase II trials, IPI monotherapy was associated with long-term survival of 4+ yrs in some pts with MM (Wolchok, et al., 2011 PIM). IPI in combination with DTIC in previously untreated MM patients significantly improved OS in phase III study CA184-024 (Robert, et al, NEJM 2011). Safety data from study 024 has been previously published. Here we report 4-yr survival data from study 024, the longest IPI survival follow-up from a phase III study. Table: 1127P Treatment group Median OS, months [95% CI] Overall survival rate, % [95% CI] 1-year 2-year 3-year 4-year IPI + DTIC N = 250 11.2 [9.4-13.6] 47.5% [41.2–53.8] 28.8% [23.2–34.6] 21.2% [16.1–26.5] 19.0% [14.2 - 24.2] Placebo + DTIC N = 252 9.1 [7.8-10.5] 36.4% [30.4–42.4] 17.8% [13.2–22.6] 12.1% [8.1–16.3] 9.6% [6.1 - 13.5] Methods Pts with treatment-naive MM were randomized to receive either IPI (10 mg/kg) + DTIC (850 mg/m2) or placebo + DTIC (850 mg/m2) given at Wks 1, 4, 7, 10 followed by DTIC q 3 wks through Wk 22. Pts with stable disease or better then received IPI or placebo q 12 wks as maintenance. This analysis reports OS with updated last known alive date or death date based on data collected through April 2012. Results The table summarizes median OS, previously reported survival rates at 1, 2, and 3 years, and current analyses for 4-year survival rates by treatment group. Conclusions The 4-year survival rates observed in an extended follow-up of a completed phase III trial suggests that IPI 10 mg/kg in combination with DTIC continues to demonstrate a survival benefit compared to the control arm. The continued survival of some patients at 4 yrs suggests that prolonged survival may indeed be obtained in some pts with treatment-naive MM. This observation of long-term survival benefit in a phase III RCT is consistent with observations from phase I/II studies of IPI in patients with advanced melanoma. Disclosure M. Maio: Paid advisor in boards from BMS and Roche. C. Robert: Consultant for BMS, GSK, Roche and Novartis. C. Garbe: I received honoraria and research funding from BMS. S. Francis: Employed by BMS. K. Chin: Employed by BMS and have Stock ownership. J. Wolchok: I am a consultant to BMS, Merck and GSK. I receive rsearch funding from BMS. All other authors have declared no conflicts of interest.

Disease-Free Survival Versus Overall Survival As a Primary End Point for Adjuvant Colon Cancer Studies: A Commentary

In this issue of the Journal of Clinical Oncology, Sargent et al evaluated disease-free survival with 3 years of followup (DFS3 years) as a surrogate for overall survival with 5 years of follow-up (OS5 years) and conclude that it is an appropriate primary end point to replace OS in phase III clinical trials of adjuvant fluorouracil (FU) -based therapies for colon cancer. In most definitive studies of the benefits of potential cancer therapies, OS is the primary end point because (1) it has obvious clinical importance, (2) survival of an individual patient can be unambiguously assessed, and (3) even if a patient does not return for follow-up evaluation, survival information can be obtained from death registries such as that provided by the United States Social Security Administration. These advantages are balanced by several disadvantages: (1) use of OS as the primary end point may prolong evaluation of new therapies because of the long follow-up time required to obtain adequate information for assessment; (2) studies of long duration may be weakened by decreasing patient compliance over time and increasing losses to follow-up; (3) because of this, long-term studies are more expensive to conduct; (4) studies of long duration may delay approval and dissemination of effective therapies and postpone pursuit of alternative research strategies when a therapy proves to be ineffective. For these reasons, investigators have considered the use of clinical end points that are surrogates for the true end point and that require less time to evaluate and may be less costly to assess. There are, however, significant statistical challenges to be addressed when considering use of a surrogate end point. Although the true end point is assumed to be causally related to the effectiveness of treatment, that relationship must be verified for a surrogate. Additionally, there are critical assumptions about the relationship between the surrogate and the true end point that require verification. In the current study, the authors analyzed data from 18 different trials in which there were 43 different treatment arms with a total of nearly 21,000 patients. Their evaluation of DFS as a surrogate is strengthened by their consideration of the relationship between DFS3 years and OS5 years at 3 levels: the patient, the treatment arm, and the trial. An end point that is a good surrogate at the level of the patient but not at the level of the trial is not useful for hastening evaluation of new therapies. One that meets the criteria of a good surrogate at the level of the trial but not at the level of the patient has no clinical value. One that is valid only for some treatment arms may distort the effects of therapy and is, obviously, not a useful surrogate. In this study, DFS3 years is shown to be an appropriate surrogate for OS5 years at each level of analysis. Although future studies of FU-based adjuvant therapy for patients with stages II and III colon cancer may comfortably use DFS3 years as a primary end point replacing OS5 years, casual readers are cautioned against generalizing these results to all colon cancer trials or to cancer clinical trials in general. These results depend on specific features of the disease and the current state of diagnosis and therapy. For example, colon cancer diagnosed at stages II and III has poor prognosis and, if the disease recurs, it is likely to result in imminent death, median survival time being approximately 1 year. DFS may not be an appropriate surrogate clinical end point for diseases in which treatment for recurrence is more often successful in prolonging survival. If there are significant advances in treatment for recurrence, then the statistical association between DFS and OS will be weakened, and one of the critical assumptions needed for determination of a surrogate end point will be violated. As the authors point out, if new diagnostic methods detect recurrent disease sooner than current methods, then there will be an apparent decrease in time to recurrence and an apparent increase in time from recurrence to death. Without advances in treatment for recurrence, advances in diagnosis may require consideration of other time points JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 34 DECEMBER 1 2005