Ari M. Vanderwalde

Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma

PURPOSE Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial. PATIENTS AND METHODS Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously ≥ 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate. RESULTS Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P < .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P = .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in ≥ 2% of T-VEC-treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred. CONCLUSION T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial. T-VEC was well tolerated and resulted in a higher DRR (P < .001) and longer median OS (P = .051), particularly in untreated patients or those with stage IIIB, IIIC, or IVM1a disease. T-VEC represents a novel potential therapy for patients with metastatic melanoma.

OPTiM: A randomized phase III trial of talimogene laherparepvec (T-VEC) versus subcutaneous (SC) granulocyte-macrophage colony-stimulating factor (GM-CSF) for the treatment (tx) of unresected stage IIIB/C and IV melanoma.

LBA9008 Background: T-VEC is an oncolytic immunotherapy (OI) derived from herpes simplex virus type-1 designed to selectively replicate within tumors and to produce GM-CSF to enhance systemic antitumor immune responses. OPTiM is a randomized, phase III trial of T-VEC or GM-CSF in patients (pts) with unresected melanoma with regional or distant metastases. We report the primary results of the first phase III study of OI. METHODS Key criteria: age ≥18 yrs; ECOG ≤1; unresectable melanoma stage IIIB/C or IV; injectable cutaneous, SC, or nodal lesions; LDH ≤1.5X upper limit of normal; ≤3 visceral lesions (excluding lung), none >3 cm. Pts were randomized 2:1 to intralesional T-VEC (initially ≤ 4 mL x106 pfu/mL then after 3 wks, ≤ 4 mL x108 pfu/mL Q2W) or SC GM-CSF (125 µg/m2qd x 14 days q28d). The primary endpoint was durable response rate (DRR): partial or complete response (CR) continuously for ≥6 mos starting within 12 mos. Responses were per modified WHO by blinded central review. A planned interim analysis of overall survival (OS; key secondary endpoint) was performed. RESULTS 436 pts are in the ITT set: 295 (68%) T-VEC, 141 (32%) GM-CSF. 57% were men; median age was 63 yrs. Stage distribution was: IIIB/C 30%, IVM1a 27%, IVM1b 21%, IVM1c 22%. Objective response rate with T-VEC was 26% (95% CI: 21%, 32%) with 11% CR, and with GM-CSF was 6% (95% CI: 2%, 10%) with 1% CR. DRR for T-VEC was 16% (95% CI: 12%, 21%) and 2% for GM-CSF (95% CI: 0%, 5%), p<0.0001. DRR by stage (T-VEC, GM-CSF) was IIIB/C (33%, 0%), M1a (16%, 2%), M1b (3%, 4%), and M1c (8%, 3%). Interim OS showed a trend in favor of T-VEC; HR 0.79 (95% CI: 0.61, 1.02). Most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. Serious AEs occurred in 26% of T-VEC and 13% of GM-CSF pts. No ≥ grade 3 AE occurred in ≥ 3% of pts in either arm. CONCLUSIONS T-VEC demonstrated both a statistically significant improvement in DRR over GM-CSF in pts with unresectable stage IIIB-IV melanoma and a tolerable safety profile; an interim analysis showed a trend toward improved OS. T-VEC represents a novel potential tx option for melanoma with regional or distant metastases. CLINICAL TRIAL INFORMATION NCT00769704.

Panitumumab plus radiotherapy versus chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-2): a randomised, controlled, open-label phase 2 trial.

BACKGROUND We aimed to compare panitumumab, a fully human monoclonal antibody against EGFR, plus radiotherapy with chemoradiotherapy in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 22 sites in eight countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (two cycles of cisplatin 100 mg/m(2) during radiotherapy) or to radiotherapy plus panitumumab (three cycles of panitumumab 9 mg/kg every 3 weeks administered with radiotherapy) using a stratified randomisation with a block size of five. All patients received 70-72 Gy to gross tumour and 54 Gy to areas of subclinical disease with accelerated fractionation radiotherapy. The primary endpoint was local-regional control at 2 years, analysed in all randomly assigned patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This study is registered with ClinicalTrials.gov, number NCT00547157. FINDINGS Between Nov 30, 2007, and Nov 16, 2009, 152 patients were enrolled, and 151 received treatment (61 in the chemoradiotherapy group and 90 in the radiotherapy plus panitumumab group). Local-regional control at 2 years was 61% (95% CI 47-72) in the chemoradiotherapy group and 51% (40-62) in the radiotherapy plus panitumumab group. The most frequent grade 3-4 adverse events were mucosal inflammation (25 [40%] of 62 patients in the chemoradiotherapy group vs 37 [42%] of 89 patients in the radiotherapy plus panitumumab group), dysphagia (20 [32%] vs 36 [40%]), and radiation skin injury (seven [11%] vs 21 [24%]). Serious adverse events were reported in 25 (40%) of 62 patients in the chemoradiotherapy group and in 30 (34%) of 89 patients in the radiotherapy plus panitumumab group. INTERPRETATION Panitumumab cannot replace cisplatin in the combined treatment with radiotherapy for unresected stage III-IVb squamous-cell carcinoma of the head and neck, and the role of EGFR inhibition in locally advanced squamous-cell carcinoma of the head and neck needs to be reassessed. FUNDING Amgen.

Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial

BACKGROUND Panitumumab is a fully human monoclonal antibody that targets EGFR. We aimed to compare chemoradiotherapy plus panitumumab with chemoradiotherapy alone in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck. METHODS In this international, open-label, randomised, controlled, phase 2 trial, we recruited patients with locally advanced squamous-cell carcinoma of the head and neck from 41 sites in nine countries worldwide. Patients aged 18 years and older with stage III, IVa, or IVb, previously untreated, measurable (≥ 10 mm for at least one dimension), locally advanced squamous-cell carcinoma of the head and neck (non-nasopharygeal) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (2:3) by an independent vendor to open-label chemoradiotherapy (three cycles of cisplatin 100 mg/m(2)) or panitumumab plus chemoradiotherapy (three cycles of intravenous panitumumab 9.0 mg/kg every 3 weeks plus cisplatin 75 mg/m(2)) using stratified randomisation with a block size of five. All patients received 70 Gy to gross tumour and 50 Gy to areas at risk for subclinical disease with standard fractionation. The primary endpoint was local-regional control at 2 years, analysed in all randomised patients who received at least one dose of their assigned protocol-specific treatment (chemotherapy, radiation, or panitumumab). The trial is closed and this is the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00500760. FINDINGS Between Oct 26, 2007, and March 26, 2009, 153 patients were enrolled and 150 received treatment (63 in the chemoradiotherapy group and 87 in the panitumumab plus chemoradiotherapy group). Local-regional control at 2 years was 68% (95% CI 54-78) in the chemoradiotherapy group and 61% (50-71) in the panitumumab plus chemoradiotherapy group. The most frequent grade 3-4 adverse events were dysphagia (17 [27%] of 63 patients in the chemoradiotherapy group vs 35 [40%] of 87 in the panitumumab plus chemoradiotherapy group), mucosal inflammation (15 [24%] vs 48 [55%]), and radiation skin injury (eight [13%] vs 27 [31%]). Serious adverse events were reported in 20 (32%) of 63 patients in the chemoradiotherapy group and in 37 (43%) of 87 patients in the panitumumab plus chemoradiotherapy group. INTERPRETATION In patients with locally advanced squamous-cell carcinoma of the head and neck, the addition of panitumumab to standard fractionation radiotherapy and cisplatin did not confer any benefit, and the role of EGFR inhibition in these patients needs to be reassessed. FUNDING Amgen.

Aging and osteoporosis in breast and prostate cancer

As people with cancer survive longer, and as the US population ages, skeletal effects of cancer treatment are becoming more pronounced. This is particularly true for breast and prostate cancer survivors because of the high average age of patients with these malignancies, the propensity of older adults in general toward the development of osteoporosis, and the wide use of therapeutic agents in these cancers that negatively impact bone health. Various therapies used in the treatment and prevention of cancer may cause decreases in bone mineral density and an increased risk of debilitating fracture, even in the absence of bone metastases. Aging is both a baseline risk factor in the development of osteoporosis and bony fracture, as well as a predictor of poor outcome after fracture. A variety of mechanisms may be responsible for the development of bone loss in patients with breast or prostate cancer. Cytotoxic chemotherapy may directly exert long‐term toxic effects on bone. Chemotherapy and endocrine therapy can induce hypogonadism, leading to an increased rate of bone loss. The risk of skeletal events in older adults due to cancer therapy should be appreciated by all oncologists, geriatricians, and internists. The following review may serve as a guide to the skeletal side effects of cancer therapy in older adults with breast or prostate cancer, how to screen for treatment‐related bone loss, and how to best prevent and/or treat skeletal events. CA Cancer J Clin 2011.

Conditional survival and cause-specific mortality after autologous hematopoietic cell transplantation for hematological malignancies

The probability of survival is conventionally calculated from autologous hematopoietic cell transplantation (aHCT). Conditional survival takes into account the changing probability of survival with time survived, but this is not known for aHCT populations. We determined disease- and cause-specific conditional survival for 2388 patients treated with aHCT over a period of 20 years at a single institution. A total of 1054 deaths (44% of the cohort) were observed: 78% attributed to recurrent disease; 9% to subsequent malignancies and 6% to cardiopulmonary disease. Estimated probability of relative survival was 62% at 5 years and 50% at 10 years from aHCT. On the other hand, the 5-year relative survival was 70, 75, 81 and 88% after having survived 1, 2, 5 and 10 years after aHCT, respectively. The cohort was at a 13.9-fold increased risk of death compared with the general population (95% confidence interval (CI)=13.1–14.8). The risk of death approached that of the general population for 10-year survivors (standardized mortality ratio (SMR)=1.4, 95% CI=0.9–1.9), with the exception of female Hodgkin’s lymphoma patients transplanted before 1995 at age ⩽40 years (SMR=6.0, 95% CI=1.9–14.0). Among those who had survived 10 years, nonrelapse-related mortality rates exceeded relapse-related mortality rates. This study provides clinically relevant survival estimates after aHCT, and helps inform interventional strategies.

Paying human subjects in research: where are we, how did we get here, and now what?

Both international and federal regulations exist to ensure that scientists perform research on human subjects in an environment free of coercion and in which the benefits of the research are commensurate with the risks involved. Ensuring that these conditions hold is difficult, and perhaps even more so when protocols include the issue of monetary compensation of research subjects. The morality of paying human research subjects has been hotly debated for over 40 years, and the grounds for this debate have ranged from discussion of legal rights, economic rights, philosophical principles of vulnerability and altruism to bioethical concepts of consent, best-interest determination, and justice theory. However, the thought surrounding these issues has evolved over time, and the way we think about the role of the human research subject today is markedly different than the way we thought in the past. Society first thought of the research subject as an altruist, necessarily giving of his time to benefit society as a whole. As time progressed, many suggested that the subject should not need to sacrifice himself for research: if something goes wrong, someone should compensate the subject for injuries. The concept of redress evolved into a system in which subjects were offered money as an inducement to participate in research, sometimes merely to offset the monetary costs of participation, but sometimes even to mitigate the risks of the study. This article examines ethical and legal conversations regarding compensation from the 1960s through today, examining theories of the ethics of compensation both comparatively and critically. In conclusion, we put forward an ethical framework for treating paid research subjects, with an attempt to use this framework as a means of resolving some of the more difficult problems with paying human subjects in research.

Second Malignancies Among Elderly Survivors of Cancer

The U.S. population is aging, life expectancy is increasing, and cancer is a disease associated with aging. Advances in screening and therapeutics have led to a growing number of cancer survivors who are at risk for the development of secondary malignancies. Although the risks for the development of second malignancies following a first diagnosis of cancer are well described for survivors of childhood malignancies, there are fewer data for malignancies common in older adults. With the aging of the U.S. population, and with improving survival statistics in many adult malignancies, there is an increasing need to identify those second malignancies that might develop in the older adult survivor of cancer. In this paper, we describe the types and rates of second malignancies following cancers commonly seen in older adults and review the literature on these malignancies. Comparisons are made between older and younger adults with regard to the risks for developing treatment-related cancers with different modalities. Recommendations for early detection of second malignancies are summarized, though there remains an unmet need for evidence-based guidelines for screening for second malignancies in the older adult in particular.

Microsatellite instability status determined by next-generation sequencing and compared with PD-L1 and tumor mutational burden in 11,348 patients

Microsatellite instability (MSI) testing identifies patients who may benefit from immune checkpoint inhibitors. We developed an MSI assay that uses data from a commercially available next‐generation sequencing (NGS) panel to determine MSI status. The assay is applicable across cancer types and does not require matched samples from normal tissue. Here, we describe the MSI‐NGS method and explore the relationship of MSI with tumor mutational burden (TMB) and PD‐L1. MSI examined by PCR fragment analysis and NGS was compared for 2189 matched cases. Mismatch repair status by immunohistochemistry was compared to MSI‐NGS for 1986 matched cases. TMB was examined by NGS, and PD‐L1 was determined by immunohistochemistry. Among 2189 matched cases that spanned 26 cancer types, MSI‐NGS, as compared to MSI by PCR fragment analysis, had sensitivity of 95.8% (95% confidence interval [CI] 92.24, 98.08), specificity of 99.4% (95% CI 98.94, 99.69), positive predictive value of 94.5% (95% CI 90.62, 97.14), and negative predictive value of 99.2% (95% CI, 98.75, 99.57). High MSI (MSI‐H) status was identified in 23 of 26 cancer types. Among 11,348 cases examined (including the 2189 matched cases), the overall rates of MSI‐H, TMB‐high, and PD‐L1 positivity were 3.0%, 7.7%, and 25.4%, respectively. Thirty percent of MSI‐H cases were TMB‐low, and only 26% of MSI‐H cases were PD‐L1 positive. The overlap between TMB, MSI, and PD‐L1 differed among cancer types. Only 0.6% of the cases were positive for all three markers. MSI‐H status can be determined by NGS across cancer types. MSI‐H offers distinct data for treatment decisions regarding immune checkpoint inhibitors, in addition to the data available from TMB and PD‐L1.

A Phase I/III, multicenter, open-label trial of talimogene laherparepvec (T-VEC) in combination with pembrolizumab for the treatment of unresected, stage IIIb-IV melanoma (MASTERKEY-265)

Meeting abstracts T-VEC is a herpes simplex virus-1-based oncolytic immunotherapy designed to selectively replicate in tumors, produce GM-CSF, and stimulate antitumor immune responses. OPTiM, a Phase III trial of T-VEC vs GM-CSF in unresectable stage IIIB-IV melanoma, improved the primary endpoint