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T-VEC is a modified virus that lyses tumor cells locally and induces a systemic immune response. In the phase 2 trial, neoadjuvant T-VEC plus surgery improved 3-year recurrence-free survival, when compared with immediate surgery, in patients with resectable melanoma.
“This is the first neoadjuvant trial for an approved oncolytic virus in melanoma and the largest randomized prospectively controlled neoadjuvant melanoma trial completed to date,” said investigator Reinhard Dummer, MD, of University Hospital Zürich.
The multicenter trial enrolled 150 patients with resectable stage IIIB–IV M1a melanoma (thereby including many with in-transit metastasis) who had at least one injectable lesion.
“This patient population is typically excluded from the trials that are published. Those trials typically focus on lymph node metastasis only,” Dr. Dummer noted.
The patients were randomized evenly to receive six doses over 12 weeks of intralesional T-VEC followed by surgical resection, or to the conventional approach of immediate surgical resection.
Survival results
The median follow-up for this interim analysis was 41.3 months.
The 3-year rate of recurrence-free survival, the trial’s primary endpoint, was 46.5% with T-VEC plus surgery and 31.0% with immediate surgery (hazard ratio, 0.67; P = .043). The median duration of recurrence-free survival was 27.5 months and 5.4 months, respectively.
These results were comparable with results seen at 2 years, which were published in Annals of Oncology in 2019. The 2-year rate of recurrence-free survival was 50.5% with T-VEC plus surgery and 31.0% with immediate surgery (HR, 0.66; P = .038).
“These patients appear to be in a plateau phase now,” Dr. Dummer remarked.
The 3-year rate of event-free survival, which excluded any events related to a delay of surgery, was 50.3% for T-VEC and 32.7% for immediate surgery (HR, 0.58, P = .015).
Findings for both outcomes were similar when analyses were repeated after removing events that occurred after receipt of therapy in the adjuvant or metastatic setting.
Finally, the 3-year rate of overall survival was 83.2% with T-VEC plus surgery and 71.6% with immediate surgery (HR, 0.54; P = .061). Respective 2-year values were 88.9% and 77.4% (HR, 0.49; P = .050).
In all, 50.7% of patients in the T-VEC group received subsequent anticancer therapy, compared with 76.8% in the immediate-surgery group. Respective values specifically for subsequent immunotherapy – usually immune checkpoint inhibitors – were 32.9% and 46.4%.
“I think this is a good argument that the effects we see on overall survival and recurrence-free survival are not caused by improved second-line treatments,” Dr. Dummer said.
No new safety signals emerged during the additional year of follow-up. The trial’s final analysis will be conducted after 5 years of follow-up.
“These results build upon the prior 2-year results to support the potential beneficial effect of neoadjuvant T-VEC on advanced resectable melanoma,” Dr. Dummer said.
“In general, if you compare this to the objective outcomes that we see with neoadjuvant ipilimumab-nivolumab, for example, the results do not look very attractive,” he acknowledged.
“However, we have to keep in mind that this is a difficult patient population,” he added, noting that many patients have in-transit metastases that would disqualify them from conventional neoadjuvant therapy. Also, cross-trial comparisons are complicated by the need to allow adjuvant therapy in patients who receive neoadjuvant therapy.
“I would say the combination of ipilimumab-nivolumab should be more powerful, but T-VEC has some impact, and from my understanding, T-VEC would be a perfect partner for a combination, for example, with an anti–[programmed death 1] agent,” Dr. Dummer concluded.
‘Impressive’ data support more research
“Neoadjuvant approaches are gaining enthusiasm for patients with locally advanced disease that may not be amenable to simple excision or may require large disfiguring procedures,” said Howard L. Kaufman, MD, of Massachusetts General Hospital and Dana Farber/Harvard Cancer Center, both in Boston, who was not involved in this study.
“A treatment option that could induce tumor regression while also promoting immune responses against the tumor is attractive,” Dr. Kaufman added.
“I continue to be impressed with this clinical trial as it demonstrates a consistent improvement in recurrence-free survival, event-free survival, and overall survival for patients treated with neoadjuvant T-VEC and surgery, compared to those who undergo surgery alone,” he said in an interview. “Confirmation that the responses are now maintained for another year is an important milestone.”
Given the study’s fairly small size, large treatment differences would be needed to attain the observed statistical significance, and “this is why the data at 3 years of follow-up is so impressive,” Dr. Kaufman said.
However, benefit of T-VEC’s activity in inducing a systemic immune response may not become fully evident until the end of the trial.
“Overall survival at 5 years is the most relevant endpoint,” Dr. Kaufman maintained.
An important aspect of the study is that it enrolled patients with a range of melanoma stages, including about 18% with stage IV M1a disease, he added.
“This could potentially influence the results, where earlier-stage patients may have a more durable response, compared to higher-stage patients and, thus, the data may be further diluted by the small sample size,” he proposed. “Given this possibility, my sense is that the data is even more impressive since there still appears to be a significant clinical benefit at 3 years, and I would recommend larger studies in patients with earlier-stage melanoma as fertile ground for further oncolytic virus drug development.”
The current trial was funded by Amgen. Dr. Dummer disclosed relationships with Amgen, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Takeda, Pierre Fabre, Sun Pharma, Sanofi, and CatalYm. Dr. Kaufman disclosed employment by Immuneering.
SOURCE: Dummer R et al. SITC 2020, Abstract 432.
T-VEC is a modified virus that lyses tumor cells locally and induces a systemic immune response. In the phase 2 trial, neoadjuvant T-VEC plus surgery improved 3-year recurrence-free survival, when compared with immediate surgery, in patients with resectable melanoma.
“This is the first neoadjuvant trial for an approved oncolytic virus in melanoma and the largest randomized prospectively controlled neoadjuvant melanoma trial completed to date,” said investigator Reinhard Dummer, MD, of University Hospital Zürich.
The multicenter trial enrolled 150 patients with resectable stage IIIB–IV M1a melanoma (thereby including many with in-transit metastasis) who had at least one injectable lesion.
“This patient population is typically excluded from the trials that are published. Those trials typically focus on lymph node metastasis only,” Dr. Dummer noted.
The patients were randomized evenly to receive six doses over 12 weeks of intralesional T-VEC followed by surgical resection, or to the conventional approach of immediate surgical resection.
Survival results
The median follow-up for this interim analysis was 41.3 months.
The 3-year rate of recurrence-free survival, the trial’s primary endpoint, was 46.5% with T-VEC plus surgery and 31.0% with immediate surgery (hazard ratio, 0.67; P = .043). The median duration of recurrence-free survival was 27.5 months and 5.4 months, respectively.
These results were comparable with results seen at 2 years, which were published in Annals of Oncology in 2019. The 2-year rate of recurrence-free survival was 50.5% with T-VEC plus surgery and 31.0% with immediate surgery (HR, 0.66; P = .038).
“These patients appear to be in a plateau phase now,” Dr. Dummer remarked.
The 3-year rate of event-free survival, which excluded any events related to a delay of surgery, was 50.3% for T-VEC and 32.7% for immediate surgery (HR, 0.58, P = .015).
Findings for both outcomes were similar when analyses were repeated after removing events that occurred after receipt of therapy in the adjuvant or metastatic setting.
Finally, the 3-year rate of overall survival was 83.2% with T-VEC plus surgery and 71.6% with immediate surgery (HR, 0.54; P = .061). Respective 2-year values were 88.9% and 77.4% (HR, 0.49; P = .050).
In all, 50.7% of patients in the T-VEC group received subsequent anticancer therapy, compared with 76.8% in the immediate-surgery group. Respective values specifically for subsequent immunotherapy – usually immune checkpoint inhibitors – were 32.9% and 46.4%.
“I think this is a good argument that the effects we see on overall survival and recurrence-free survival are not caused by improved second-line treatments,” Dr. Dummer said.
No new safety signals emerged during the additional year of follow-up. The trial’s final analysis will be conducted after 5 years of follow-up.
“These results build upon the prior 2-year results to support the potential beneficial effect of neoadjuvant T-VEC on advanced resectable melanoma,” Dr. Dummer said.
“In general, if you compare this to the objective outcomes that we see with neoadjuvant ipilimumab-nivolumab, for example, the results do not look very attractive,” he acknowledged.
“However, we have to keep in mind that this is a difficult patient population,” he added, noting that many patients have in-transit metastases that would disqualify them from conventional neoadjuvant therapy. Also, cross-trial comparisons are complicated by the need to allow adjuvant therapy in patients who receive neoadjuvant therapy.
“I would say the combination of ipilimumab-nivolumab should be more powerful, but T-VEC has some impact, and from my understanding, T-VEC would be a perfect partner for a combination, for example, with an anti–[programmed death 1] agent,” Dr. Dummer concluded.
‘Impressive’ data support more research
“Neoadjuvant approaches are gaining enthusiasm for patients with locally advanced disease that may not be amenable to simple excision or may require large disfiguring procedures,” said Howard L. Kaufman, MD, of Massachusetts General Hospital and Dana Farber/Harvard Cancer Center, both in Boston, who was not involved in this study.
“A treatment option that could induce tumor regression while also promoting immune responses against the tumor is attractive,” Dr. Kaufman added.
“I continue to be impressed with this clinical trial as it demonstrates a consistent improvement in recurrence-free survival, event-free survival, and overall survival for patients treated with neoadjuvant T-VEC and surgery, compared to those who undergo surgery alone,” he said in an interview. “Confirmation that the responses are now maintained for another year is an important milestone.”
Given the study’s fairly small size, large treatment differences would be needed to attain the observed statistical significance, and “this is why the data at 3 years of follow-up is so impressive,” Dr. Kaufman said.
However, benefit of T-VEC’s activity in inducing a systemic immune response may not become fully evident until the end of the trial.
“Overall survival at 5 years is the most relevant endpoint,” Dr. Kaufman maintained.
An important aspect of the study is that it enrolled patients with a range of melanoma stages, including about 18% with stage IV M1a disease, he added.
“This could potentially influence the results, where earlier-stage patients may have a more durable response, compared to higher-stage patients and, thus, the data may be further diluted by the small sample size,” he proposed. “Given this possibility, my sense is that the data is even more impressive since there still appears to be a significant clinical benefit at 3 years, and I would recommend larger studies in patients with earlier-stage melanoma as fertile ground for further oncolytic virus drug development.”
The current trial was funded by Amgen. Dr. Dummer disclosed relationships with Amgen, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Takeda, Pierre Fabre, Sun Pharma, Sanofi, and CatalYm. Dr. Kaufman disclosed employment by Immuneering.
SOURCE: Dummer R et al. SITC 2020, Abstract 432.
T-VEC is a modified virus that lyses tumor cells locally and induces a systemic immune response. In the phase 2 trial, neoadjuvant T-VEC plus surgery improved 3-year recurrence-free survival, when compared with immediate surgery, in patients with resectable melanoma.
“This is the first neoadjuvant trial for an approved oncolytic virus in melanoma and the largest randomized prospectively controlled neoadjuvant melanoma trial completed to date,” said investigator Reinhard Dummer, MD, of University Hospital Zürich.
The multicenter trial enrolled 150 patients with resectable stage IIIB–IV M1a melanoma (thereby including many with in-transit metastasis) who had at least one injectable lesion.
“This patient population is typically excluded from the trials that are published. Those trials typically focus on lymph node metastasis only,” Dr. Dummer noted.
The patients were randomized evenly to receive six doses over 12 weeks of intralesional T-VEC followed by surgical resection, or to the conventional approach of immediate surgical resection.
Survival results
The median follow-up for this interim analysis was 41.3 months.
The 3-year rate of recurrence-free survival, the trial’s primary endpoint, was 46.5% with T-VEC plus surgery and 31.0% with immediate surgery (hazard ratio, 0.67; P = .043). The median duration of recurrence-free survival was 27.5 months and 5.4 months, respectively.
These results were comparable with results seen at 2 years, which were published in Annals of Oncology in 2019. The 2-year rate of recurrence-free survival was 50.5% with T-VEC plus surgery and 31.0% with immediate surgery (HR, 0.66; P = .038).
“These patients appear to be in a plateau phase now,” Dr. Dummer remarked.
The 3-year rate of event-free survival, which excluded any events related to a delay of surgery, was 50.3% for T-VEC and 32.7% for immediate surgery (HR, 0.58, P = .015).
Findings for both outcomes were similar when analyses were repeated after removing events that occurred after receipt of therapy in the adjuvant or metastatic setting.
Finally, the 3-year rate of overall survival was 83.2% with T-VEC plus surgery and 71.6% with immediate surgery (HR, 0.54; P = .061). Respective 2-year values were 88.9% and 77.4% (HR, 0.49; P = .050).
In all, 50.7% of patients in the T-VEC group received subsequent anticancer therapy, compared with 76.8% in the immediate-surgery group. Respective values specifically for subsequent immunotherapy – usually immune checkpoint inhibitors – were 32.9% and 46.4%.
“I think this is a good argument that the effects we see on overall survival and recurrence-free survival are not caused by improved second-line treatments,” Dr. Dummer said.
No new safety signals emerged during the additional year of follow-up. The trial’s final analysis will be conducted after 5 years of follow-up.
“These results build upon the prior 2-year results to support the potential beneficial effect of neoadjuvant T-VEC on advanced resectable melanoma,” Dr. Dummer said.
“In general, if you compare this to the objective outcomes that we see with neoadjuvant ipilimumab-nivolumab, for example, the results do not look very attractive,” he acknowledged.
“However, we have to keep in mind that this is a difficult patient population,” he added, noting that many patients have in-transit metastases that would disqualify them from conventional neoadjuvant therapy. Also, cross-trial comparisons are complicated by the need to allow adjuvant therapy in patients who receive neoadjuvant therapy.
“I would say the combination of ipilimumab-nivolumab should be more powerful, but T-VEC has some impact, and from my understanding, T-VEC would be a perfect partner for a combination, for example, with an anti–[programmed death 1] agent,” Dr. Dummer concluded.
‘Impressive’ data support more research
“Neoadjuvant approaches are gaining enthusiasm for patients with locally advanced disease that may not be amenable to simple excision or may require large disfiguring procedures,” said Howard L. Kaufman, MD, of Massachusetts General Hospital and Dana Farber/Harvard Cancer Center, both in Boston, who was not involved in this study.
“A treatment option that could induce tumor regression while also promoting immune responses against the tumor is attractive,” Dr. Kaufman added.
“I continue to be impressed with this clinical trial as it demonstrates a consistent improvement in recurrence-free survival, event-free survival, and overall survival for patients treated with neoadjuvant T-VEC and surgery, compared to those who undergo surgery alone,” he said in an interview. “Confirmation that the responses are now maintained for another year is an important milestone.”
Given the study’s fairly small size, large treatment differences would be needed to attain the observed statistical significance, and “this is why the data at 3 years of follow-up is so impressive,” Dr. Kaufman said.
However, benefit of T-VEC’s activity in inducing a systemic immune response may not become fully evident until the end of the trial.
“Overall survival at 5 years is the most relevant endpoint,” Dr. Kaufman maintained.
An important aspect of the study is that it enrolled patients with a range of melanoma stages, including about 18% with stage IV M1a disease, he added.
“This could potentially influence the results, where earlier-stage patients may have a more durable response, compared to higher-stage patients and, thus, the data may be further diluted by the small sample size,” he proposed. “Given this possibility, my sense is that the data is even more impressive since there still appears to be a significant clinical benefit at 3 years, and I would recommend larger studies in patients with earlier-stage melanoma as fertile ground for further oncolytic virus drug development.”
The current trial was funded by Amgen. Dr. Dummer disclosed relationships with Amgen, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb, Roche, Takeda, Pierre Fabre, Sun Pharma, Sanofi, and CatalYm. Dr. Kaufman disclosed employment by Immuneering.
SOURCE: Dummer R et al. SITC 2020, Abstract 432.
FROM SITC 2020