FDA panel backs T-VEC for advanced melanoma, with precautions

SILVER SPRING, MD. – A Food and Drug Administration advisory panel supports approval of talimogene laherparepvec (T-VEC), an oncolytic immunotherapy, voting 22-1 that the overall risk-benefit profile is favorable for treatment of patients with injectable regionally or distantly metastatic melanoma.

At a joint meeting of the FDA’s Oncologic Drugs Advisory Committee and the Cellular, Tissue and Gene Therapies Advisory Committee on April 29, panelists agreed that it was clear that at least some subpopulations of patients can benefit from this treatment, but cautioned that while nonvisceral metastases may respond to treatment, it was not clear whether visceral metastases responded, and that it should not be used to treat visceral disease. They also recommended that labeling should discourage clinicians from using this treatment in patients with substantial metastatic disease.

T-VEC is a first-in-class oncolytic immunotherapy derived from herpes simplex virus type 1 (HSV-1) the virus that causes most cold sores. It has been genetically modified to attenuate its virulence and engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF), while remaining susceptible to antiviral treatments such as acyclovir. T-VEC is injected directly into cutaneous, subcutaneous, or nodal lesions, “resulting in selective lysis of the injected tumor cells (and not normal tissue),” which “results in the release and presentation of tumor-derived antigens and local expression of GM-CSF to initiate a systemic anti-tumor immune response that also induces regression of non-injected and distant lesions,” according to the Amgen briefing documents. If approved, this would be the first virus-based cancer treatment, the company noted.

The FDA panel looked at a phase III, open-label, multicenter randomized study that compared treatment with T-VEC to GM-CSF (administered subcutaneously) in 436 people with melanoma (stage IIIB/C or stage IV with limited visceral disease burden that was considered unresectable); the trial began before several targeted and biologic treatments that are now available for advanced melanoma were approved. About half the patients had been treated previously for melanoma and more than 20% were older than 75 years; 292 patients were treated with T-VEC (up to 4 mL injected into one or more subcutaneous or nodal melanoma lesions every 1 or 2 weeks until clinically relevant disease progression occurred or there was no more residual tumor to inject) and 141 received GM-CSF daily in the control arm (for 14 days and off for 14 days).

The primary efficacy endpoint was the durable response rate (DRR), defined as the proportion of patients with responses (complete or partial) “maintained continuously for 6 or more months and beginning at any point within 12 months of initiating therapy,” as assessed by a blinded independent committee. That endpoint was met by 16.3% of those treated with T-VEC vs. 2.1% of those on GM-CSF, a significant difference (P < .0001).

Other results included the overall response rate – complete or partial – which was 26.4% in the T-VEC group vs. 5.7% in the control group; Complete response was 10.8% among those on T-VEC, vs. 0.7% among those on GM-CSF.

Among the approximately 400 patients treated with T-VEC in this and five other studies, the most common adverse events were expected, namely, cellulitis and flu-like symptoms, and most adverse events were mild or moderate.

Disease progression and cellulitis were the most common serious adverse events and occurred more often among those on T-VEC (3.1% vs. 1.6%, and 2.4% vs. 0.8%, respectively). Fatal adverse events were higher among those on T-VEC (3.4% vs. 1.6%); disease progression was the most commonly reported.

Almost 6% of those on T-VEC reported herpetic events, mostly oral herpes, but there were no serious herpes complications or cases of secondary transmission. Amgen has proposed a risk management plan to address the risks of the treatment, including herpetic lesions, accidental exposures to health care professionals, and secondary transmission, and postmarketing studies.

Several panelists pointed out that the company‘s claims that T-VEC has a systemic effect was not necessarily substantiated by the data, and that the unresectable disease qualifier should be added to the indication. Other points made by panel members were that the dosing instructions were not sufficient, and that while the safety profile was acceptable, the risks of cellulitis and of shedding on family members, pregnant women, children, health care professionals, and other cancer patients were concerns. Panelists also noted that it is unclear how T-VEC compares to the other treatments that have been approved for advanced melanoma over the past several years.

“What’s very, very clear is there is a response of the injected lesions.” and local control of lesions is important to patients, said panelist Dr. Patrick Hwu, professor in the department of melanoma medical oncology, University of Texas M.D. Anderson Cancer Center, Houston. Based on the data, “this clearly ... will be among the least toxic agents for cancer given in the [melanoma] clinic,” compared to other treatments, he added.

The FDA usually follows advisory panels’ recommendations. An FDA decision on approval is expected by Oct. 27, 2015, according to Amgen. Panelists had no potential conflicts of interest related to this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel supports approval of talimogene laherparepvec (T-VEC), an oncolytic immunotherapy, voting 22-1 that the overall risk-benefit profile is favorable for treatment of patients with injectable regionally or distantly metastatic melanoma.

At a joint meeting of the FDA’s Oncologic Drugs Advisory Committee and the Cellular, Tissue and Gene Therapies Advisory Committee on April 29, panelists agreed that it was clear that at least some subpopulations of patients can benefit from this treatment, but cautioned that while nonvisceral metastases may respond to treatment, it was not clear whether visceral metastases responded, and that it should not be used to treat visceral disease. They also recommended that labeling should discourage clinicians from using this treatment in patients with substantial metastatic disease.

T-VEC is a first-in-class oncolytic immunotherapy derived from herpes simplex virus type 1 (HSV-1) the virus that causes most cold sores. It has been genetically modified to attenuate its virulence and engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF), while remaining susceptible to antiviral treatments such as acyclovir. T-VEC is injected directly into cutaneous, subcutaneous, or nodal lesions, “resulting in selective lysis of the injected tumor cells (and not normal tissue),” which “results in the release and presentation of tumor-derived antigens and local expression of GM-CSF to initiate a systemic anti-tumor immune response that also induces regression of non-injected and distant lesions,” according to the Amgen briefing documents. If approved, this would be the first virus-based cancer treatment, the company noted.

The FDA panel looked at a phase III, open-label, multicenter randomized study that compared treatment with T-VEC to GM-CSF (administered subcutaneously) in 436 people with melanoma (stage IIIB/C or stage IV with limited visceral disease burden that was considered unresectable); the trial began before several targeted and biologic treatments that are now available for advanced melanoma were approved. About half the patients had been treated previously for melanoma and more than 20% were older than 75 years; 292 patients were treated with T-VEC (up to 4 mL injected into one or more subcutaneous or nodal melanoma lesions every 1 or 2 weeks until clinically relevant disease progression occurred or there was no more residual tumor to inject) and 141 received GM-CSF daily in the control arm (for 14 days and off for 14 days).

The primary efficacy endpoint was the durable response rate (DRR), defined as the proportion of patients with responses (complete or partial) “maintained continuously for 6 or more months and beginning at any point within 12 months of initiating therapy,” as assessed by a blinded independent committee. That endpoint was met by 16.3% of those treated with T-VEC vs. 2.1% of those on GM-CSF, a significant difference (P < .0001).

Other results included the overall response rate – complete or partial – which was 26.4% in the T-VEC group vs. 5.7% in the control group; Complete response was 10.8% among those on T-VEC, vs. 0.7% among those on GM-CSF.

Among the approximately 400 patients treated with T-VEC in this and five other studies, the most common adverse events were expected, namely, cellulitis and flu-like symptoms, and most adverse events were mild or moderate.

Disease progression and cellulitis were the most common serious adverse events and occurred more often among those on T-VEC (3.1% vs. 1.6%, and 2.4% vs. 0.8%, respectively). Fatal adverse events were higher among those on T-VEC (3.4% vs. 1.6%); disease progression was the most commonly reported.

Almost 6% of those on T-VEC reported herpetic events, mostly oral herpes, but there were no serious herpes complications or cases of secondary transmission. Amgen has proposed a risk management plan to address the risks of the treatment, including herpetic lesions, accidental exposures to health care professionals, and secondary transmission, and postmarketing studies.

Several panelists pointed out that the company‘s claims that T-VEC has a systemic effect was not necessarily substantiated by the data, and that the unresectable disease qualifier should be added to the indication. Other points made by panel members were that the dosing instructions were not sufficient, and that while the safety profile was acceptable, the risks of cellulitis and of shedding on family members, pregnant women, children, health care professionals, and other cancer patients were concerns. Panelists also noted that it is unclear how T-VEC compares to the other treatments that have been approved for advanced melanoma over the past several years.

“What’s very, very clear is there is a response of the injected lesions.” and local control of lesions is important to patients, said panelist Dr. Patrick Hwu, professor in the department of melanoma medical oncology, University of Texas M.D. Anderson Cancer Center, Houston. Based on the data, “this clearly ... will be among the least toxic agents for cancer given in the [melanoma] clinic,” compared to other treatments, he added.

The FDA usually follows advisory panels’ recommendations. An FDA decision on approval is expected by Oct. 27, 2015, according to Amgen. Panelists had no potential conflicts of interest related to this meeting.

[email protected]

SILVER SPRING, MD. – A Food and Drug Administration advisory panel supports approval of talimogene laherparepvec (T-VEC), an oncolytic immunotherapy, voting 22-1 that the overall risk-benefit profile is favorable for treatment of patients with injectable regionally or distantly metastatic melanoma.

At a joint meeting of the FDA’s Oncologic Drugs Advisory Committee and the Cellular, Tissue and Gene Therapies Advisory Committee on April 29, panelists agreed that it was clear that at least some subpopulations of patients can benefit from this treatment, but cautioned that while nonvisceral metastases may respond to treatment, it was not clear whether visceral metastases responded, and that it should not be used to treat visceral disease. They also recommended that labeling should discourage clinicians from using this treatment in patients with substantial metastatic disease.

T-VEC is a first-in-class oncolytic immunotherapy derived from herpes simplex virus type 1 (HSV-1) the virus that causes most cold sores. It has been genetically modified to attenuate its virulence and engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF), while remaining susceptible to antiviral treatments such as acyclovir. T-VEC is injected directly into cutaneous, subcutaneous, or nodal lesions, “resulting in selective lysis of the injected tumor cells (and not normal tissue),” which “results in the release and presentation of tumor-derived antigens and local expression of GM-CSF to initiate a systemic anti-tumor immune response that also induces regression of non-injected and distant lesions,” according to the Amgen briefing documents. If approved, this would be the first virus-based cancer treatment, the company noted.

The FDA panel looked at a phase III, open-label, multicenter randomized study that compared treatment with T-VEC to GM-CSF (administered subcutaneously) in 436 people with melanoma (stage IIIB/C or stage IV with limited visceral disease burden that was considered unresectable); the trial began before several targeted and biologic treatments that are now available for advanced melanoma were approved. About half the patients had been treated previously for melanoma and more than 20% were older than 75 years; 292 patients were treated with T-VEC (up to 4 mL injected into one or more subcutaneous or nodal melanoma lesions every 1 or 2 weeks until clinically relevant disease progression occurred or there was no more residual tumor to inject) and 141 received GM-CSF daily in the control arm (for 14 days and off for 14 days).

The primary efficacy endpoint was the durable response rate (DRR), defined as the proportion of patients with responses (complete or partial) “maintained continuously for 6 or more months and beginning at any point within 12 months of initiating therapy,” as assessed by a blinded independent committee. That endpoint was met by 16.3% of those treated with T-VEC vs. 2.1% of those on GM-CSF, a significant difference (P < .0001).

Other results included the overall response rate – complete or partial – which was 26.4% in the T-VEC group vs. 5.7% in the control group; Complete response was 10.8% among those on T-VEC, vs. 0.7% among those on GM-CSF.

Among the approximately 400 patients treated with T-VEC in this and five other studies, the most common adverse events were expected, namely, cellulitis and flu-like symptoms, and most adverse events were mild or moderate.

Disease progression and cellulitis were the most common serious adverse events and occurred more often among those on T-VEC (3.1% vs. 1.6%, and 2.4% vs. 0.8%, respectively). Fatal adverse events were higher among those on T-VEC (3.4% vs. 1.6%); disease progression was the most commonly reported.

Almost 6% of those on T-VEC reported herpetic events, mostly oral herpes, but there were no serious herpes complications or cases of secondary transmission. Amgen has proposed a risk management plan to address the risks of the treatment, including herpetic lesions, accidental exposures to health care professionals, and secondary transmission, and postmarketing studies.

Several panelists pointed out that the company‘s claims that T-VEC has a systemic effect was not necessarily substantiated by the data, and that the unresectable disease qualifier should be added to the indication. Other points made by panel members were that the dosing instructions were not sufficient, and that while the safety profile was acceptable, the risks of cellulitis and of shedding on family members, pregnant women, children, health care professionals, and other cancer patients were concerns. Panelists also noted that it is unclear how T-VEC compares to the other treatments that have been approved for advanced melanoma over the past several years.

“What’s very, very clear is there is a response of the injected lesions.” and local control of lesions is important to patients, said panelist Dr. Patrick Hwu, professor in the department of melanoma medical oncology, University of Texas M.D. Anderson Cancer Center, Houston. Based on the data, “this clearly ... will be among the least toxic agents for cancer given in the [melanoma] clinic,” compared to other treatments, he added.

The FDA usually follows advisory panels’ recommendations. An FDA decision on approval is expected by Oct. 27, 2015, according to Amgen. Panelists had no potential conflicts of interest related to this meeting.

[email protected]