Meeting Highlights
European Society of Medical Oncology Walter Alexander
European Society of Medical Oncology The European Society of Medical Oncology (ESMO) 2014 Congress welcomed 19,809 oncologists and colleagues for a wide variety of basic and clinical research presentations in Madrid, Spain, from September 26–30. Key sessions focused on metastatic breast cancer, on treatment for cachexia in non–small-cell lung cancer, on recurrent and/or metastatic head and neck squamous-cell carcinoma, and on advanced melanoma.
Final Overall Survival Analysis From the CLEOPATRA Study of First-Line Pertuzumab, Trastuzumab, and Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer
• Sandra Swain, MD, Medical Director, Washington Cancer Institute, Medstar Washington Hospital Center, Washington, D.C. In the CLEOPATRA trial, when compared with trastuzumab and chemotherapy, a dual HER2 blockade of pertuzumab added to trastuzumab with chemotherapy increased overall survival (OS) among women with HER2-positive metastatic breast cancer. Dr. Swain, the lead investigator, called the size of the benefit “unprecedented” at an ESMO press conference. The press conference moderator, Eric Van Cutsem, MD, University of Leuven, Belgium, affirmed the importance of the CLEOPATRA findings. “I think these data are practice-changing,” he said. The dual HER2 blockade had already shown significant gains in progression-free survival (PFS) in shorter-term reporting of CLEOPATRA results. The two antibodies, Dr. Swain pointed out, bind to different sites. In CLEOPATRA, which was conducted at 204 centers in 20 countries, 406 women received placebo plus trastuzumab (8 mg/kg loading followed by 6 mg/kg maintenance) with six or more cycles of docetaxel (75 mg/m2 followed by 100 mg/m2 with escalation if tolerated) and 402 patients received pertuzumab (840 mg loading followed by 420 mg maintenance) and trastuzumab plus docetaxel. Trastuzumab and pertuzumab were dosed for a much longer period, Dr. Swain said, until progressive disease. Chemotherapy was actually administered for a median of eight cycles. After a median follow-up of 50 months, OS was 40.8 months for the arm receiving chemotherapy and trastuzumab and 56.5 months for chemotherapy with both trastuzumab and pertuzumab (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.56–0.84; P = 0.0002). Regarding the OS gain of 15.7 months, Dr. Swain said, “I have never seen that in any other trial of metastatic breast cancer.” Benefits were consistent across all subgroups. “The results, I think, are phenomenal.” An updated PFS analysis showing an improvement of 6.3 months also demonstrated a strong consistency for this The author is a freelance medical writer living in New York City.
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measure as a good surrogate for OS, Dr. Swain commented. Adding pertuzumab raised rates of rash, mucositis, and diarrhea, but in general no new safety issues came up. While the potential for increased cardiac toxicity with the two monoclonal antibodies had been a concern, investigators actually observed lower rates of ventricular dysfunction and left ventricular ejection fraction declines of 10% or greater in less than 50% of the group receiving both trastuzumab and pertuzumab. The findings, Dr. Swain concluded, “confirm the pertuzumab regimen as first-line standard of care for patients with HER2-positive metastatic breast cancer.” She added, “Based on the study results and the consistency in the subgroups, I would recommend dual antibody therapy for all patients [with metastatic breast cancer].”
Anamorelin for the Treatment of Cancer AnorexiaCachexia in NSCLC: Results From the Phase 3 Studies Romana 1 and 2
• David Currow, MD, Professor of Palliative and Supportive Services, Flinders University, Adelaide, Australia Cancer anorexia-cachexia syndrome is a common, debilitating condition characterized by decreased body weight (mainly through the loss of lean body mass). It harms quality of life and prognosis. In the ROMANA 1 and 2 clinical trials, anamorelin HCl significantly increased lean body mass and body weight in patients with advanced, unresectable non–small-cell lung cancer and cancer anorexia-cachexia. Anamorelin is a novel selective ghrelin receptor agonist with appetite-enhancing and anabolic activity. Dr. Currow noted that more than 50% of cancer patients develop cachexia, and 30% of cancer deaths are directly related to it. “If you will, it is the final common pathway for most people with advanced cancer and a number of other diseases,” Dr. Currow added. “It is also the leading limiting factor for treating many people as their cancer advances.” In phase 2 reasearch,1 patients receiving anamorelin demonstrated significant mean body-weight gains after 12 weeks, Dr. Currow said. Ghrelin, which is released by the stomach, stimulates multiple pathways that regulate body weight, lean body mass, appetite, and metabolism. ROMANA 1 and 2 were international, double-blind, phase 3 trials, randomizing patients 2:1 to anamorelin 100 mg daily or placebo. The primary endpoints of both trials were lean body mass (measured by dual energy X-ray absorptiometry) and handgrip strength. Cachexia was defined as a weight loss of at least 5% within the prior six months or a body mass index of less than 20 kg/m2. In ROMANA 1, among 484 participants, lean body mass increased a median of 1.10 kg in 12 weeks in those receiving anamorelin (95% CI, 0.76–1.42) and dropped a median of 0.44 kg in those receiving placebo (95% CI, –0.88 to 0.20). Among the 495 patients in ROMANA 2, benefits were similar, with an average lean body mass increase of 0.95 kg for anamorelin (95% CI, 0.51–1.00) and a 0.57-kg loss for placebo (95% CI, –1.27 to –0.46). Differences
Meeting Highlights: European Society of Medical Oncology between anamorelin and placebo were significant in both trials (P < 0.0001). In addition, patient symptoms and concerns regarding anorexia-cachexia improved significantly over 12 weeks. Body weight increased by 2.20 kg and 0.95 kg in ROMANA 1 and 2 with anamorelin, respectively, compared with 0.14 kg and –0.57 kg with placebo (P < 0.001 for both). Hyperglycemia and nausea, the most frequent drug-related adverse events, were easily managed, Dr. Currow said. Benefits were significant for anamorelin in the two trials when considered together or separately. He added that handgrip strength was not improved with anamorelin, but suggested that the trial’s short duration may account for the lack of improvement. Dr. Currow concluded: “Positive results from phase 3 ROMANA 1 and ROMANA 2 demonstrate the potential of anamorelin as an effective treatment for cachexia in cancer patients.”
Afatinib Versus Methotrexate as Second-Line Treatment for Patients With Recurrent and/or Metastatic Head and Neck Squamous-Cell Carcinoma Who Progressed After Platinum-Based Therapy: Primary Efficacy Results of Lux-Head And Neck 1, a Phase 3 Trial
in a phase 3 trial in this setting,” Dr. Machiels concluded. “Afatinib is an active oral agent,” said ESMO discussant Tanguy Seiwert, MD, of the University of Chicago, Illinois, “but given the small effect size, it is hard to see how by itself this trial could lead to clinically meaningful use for patients or approval.” He added that while the PFS increase of 0.9 months with afatinib was of “unclear” significance, better results in patients with no prior EGFR-targeted antibody exposure, age of 65 years or older, and p16 mutation negativity invite work on predictive biomarkers to identify a population with larger effect size and more benefit.
CALM Study: Secondary Endpoints of a Phase 2 Study of a Novel Oncolytic Immunotherapeutic Agent, Coxsackievirus A21, Delivered Intratumorally In Patients With Advanced Malignant Melanoma
• Robert Hans Andtbacka, MD, Associate Professor, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
Subgroup Efficacy in Patients Receiving Rose Bengal to All Existing Melanoma in Phase 2 Study PV-10-MM-02
• Jean Pascal Machiels, MD, Medical Oncologist, Institut Roi Albert II, Cliniques Universitaires St. Luc, Brussels, Belgium
• Sanjiv Agarwala, MD, Chief of Medical Oncology and Hematology, St. Luke’s University Hospital and Health Network, Bethlehem, Pennsylvania
Afatinib is an orally available irreversible blocker of the ErbB family of cell surface receptors. In a phase 3 trial among patients with recurrent or metastatic head and neck squamouscell carcinomas who progressed after first-line platinum-based therapy, afatinib improved the primary endpoint of PFS and delayed deterioration of patient-reported outcomes compared with methotrexate. Patients with recurrent or metastatic head and neck squamous-cell carcinomas who progress after platinum-based therapy have a “dismal” prognosis and no well-defined treatment, said Dr. Machiels, lead investigator of the Lux-Head and Neck 1 trial. He noted that around 90% of squamous-cell carcinomas of the head and neck overexpress epidermal growth factor receptor (EGFR), which is included in the ErbB family. Lux-Head and Neck 1 included 474 patients randomized 2:1 to afatinib 40 mg once daily (n = 316) or methotrexate (40 mg/m2 intravenous weekly, n = 158). Median PFS was 2.6 months in the afatinib group and 1.7 months in the methotrexate group (HR, 0.80; 95% CI, 0.65–0.98; P = 0.030). Patients in the afatinib arm had a significantly delayed worsening of symptoms, such as pain, difficulty swallowing, and global health status (all P ≤ 0.03) compared with methotrexate. Afatinib patients had less pain over time (P = 0.03), with increases in tumor shrinkage, higher response rates, and higher disease control rates than those in the methotrexate arm. OS, however, at 6.8 months for afatinib and 6.0 months for methotrexate, was not significantly improved (P = 0.70). Rash/acne (9.7%) and diarrhea (9.4%) were the most frequent grade 3 or 4 drug-related adverse events with afatinib. In the methotrexate group, leukopenia (15.6%) and stomatitis (8.1%) were most common. “Afatinib is the first oral tyrosine kinase inhibitor to demonstrate efficacy and improved patient-reported outcomes
Research into intralesional therapies for advanced melanoma presented in two posters, one on coxsackievirus a21 (CVA21: CAVATAKTM) and the other on PV-10, revealed positive findings and strong potential both as monotherapies and in combination with systemic immunotherapies. CVA21 is a naturally occurring “common cold” intercellular adhesion molecule-1 (ICAM-1) targeted RNA virus. Surface ICAM-1, Dr. Andtbacka said, is up-regulated on a number of cancers, including melanoma. In animal models, it has been shown that CVA21-lysed tumor cells can induce a secondary systemic host-generated antitumor immune response. CVA21 was tested in CALM (CAVATAK in Late Stage Melanoma), a study including 57 patients (21 female, 36 male) with stage IIIC and IV melanoma. All had at least one injectable dermal, cutaneous, subcutaneous, or lymph node lesion. They received 10 series of multi-intratumoral CVA21 injections. The CALM primary endpoint, immune-related progressionfree survival (irPFS), was calculated as the proportion of patients demonstrating a complete response, partial response, or stable disease by immune-related RECIST 1.1 criteria six months after the initiation of treatment. Dr. Andtbacka said investigators had hoped that at least 10 patients would reach that milestone, but to date 22 patients have achieved irPFS, for a rate of 38.6% (22 of 57). The secondary endpoint of objective response rate (complete response plus partial response, irRECIST 1.1) was 28.1% (16 of 57). Median time to response was 2.8 months, and the one-year survival rate was 73.3% (33 of 45 patients). Tumor responses were observed in both injected lesions and noninjected lesions, noninjected visceral lesions at times of high levels of anti-CVA21 neutralizing antibody, and in the absence of circulating infectious CVA21. CVA21 given as multidose intralesional therapy was generally well tolerated. No
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Meeting Highlights: ESMO grade 3 or 4 treatment-related adverse events were reported. Were the responses immune-related, or was the CVA21 virus entering the tumor and causing the responses? Investigators were aware that 85% or more of patients do not have neutralizing antibodies to CVA21. “But we found out that after the fifth injection, around day 22, virtually all patients had developed neutralizing antibodies,” Dr. Andtbacka said. “Yet even in the presence of these neutralizing antibodies, we saw objective responses—indicating to us that the response is likely immune-mediated rather than caused by the virus itself. So this is very encouraging data that sets us up nicely for combination studies and neoadjuvant protocols and also other monotherapy studies.” Further clinical evaluations of CVA21 are warranted in combination with other immunotherapeutic agents, such as immune checkpoint inhibitors with anti-CTLA-4 or anti-PD-1 or targeted small molecules (i.e., BRAF and MEK kinase inhibitors), Dr. Andtbacka said. A report on the subset of patients in the phase 2 trial of intralesional PV-10 who had all of their cutaneous melanoma lesions injected with PV-10 revealed that response rates were high and that responses occurred quickly in most patients. “The finding,” Dr. Agarwala said, “has really helped us toward finalizing our phase 3 trial design.” In the original trial of 80 patients, some had a portion of lesions left untreated as “bystander lesions.” The response rate in this group was 23% (CI, 9–44%), and the complete response rate for the full population of 80 patients was 26%, with an objective response (complete plus partial response) of 51% (CI, 40–63%). The complete response rate among 28 patients in the alllesions-treated group was 50% (CI, 31–70%), and the objective response rate was 71% (CI, 51–87%). Patients had a median of eight study lesions (range, one to 22), with a time to response of 1.8 months. The partial response rate in the all-lesions-treated group was 21%, with stable disease in 11%. An analysis by lesion showed that among 232 complete responses in 363 lesions (64%) in the all-lesions-treated group, 121 were observed after one injection, 84 after two injections, 22 after three injections, and five after four injections. PFS in the all-lesions-treated group was 9.8 months. In the uninjected bystander lesion group, PFS was 8.9 months. The finding of such rapid responses, Dr. Agarwala said in an interview, showed that PV-10 responses had occurred already in a period where chemotherapy responses are not expected. “We should see a difference very quickly between PV-10 and chemotherapy responses.” Based on these data, investigators will treat all lesions in the phase 3 trial, and include only BRAF wild-type patients (who do not respond to BRAF inhibitors) and those who have become refractory to systemic immunotherapy or are not candidates because of advanced age or comorbidities. Planned enrollment for the phase 3 trial is 219 patients with locoregional disease only. They will be randomized 2:1 to intra lesional PV-10 or systemic chemotherapy with dacarbazine or temozolomide. Dr. Agarwala noted that about a third of melanoma patients are diagnosed with predominantly locoregional disease.
REFERENCE 1.
Temel JB, et al. Efficacy and safety of anamorelin HCl in NSCLC patients: results from a randomized, double-blind, placebo-controlled, multicenter phase II study. Presentation at the European Cancer Congress, Amsterdam, Netherlands, September 27–October 1, 2013. Abstract 1308. Abstract published in Eur J Cancer 2013;49(suppl 2). n
876 P&T • ®
December 2014 • Vol. 39 No. 12
European Society of Medical Oncology Walter Alexander
European Society of Medical Oncology The European Society of Medical Oncology (ESMO) 2014 Congress welcomed 19,809 oncologists and colleagues for a wide variety of basic and clinical research presentations in Madrid, Spain, from September 26–30. Key sessions focused on metastatic breast cancer, on treatment for cachexia in non–small-cell lung cancer, on recurrent and/or metastatic head and neck squamous-cell carcinoma, and on advanced melanoma.
Final Overall Survival Analysis From the CLEOPATRA Study of First-Line Pertuzumab, Trastuzumab, and Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer
• Sandra Swain, MD, Medical Director, Washington Cancer Institute, Medstar Washington Hospital Center, Washington, D.C. In the CLEOPATRA trial, when compared with trastuzumab and chemotherapy, a dual HER2 blockade of pertuzumab added to trastuzumab with chemotherapy increased overall survival (OS) among women with HER2-positive metastatic breast cancer. Dr. Swain, the lead investigator, called the size of the benefit “unprecedented” at an ESMO press conference. The press conference moderator, Eric Van Cutsem, MD, University of Leuven, Belgium, affirmed the importance of the CLEOPATRA findings. “I think these data are practice-changing,” he said. The dual HER2 blockade had already shown significant gains in progression-free survival (PFS) in shorter-term reporting of CLEOPATRA results. The two antibodies, Dr. Swain pointed out, bind to different sites. In CLEOPATRA, which was conducted at 204 centers in 20 countries, 406 women received placebo plus trastuzumab (8 mg/kg loading followed by 6 mg/kg maintenance) with six or more cycles of docetaxel (75 mg/m2 followed by 100 mg/m2 with escalation if tolerated) and 402 patients received pertuzumab (840 mg loading followed by 420 mg maintenance) and trastuzumab plus docetaxel. Trastuzumab and pertuzumab were dosed for a much longer period, Dr. Swain said, until progressive disease. Chemotherapy was actually administered for a median of eight cycles. After a median follow-up of 50 months, OS was 40.8 months for the arm receiving chemotherapy and trastuzumab and 56.5 months for chemotherapy with both trastuzumab and pertuzumab (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.56–0.84; P = 0.0002). Regarding the OS gain of 15.7 months, Dr. Swain said, “I have never seen that in any other trial of metastatic breast cancer.” Benefits were consistent across all subgroups. “The results, I think, are phenomenal.” An updated PFS analysis showing an improvement of 6.3 months also demonstrated a strong consistency for this The author is a freelance medical writer living in New York City.
874 P&T • ®
December 2014 • Vol. 39 No. 12
measure as a good surrogate for OS, Dr. Swain commented. Adding pertuzumab raised rates of rash, mucositis, and diarrhea, but in general no new safety issues came up. While the potential for increased cardiac toxicity with the two monoclonal antibodies had been a concern, investigators actually observed lower rates of ventricular dysfunction and left ventricular ejection fraction declines of 10% or greater in less than 50% of the group receiving both trastuzumab and pertuzumab. The findings, Dr. Swain concluded, “confirm the pertuzumab regimen as first-line standard of care for patients with HER2-positive metastatic breast cancer.” She added, “Based on the study results and the consistency in the subgroups, I would recommend dual antibody therapy for all patients [with metastatic breast cancer].”
Anamorelin for the Treatment of Cancer AnorexiaCachexia in NSCLC: Results From the Phase 3 Studies Romana 1 and 2
• David Currow, MD, Professor of Palliative and Supportive Services, Flinders University, Adelaide, Australia Cancer anorexia-cachexia syndrome is a common, debilitating condition characterized by decreased body weight (mainly through the loss of lean body mass). It harms quality of life and prognosis. In the ROMANA 1 and 2 clinical trials, anamorelin HCl significantly increased lean body mass and body weight in patients with advanced, unresectable non–small-cell lung cancer and cancer anorexia-cachexia. Anamorelin is a novel selective ghrelin receptor agonist with appetite-enhancing and anabolic activity. Dr. Currow noted that more than 50% of cancer patients develop cachexia, and 30% of cancer deaths are directly related to it. “If you will, it is the final common pathway for most people with advanced cancer and a number of other diseases,” Dr. Currow added. “It is also the leading limiting factor for treating many people as their cancer advances.” In phase 2 reasearch,1 patients receiving anamorelin demonstrated significant mean body-weight gains after 12 weeks, Dr. Currow said. Ghrelin, which is released by the stomach, stimulates multiple pathways that regulate body weight, lean body mass, appetite, and metabolism. ROMANA 1 and 2 were international, double-blind, phase 3 trials, randomizing patients 2:1 to anamorelin 100 mg daily or placebo. The primary endpoints of both trials were lean body mass (measured by dual energy X-ray absorptiometry) and handgrip strength. Cachexia was defined as a weight loss of at least 5% within the prior six months or a body mass index of less than 20 kg/m2. In ROMANA 1, among 484 participants, lean body mass increased a median of 1.10 kg in 12 weeks in those receiving anamorelin (95% CI, 0.76–1.42) and dropped a median of 0.44 kg in those receiving placebo (95% CI, –0.88 to 0.20). Among the 495 patients in ROMANA 2, benefits were similar, with an average lean body mass increase of 0.95 kg for anamorelin (95% CI, 0.51–1.00) and a 0.57-kg loss for placebo (95% CI, –1.27 to –0.46). Differences
Meeting Highlights: European Society of Medical Oncology between anamorelin and placebo were significant in both trials (P < 0.0001). In addition, patient symptoms and concerns regarding anorexia-cachexia improved significantly over 12 weeks. Body weight increased by 2.20 kg and 0.95 kg in ROMANA 1 and 2 with anamorelin, respectively, compared with 0.14 kg and –0.57 kg with placebo (P < 0.001 for both). Hyperglycemia and nausea, the most frequent drug-related adverse events, were easily managed, Dr. Currow said. Benefits were significant for anamorelin in the two trials when considered together or separately. He added that handgrip strength was not improved with anamorelin, but suggested that the trial’s short duration may account for the lack of improvement. Dr. Currow concluded: “Positive results from phase 3 ROMANA 1 and ROMANA 2 demonstrate the potential of anamorelin as an effective treatment for cachexia in cancer patients.”
Afatinib Versus Methotrexate as Second-Line Treatment for Patients With Recurrent and/or Metastatic Head and Neck Squamous-Cell Carcinoma Who Progressed After Platinum-Based Therapy: Primary Efficacy Results of Lux-Head And Neck 1, a Phase 3 Trial
in a phase 3 trial in this setting,” Dr. Machiels concluded. “Afatinib is an active oral agent,” said ESMO discussant Tanguy Seiwert, MD, of the University of Chicago, Illinois, “but given the small effect size, it is hard to see how by itself this trial could lead to clinically meaningful use for patients or approval.” He added that while the PFS increase of 0.9 months with afatinib was of “unclear” significance, better results in patients with no prior EGFR-targeted antibody exposure, age of 65 years or older, and p16 mutation negativity invite work on predictive biomarkers to identify a population with larger effect size and more benefit.
CALM Study: Secondary Endpoints of a Phase 2 Study of a Novel Oncolytic Immunotherapeutic Agent, Coxsackievirus A21, Delivered Intratumorally In Patients With Advanced Malignant Melanoma
• Robert Hans Andtbacka, MD, Associate Professor, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
Subgroup Efficacy in Patients Receiving Rose Bengal to All Existing Melanoma in Phase 2 Study PV-10-MM-02
• Jean Pascal Machiels, MD, Medical Oncologist, Institut Roi Albert II, Cliniques Universitaires St. Luc, Brussels, Belgium
• Sanjiv Agarwala, MD, Chief of Medical Oncology and Hematology, St. Luke’s University Hospital and Health Network, Bethlehem, Pennsylvania
Afatinib is an orally available irreversible blocker of the ErbB family of cell surface receptors. In a phase 3 trial among patients with recurrent or metastatic head and neck squamouscell carcinomas who progressed after first-line platinum-based therapy, afatinib improved the primary endpoint of PFS and delayed deterioration of patient-reported outcomes compared with methotrexate. Patients with recurrent or metastatic head and neck squamous-cell carcinomas who progress after platinum-based therapy have a “dismal” prognosis and no well-defined treatment, said Dr. Machiels, lead investigator of the Lux-Head and Neck 1 trial. He noted that around 90% of squamous-cell carcinomas of the head and neck overexpress epidermal growth factor receptor (EGFR), which is included in the ErbB family. Lux-Head and Neck 1 included 474 patients randomized 2:1 to afatinib 40 mg once daily (n = 316) or methotrexate (40 mg/m2 intravenous weekly, n = 158). Median PFS was 2.6 months in the afatinib group and 1.7 months in the methotrexate group (HR, 0.80; 95% CI, 0.65–0.98; P = 0.030). Patients in the afatinib arm had a significantly delayed worsening of symptoms, such as pain, difficulty swallowing, and global health status (all P ≤ 0.03) compared with methotrexate. Afatinib patients had less pain over time (P = 0.03), with increases in tumor shrinkage, higher response rates, and higher disease control rates than those in the methotrexate arm. OS, however, at 6.8 months for afatinib and 6.0 months for methotrexate, was not significantly improved (P = 0.70). Rash/acne (9.7%) and diarrhea (9.4%) were the most frequent grade 3 or 4 drug-related adverse events with afatinib. In the methotrexate group, leukopenia (15.6%) and stomatitis (8.1%) were most common. “Afatinib is the first oral tyrosine kinase inhibitor to demonstrate efficacy and improved patient-reported outcomes
Research into intralesional therapies for advanced melanoma presented in two posters, one on coxsackievirus a21 (CVA21: CAVATAKTM) and the other on PV-10, revealed positive findings and strong potential both as monotherapies and in combination with systemic immunotherapies. CVA21 is a naturally occurring “common cold” intercellular adhesion molecule-1 (ICAM-1) targeted RNA virus. Surface ICAM-1, Dr. Andtbacka said, is up-regulated on a number of cancers, including melanoma. In animal models, it has been shown that CVA21-lysed tumor cells can induce a secondary systemic host-generated antitumor immune response. CVA21 was tested in CALM (CAVATAK in Late Stage Melanoma), a study including 57 patients (21 female, 36 male) with stage IIIC and IV melanoma. All had at least one injectable dermal, cutaneous, subcutaneous, or lymph node lesion. They received 10 series of multi-intratumoral CVA21 injections. The CALM primary endpoint, immune-related progressionfree survival (irPFS), was calculated as the proportion of patients demonstrating a complete response, partial response, or stable disease by immune-related RECIST 1.1 criteria six months after the initiation of treatment. Dr. Andtbacka said investigators had hoped that at least 10 patients would reach that milestone, but to date 22 patients have achieved irPFS, for a rate of 38.6% (22 of 57). The secondary endpoint of objective response rate (complete response plus partial response, irRECIST 1.1) was 28.1% (16 of 57). Median time to response was 2.8 months, and the one-year survival rate was 73.3% (33 of 45 patients). Tumor responses were observed in both injected lesions and noninjected lesions, noninjected visceral lesions at times of high levels of anti-CVA21 neutralizing antibody, and in the absence of circulating infectious CVA21. CVA21 given as multidose intralesional therapy was generally well tolerated. No
Vol. 39 No. 12 • December 2014 • P&T 875 ®
Meeting Highlights: ESMO grade 3 or 4 treatment-related adverse events were reported. Were the responses immune-related, or was the CVA21 virus entering the tumor and causing the responses? Investigators were aware that 85% or more of patients do not have neutralizing antibodies to CVA21. “But we found out that after the fifth injection, around day 22, virtually all patients had developed neutralizing antibodies,” Dr. Andtbacka said. “Yet even in the presence of these neutralizing antibodies, we saw objective responses—indicating to us that the response is likely immune-mediated rather than caused by the virus itself. So this is very encouraging data that sets us up nicely for combination studies and neoadjuvant protocols and also other monotherapy studies.” Further clinical evaluations of CVA21 are warranted in combination with other immunotherapeutic agents, such as immune checkpoint inhibitors with anti-CTLA-4 or anti-PD-1 or targeted small molecules (i.e., BRAF and MEK kinase inhibitors), Dr. Andtbacka said. A report on the subset of patients in the phase 2 trial of intralesional PV-10 who had all of their cutaneous melanoma lesions injected with PV-10 revealed that response rates were high and that responses occurred quickly in most patients. “The finding,” Dr. Agarwala said, “has really helped us toward finalizing our phase 3 trial design.” In the original trial of 80 patients, some had a portion of lesions left untreated as “bystander lesions.” The response rate in this group was 23% (CI, 9–44%), and the complete response rate for the full population of 80 patients was 26%, with an objective response (complete plus partial response) of 51% (CI, 40–63%). The complete response rate among 28 patients in the alllesions-treated group was 50% (CI, 31–70%), and the objective response rate was 71% (CI, 51–87%). Patients had a median of eight study lesions (range, one to 22), with a time to response of 1.8 months. The partial response rate in the all-lesions-treated group was 21%, with stable disease in 11%. An analysis by lesion showed that among 232 complete responses in 363 lesions (64%) in the all-lesions-treated group, 121 were observed after one injection, 84 after two injections, 22 after three injections, and five after four injections. PFS in the all-lesions-treated group was 9.8 months. In the uninjected bystander lesion group, PFS was 8.9 months. The finding of such rapid responses, Dr. Agarwala said in an interview, showed that PV-10 responses had occurred already in a period where chemotherapy responses are not expected. “We should see a difference very quickly between PV-10 and chemotherapy responses.” Based on these data, investigators will treat all lesions in the phase 3 trial, and include only BRAF wild-type patients (who do not respond to BRAF inhibitors) and those who have become refractory to systemic immunotherapy or are not candidates because of advanced age or comorbidities. Planned enrollment for the phase 3 trial is 219 patients with locoregional disease only. They will be randomized 2:1 to intra lesional PV-10 or systemic chemotherapy with dacarbazine or temozolomide. Dr. Agarwala noted that about a third of melanoma patients are diagnosed with predominantly locoregional disease.
REFERENCE 1.
Temel JB, et al. Efficacy and safety of anamorelin HCl in NSCLC patients: results from a randomized, double-blind, placebo-controlled, multicenter phase II study. Presentation at the European Cancer Congress, Amsterdam, Netherlands, September 27–October 1, 2013. Abstract 1308. Abstract published in Eur J Cancer 2013;49(suppl 2). n
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