2012 ASCO Annual Meeting

CHICAGO – Vemurafenib has a persistent survival benefit when given as first-line therapy for advanced BRAF-mutant melanoma, but the magnitude of benefit diminishes over time, according to an update of the BRIM-3 randomized trial.

With a median follow-up of about a year, vemurafenib was associated with a 30% relative reduction in the risk of death, relative to dacarbazine, presenting author Dr. Paul Chapman reported at the annual meeting of the American Society of Clinical Oncology. This is roughly half of the 63% relative risk reduction seen at a median follow-up of about 3 months, as reported at last year’s meeting.

The safety profile of vemurafenib was largely consistent with the earlier experience; the main high-grade adverse effects were skin toxicity (seen in about a third of patients) and liver toxicity (seen in about a tenth). But a few patients have developed second primary melanomas.

The observed temporal trend for overall survival benefit suggests "perhaps that most of the benefit in overall survival may be due to decreasing early deaths," said Dr. Chapman, an oncologist at Memorial Sloan-Kettering Cancer Center in New York.

Discussant Dr. Michael B. Atkins of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington maintained that "the mature overall survival data [confirm] that vemurafenib is better than dacarbazine," and noted that it was "reassuring" that findings were similar, whether patients who crossed over to the vemurafenib arm were censored or not, "probably the most stringent test of survival."

However, he called attention to the fact that the median survival of 13-plus months with vemurafenib seen in BRIM-3 falls short of the 16-plus months seen in BRIM-2, a phase II trial in patients with previously treated advanced melanoma. "Did first-line patients have more aggressive disease and therefore fall off early?" he wondered. "Alternatively, was there less continuation of vemurafenib after progressive disease in the BRIM-3 trial relative to the BRIM-2 trial? If that was the case, some sort of confirmatory analysis should be done to see whether that can impact overall survival."

The decrease in vemurafenib efficacy seen over time might have several explanations, Dr. Atkins proposed. "Is it that the early, more robust hazard ratio was a manifestation of the so-called Lazarus effect, that these targeted therapies can cause patients who are really in bad shape and would have a short survival to have their survival prolonged, even though it was less than the survival of patients with less-aggressive tumors?" he wondered, echoing Dr. Chapman’s suggestion. Alternatively, maturation of the survival data might have contributed to the change in efficacy in patients with stage IIIC, M1a, and M1b disease who did not appear to benefit from vemurafenib.

In the larger context, the findings raise an important question pertaining to the clinical trials process generally, according to Dr. Atkins: "What does this say about the early analysis of trials like this, and reporting forever more that the hazard ratio is 0.35 or so, rather than what the more accurate 0.70 is?"

A Genentech spokesperson said that "due to differences in the study populations and trial designs, the results from these trials cannot be directly compared. BRIM3 was a global, randomized, Phase III trial comparing Zelboraf (vemurafenib) to DTIC chemotherapy in people with newly diagnosed BRAF V600 mutation-positive metastatic melanoma, while BRIM2 was a Phase II study that evaluated patients with previously treated disease."

The 675 patients in BRIM-3 had stage IIIC or IV melanoma harboring the BRAF V600E mutation. They were assigned evenly to intravenous dacarbazine or oral vemurafenib, the only targeted agent approved specifically for treating BRAF-mutant melanoma.

Large proportions of patients in both the vemurafenib and dacarbazine arms (36% and 44%, respectively) received other anticancer therapies after coming off the trial, Dr. Chapman reported. About a fifth of all patients in each arm went on to receive ipilimumab, and a fourth in the dacarbazine arm crossed over to vemurafenib.

Updated results – after a median follow-up of 9.5 months in the dacarbazine arm and 12.5 months in the vemurafenib arm – showed persistence of a progression-free survival benefit in favor of vemurafenib with censoring of patients at crossover (6.9 vs. 1.6 months; hazard ratio, 0.38; P less than .001).

There was also still an improvement in overall survival, regardless of whether patients were censored at crossover (13.6 vs. 9.7 months; HR, 0.70; P less than .001) or not (13.6 vs. 10.3 months; HR, 0.76; P less than .01).

The leading grade 3 or worse adverse events with vemurafenib remained cutaneous squamous cell carcinomas (seen in 19% of patients), keratoacanthomas (10%), and elevations of liver function tests (10%). In addition, eight patients developed new primary melanomas.

Dr. Chapman disclosed that he receives honoraria and research funding from Roche/Genentech. The trial was sponsored by Hoffman-LaRoche. Dr. Atkins disclosed that he is a consultant to Bristol-Myers Squibb, Celgene, Curetech, Genentech, Merck, Novartis, and Prometheus.

This article was updated on July 3, 2012.

CHICAGO – Vemurafenib has a persistent survival benefit when given as first-line therapy for advanced BRAF-mutant melanoma, but the magnitude of benefit diminishes over time, according to an update of the BRIM-3 randomized trial.

With a median follow-up of about a year, vemurafenib was associated with a 30% relative reduction in the risk of death, relative to dacarbazine, presenting author Dr. Paul Chapman reported at the annual meeting of the American Society of Clinical Oncology. This is roughly half of the 63% relative risk reduction seen at a median follow-up of about 3 months, as reported at last year’s meeting.

The safety profile of vemurafenib was largely consistent with the earlier experience; the main high-grade adverse effects were skin toxicity (seen in about a third of patients) and liver toxicity (seen in about a tenth). But a few patients have developed second primary melanomas.

The observed temporal trend for overall survival benefit suggests "perhaps that most of the benefit in overall survival may be due to decreasing early deaths," said Dr. Chapman, an oncologist at Memorial Sloan-Kettering Cancer Center in New York.

Discussant Dr. Michael B. Atkins of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington maintained that "the mature overall survival data [confirm] that vemurafenib is better than dacarbazine," and noted that it was "reassuring" that findings were similar, whether patients who crossed over to the vemurafenib arm were censored or not, "probably the most stringent test of survival."

However, he called attention to the fact that the median survival of 13-plus months with vemurafenib seen in BRIM-3 falls short of the 16-plus months seen in BRIM-2, a phase II trial in patients with previously treated advanced melanoma. "Did first-line patients have more aggressive disease and therefore fall off early?" he wondered. "Alternatively, was there less continuation of vemurafenib after progressive disease in the BRIM-3 trial relative to the BRIM-2 trial? If that was the case, some sort of confirmatory analysis should be done to see whether that can impact overall survival."

The decrease in vemurafenib efficacy seen over time might have several explanations, Dr. Atkins proposed. "Is it that the early, more robust hazard ratio was a manifestation of the so-called Lazarus effect, that these targeted therapies can cause patients who are really in bad shape and would have a short survival to have their survival prolonged, even though it was less than the survival of patients with less-aggressive tumors?" he wondered, echoing Dr. Chapman’s suggestion. Alternatively, maturation of the survival data might have contributed to the change in efficacy in patients with stage IIIC, M1a, and M1b disease who did not appear to benefit from vemurafenib.

In the larger context, the findings raise an important question pertaining to the clinical trials process generally, according to Dr. Atkins: "What does this say about the early analysis of trials like this, and reporting forever more that the hazard ratio is 0.35 or so, rather than what the more accurate 0.70 is?"

A Genentech spokesperson said that "due to differences in the study populations and trial designs, the results from these trials cannot be directly compared. BRIM3 was a global, randomized, Phase III trial comparing Zelboraf (vemurafenib) to DTIC chemotherapy in people with newly diagnosed BRAF V600 mutation-positive metastatic melanoma, while BRIM2 was a Phase II study that evaluated patients with previously treated disease."

The 675 patients in BRIM-3 had stage IIIC or IV melanoma harboring the BRAF V600E mutation. They were assigned evenly to intravenous dacarbazine or oral vemurafenib, the only targeted agent approved specifically for treating BRAF-mutant melanoma.

Large proportions of patients in both the vemurafenib and dacarbazine arms (36% and 44%, respectively) received other anticancer therapies after coming off the trial, Dr. Chapman reported. About a fifth of all patients in each arm went on to receive ipilimumab, and a fourth in the dacarbazine arm crossed over to vemurafenib.

Updated results – after a median follow-up of 9.5 months in the dacarbazine arm and 12.5 months in the vemurafenib arm – showed persistence of a progression-free survival benefit in favor of vemurafenib with censoring of patients at crossover (6.9 vs. 1.6 months; hazard ratio, 0.38; P less than .001).

There was also still an improvement in overall survival, regardless of whether patients were censored at crossover (13.6 vs. 9.7 months; HR, 0.70; P less than .001) or not (13.6 vs. 10.3 months; HR, 0.76; P less than .01).

The leading grade 3 or worse adverse events with vemurafenib remained cutaneous squamous cell carcinomas (seen in 19% of patients), keratoacanthomas (10%), and elevations of liver function tests (10%). In addition, eight patients developed new primary melanomas.

Dr. Chapman disclosed that he receives honoraria and research funding from Roche/Genentech. The trial was sponsored by Hoffman-LaRoche. Dr. Atkins disclosed that he is a consultant to Bristol-Myers Squibb, Celgene, Curetech, Genentech, Merck, Novartis, and Prometheus.

This article was updated on July 3, 2012.

CHICAGO – Vemurafenib has a persistent survival benefit when given as first-line therapy for advanced BRAF-mutant melanoma, but the magnitude of benefit diminishes over time, according to an update of the BRIM-3 randomized trial.

With a median follow-up of about a year, vemurafenib was associated with a 30% relative reduction in the risk of death, relative to dacarbazine, presenting author Dr. Paul Chapman reported at the annual meeting of the American Society of Clinical Oncology. This is roughly half of the 63% relative risk reduction seen at a median follow-up of about 3 months, as reported at last year’s meeting.

The safety profile of vemurafenib was largely consistent with the earlier experience; the main high-grade adverse effects were skin toxicity (seen in about a third of patients) and liver toxicity (seen in about a tenth). But a few patients have developed second primary melanomas.

The observed temporal trend for overall survival benefit suggests "perhaps that most of the benefit in overall survival may be due to decreasing early deaths," said Dr. Chapman, an oncologist at Memorial Sloan-Kettering Cancer Center in New York.

Discussant Dr. Michael B. Atkins of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington maintained that "the mature overall survival data [confirm] that vemurafenib is better than dacarbazine," and noted that it was "reassuring" that findings were similar, whether patients who crossed over to the vemurafenib arm were censored or not, "probably the most stringent test of survival."

However, he called attention to the fact that the median survival of 13-plus months with vemurafenib seen in BRIM-3 falls short of the 16-plus months seen in BRIM-2, a phase II trial in patients with previously treated advanced melanoma. "Did first-line patients have more aggressive disease and therefore fall off early?" he wondered. "Alternatively, was there less continuation of vemurafenib after progressive disease in the BRIM-3 trial relative to the BRIM-2 trial? If that was the case, some sort of confirmatory analysis should be done to see whether that can impact overall survival."

The decrease in vemurafenib efficacy seen over time might have several explanations, Dr. Atkins proposed. "Is it that the early, more robust hazard ratio was a manifestation of the so-called Lazarus effect, that these targeted therapies can cause patients who are really in bad shape and would have a short survival to have their survival prolonged, even though it was less than the survival of patients with less-aggressive tumors?" he wondered, echoing Dr. Chapman’s suggestion. Alternatively, maturation of the survival data might have contributed to the change in efficacy in patients with stage IIIC, M1a, and M1b disease who did not appear to benefit from vemurafenib.

In the larger context, the findings raise an important question pertaining to the clinical trials process generally, according to Dr. Atkins: "What does this say about the early analysis of trials like this, and reporting forever more that the hazard ratio is 0.35 or so, rather than what the more accurate 0.70 is?"

A Genentech spokesperson said that "due to differences in the study populations and trial designs, the results from these trials cannot be directly compared. BRIM3 was a global, randomized, Phase III trial comparing Zelboraf (vemurafenib) to DTIC chemotherapy in people with newly diagnosed BRAF V600 mutation-positive metastatic melanoma, while BRIM2 was a Phase II study that evaluated patients with previously treated disease."

The 675 patients in BRIM-3 had stage IIIC or IV melanoma harboring the BRAF V600E mutation. They were assigned evenly to intravenous dacarbazine or oral vemurafenib, the only targeted agent approved specifically for treating BRAF-mutant melanoma.

Large proportions of patients in both the vemurafenib and dacarbazine arms (36% and 44%, respectively) received other anticancer therapies after coming off the trial, Dr. Chapman reported. About a fifth of all patients in each arm went on to receive ipilimumab, and a fourth in the dacarbazine arm crossed over to vemurafenib.

Updated results – after a median follow-up of 9.5 months in the dacarbazine arm and 12.5 months in the vemurafenib arm – showed persistence of a progression-free survival benefit in favor of vemurafenib with censoring of patients at crossover (6.9 vs. 1.6 months; hazard ratio, 0.38; P less than .001).

There was also still an improvement in overall survival, regardless of whether patients were censored at crossover (13.6 vs. 9.7 months; HR, 0.70; P less than .001) or not (13.6 vs. 10.3 months; HR, 0.76; P less than .01).

The leading grade 3 or worse adverse events with vemurafenib remained cutaneous squamous cell carcinomas (seen in 19% of patients), keratoacanthomas (10%), and elevations of liver function tests (10%). In addition, eight patients developed new primary melanomas.

Dr. Chapman disclosed that he receives honoraria and research funding from Roche/Genentech. The trial was sponsored by Hoffman-LaRoche. Dr. Atkins disclosed that he is a consultant to Bristol-Myers Squibb, Celgene, Curetech, Genentech, Merck, Novartis, and Prometheus.

This article was updated on July 3, 2012.

CHICAGO – Patients with good-risk acute myeloid leukemia might benefit from a combination of azacitidine and gemtuzumab followed by azacitidine maintenance – if gemtuzumab were available in the United States.

The combination produced a 44% complete remission (CR) rate in 79 patients aged 60-69 years with acute myeloid leukemia (AML) or a Zubrod performance score of 0 or 1, reported investigators from the Southwest Oncology Group (SWOG) at the annual meeting of the American Society of Clinical Oncology

Median overall survival was 11 months and median relapse-free survival was 8 months among patients who achieved a CR or CR with complete remission in marrow but without recovery of neutrophil or platelet counts (CRi), said Dr. Sucha Nand, professor of medicine at Loyola University in Maywood, Ill.

The induction regimen is safe enough to be provided in an outpatient setting, noted Dr. Nand, who presented the data on behalf of coinvestigators in the Southwest Oncology Group (SWOG) S0703 protocol.

"In our opinion, these results are sufficiently encouraging to warrant further studies of this approach. Continuation of azacitidine therapy after completion of this regimen may prove to be of additional benefit," he said.

The problem is that gemtuzumab ozogamicin (Mylotarg) is no longer on the market, having been voluntarily withdrawn by Pfizer in 2010 after questions arose about its efficacy and safety.

"If gemtuzumab were suddenly to become available, I think this is a reasonable treatment regimen," commented Dr. Bruno Medeiros of Stanford (Calif.) University, the invited discussant.

The combination of gemtuzumab and azacitidine (Vidaza) produces CR rates, response duration, and survival similar to that of other AML regimens, with a lower incidence of early death and manageable toxicities that allow it to be delivered in an outpatient setting, said Dr. Medeiros.

Age has a significant effect on outcomes in patients with AML, with the proportion of patients in one study (Blood 2006;107:3481-5) who achieved a complete response to therapy declining from 65% for patients under age 56 years, to 33% for those older than 75 years. In the same study, the proportion of patients who died within 30 days of study entry rose from 2.7% of the youngest patients, to 31.6% of the oldest, Dr. Nand noted.

The SWOG investigators examined the combination to see whether previously untreated patients with non-M3 (acute promyelocytic leukemia) AML with a favorable risk factor profile could benefit in terms of the safety profile, efficacy, or both.

Patients with high white blood cell counts (10,000 mcL of higher) were pretreated with hydroxyurea 1,500 mg orally twice day, then started on induction with azacitidine 75 mg.m² subcutaneously or intravenously on days 1-7, followed by gemtuzumab 3 mg/m² on day 8. The induction regimen was repeated if bone marrow showed residual leukemia on day 14.

Patients then underwent consolidation with one treatment of azacitidine and gemtuzumab in the same doses, followed by azacitidine maintenance given every 28 days for up to four cycles.

Of the 79 patients available for evaluation, 75 completed planned treatment. One patient died, one discontinued because of toxicities, and two discontinued for reasons not related to the protocol.

A total of 35 patients achieved either a CR or a CRi, 1 had a partial response, 40 had resistant disease, and 1 had inadequate data for assessment.

Two patients had complete responses that occurred after being removed from the study on day 28 for residual disease. Both of these patients had had significant reduction in marrow blast count, and were continued on azacitidine alone.

At a median of 8.3 months follow-up, 35 patients remained relapse free. At a median of 11 months follow-up, 53 of the 79 patients had died.

The study was supported by the National Institutes of Health. Dr. Nand disclosed ties with Celgene. Dr. Medeiros disclosed ties with Millennium, Celgene, and Novartis.

CHICAGO – Patients with good-risk acute myeloid leukemia might benefit from a combination of azacitidine and gemtuzumab followed by azacitidine maintenance – if gemtuzumab were available in the United States.

The combination produced a 44% complete remission (CR) rate in 79 patients aged 60-69 years with acute myeloid leukemia (AML) or a Zubrod performance score of 0 or 1, reported investigators from the Southwest Oncology Group (SWOG) at the annual meeting of the American Society of Clinical Oncology

Median overall survival was 11 months and median relapse-free survival was 8 months among patients who achieved a CR or CR with complete remission in marrow but without recovery of neutrophil or platelet counts (CRi), said Dr. Sucha Nand, professor of medicine at Loyola University in Maywood, Ill.

The induction regimen is safe enough to be provided in an outpatient setting, noted Dr. Nand, who presented the data on behalf of coinvestigators in the Southwest Oncology Group (SWOG) S0703 protocol.

"In our opinion, these results are sufficiently encouraging to warrant further studies of this approach. Continuation of azacitidine therapy after completion of this regimen may prove to be of additional benefit," he said.

The problem is that gemtuzumab ozogamicin (Mylotarg) is no longer on the market, having been voluntarily withdrawn by Pfizer in 2010 after questions arose about its efficacy and safety.

"If gemtuzumab were suddenly to become available, I think this is a reasonable treatment regimen," commented Dr. Bruno Medeiros of Stanford (Calif.) University, the invited discussant.

The combination of gemtuzumab and azacitidine (Vidaza) produces CR rates, response duration, and survival similar to that of other AML regimens, with a lower incidence of early death and manageable toxicities that allow it to be delivered in an outpatient setting, said Dr. Medeiros.

Age has a significant effect on outcomes in patients with AML, with the proportion of patients in one study (Blood 2006;107:3481-5) who achieved a complete response to therapy declining from 65% for patients under age 56 years, to 33% for those older than 75 years. In the same study, the proportion of patients who died within 30 days of study entry rose from 2.7% of the youngest patients, to 31.6% of the oldest, Dr. Nand noted.

The SWOG investigators examined the combination to see whether previously untreated patients with non-M3 (acute promyelocytic leukemia) AML with a favorable risk factor profile could benefit in terms of the safety profile, efficacy, or both.

Patients with high white blood cell counts (10,000 mcL of higher) were pretreated with hydroxyurea 1,500 mg orally twice day, then started on induction with azacitidine 75 mg.m² subcutaneously or intravenously on days 1-7, followed by gemtuzumab 3 mg/m² on day 8. The induction regimen was repeated if bone marrow showed residual leukemia on day 14.

Patients then underwent consolidation with one treatment of azacitidine and gemtuzumab in the same doses, followed by azacitidine maintenance given every 28 days for up to four cycles.

Of the 79 patients available for evaluation, 75 completed planned treatment. One patient died, one discontinued because of toxicities, and two discontinued for reasons not related to the protocol.

A total of 35 patients achieved either a CR or a CRi, 1 had a partial response, 40 had resistant disease, and 1 had inadequate data for assessment.

Two patients had complete responses that occurred after being removed from the study on day 28 for residual disease. Both of these patients had had significant reduction in marrow blast count, and were continued on azacitidine alone.

At a median of 8.3 months follow-up, 35 patients remained relapse free. At a median of 11 months follow-up, 53 of the 79 patients had died.

The study was supported by the National Institutes of Health. Dr. Nand disclosed ties with Celgene. Dr. Medeiros disclosed ties with Millennium, Celgene, and Novartis.

CHICAGO – Patients with good-risk acute myeloid leukemia might benefit from a combination of azacitidine and gemtuzumab followed by azacitidine maintenance – if gemtuzumab were available in the United States.

The combination produced a 44% complete remission (CR) rate in 79 patients aged 60-69 years with acute myeloid leukemia (AML) or a Zubrod performance score of 0 or 1, reported investigators from the Southwest Oncology Group (SWOG) at the annual meeting of the American Society of Clinical Oncology

Median overall survival was 11 months and median relapse-free survival was 8 months among patients who achieved a CR or CR with complete remission in marrow but without recovery of neutrophil or platelet counts (CRi), said Dr. Sucha Nand, professor of medicine at Loyola University in Maywood, Ill.

The induction regimen is safe enough to be provided in an outpatient setting, noted Dr. Nand, who presented the data on behalf of coinvestigators in the Southwest Oncology Group (SWOG) S0703 protocol.

"In our opinion, these results are sufficiently encouraging to warrant further studies of this approach. Continuation of azacitidine therapy after completion of this regimen may prove to be of additional benefit," he said.

The problem is that gemtuzumab ozogamicin (Mylotarg) is no longer on the market, having been voluntarily withdrawn by Pfizer in 2010 after questions arose about its efficacy and safety.

"If gemtuzumab were suddenly to become available, I think this is a reasonable treatment regimen," commented Dr. Bruno Medeiros of Stanford (Calif.) University, the invited discussant.

The combination of gemtuzumab and azacitidine (Vidaza) produces CR rates, response duration, and survival similar to that of other AML regimens, with a lower incidence of early death and manageable toxicities that allow it to be delivered in an outpatient setting, said Dr. Medeiros.

Age has a significant effect on outcomes in patients with AML, with the proportion of patients in one study (Blood 2006;107:3481-5) who achieved a complete response to therapy declining from 65% for patients under age 56 years, to 33% for those older than 75 years. In the same study, the proportion of patients who died within 30 days of study entry rose from 2.7% of the youngest patients, to 31.6% of the oldest, Dr. Nand noted.

The SWOG investigators examined the combination to see whether previously untreated patients with non-M3 (acute promyelocytic leukemia) AML with a favorable risk factor profile could benefit in terms of the safety profile, efficacy, or both.

Patients with high white blood cell counts (10,000 mcL of higher) were pretreated with hydroxyurea 1,500 mg orally twice day, then started on induction with azacitidine 75 mg.m² subcutaneously or intravenously on days 1-7, followed by gemtuzumab 3 mg/m² on day 8. The induction regimen was repeated if bone marrow showed residual leukemia on day 14.

Patients then underwent consolidation with one treatment of azacitidine and gemtuzumab in the same doses, followed by azacitidine maintenance given every 28 days for up to four cycles.

Of the 79 patients available for evaluation, 75 completed planned treatment. One patient died, one discontinued because of toxicities, and two discontinued for reasons not related to the protocol.

A total of 35 patients achieved either a CR or a CRi, 1 had a partial response, 40 had resistant disease, and 1 had inadequate data for assessment.

Two patients had complete responses that occurred after being removed from the study on day 28 for residual disease. Both of these patients had had significant reduction in marrow blast count, and were continued on azacitidine alone.

At a median of 8.3 months follow-up, 35 patients remained relapse free. At a median of 11 months follow-up, 53 of the 79 patients had died.

The study was supported by the National Institutes of Health. Dr. Nand disclosed ties with Celgene. Dr. Medeiros disclosed ties with Millennium, Celgene, and Novartis.

CHICAGO – The experimental immunotherapeutic anti-PD-1 agent known as BMS-936558 appears active in non–small cell lung cancer, a malignancy notoriously resistant to immunotherapy.

Among 76 evaluable patients with advanced NSCLC who were enrolled in a multidose phase I trial, 14 patients (18%) had a response. The progression-free survival rate at 24 weeks was 26%.

Patrice Wendling/IMNG Medical Media

The responses were durable, lasting anywhere from 2 to 21 months, Dr. Julie R. Brahmer, an oncologist at Johns Hopkins Hospital in Baltimore, reported at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a fully human IgG4 antibody that blocks the programmed death–1 (PD-1) protein. PD-1 is highly expressed by regulatory T cells and tumor-infiltrating lymphocytes in many tumor types, and plays a key role – along with one of its ligands, PD-L1 – in the ability of tumor cells to evade the host’s immune system. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response, Dr. Brahmer noted.

When responses to BMS-936558 were evaluated by histology, the overall response rate was 33% (6 of 18) in patients with squamous histology, and 12.5% (7 of 56) in those with nonsquamous histology.

"Both of these responses are higher than the drugs we have for patients who fail chemotherapy," said discussant Dr. Giuseppe Giaccone of the Medical Oncology Branch at the National Cancer Institute. Moreover, there are no effective targeted agents for NSCLC patients with squamous cell histology.

He pointed out that tumor-infiltrating lymphocytes were associated with better survival in squamous cell carcinomas in a large retrospective analysis of patients with resected lung neoplasms (Ann. Thorac. Surg. 2009;87:365-71), suggesting that there are differences in immunogenicity and that squamous cell histology might be more immunogenic than other types.

Dr. Giaccone went on to highlight a recent phase II study reporting that first-line treatment with another immunomodulatory agent, ipilimumab (Yervoy), added in a phased fashion with paclitaxel (Taxol) and carboplatin chemotherapy, was superior to paclitaxel and carboplatin plus placebo in chemotherapy-naive patients with advanced NSCLC (J. Clin. Oncol. 2012;30:2046-54). Survival was much higher in patients with squamous cell vs. nonsquamous histology, which again suggested a difference between the two types with regard to immunogenicity.

Patients in the current phase I trial with advanced NSCLC and other solid tumors that had progressed after one to five systemic therapies received intravenous BMS-936558 at varying doses until disease progression or clinical deterioration or unacceptable toxicity. Patients who responded or had stable disease, or who had progressive disease but were clinically stable, were treated until they achieved a complete response, worsening progressive disease, or unacceptable toxicity for up to 12 cycles (96 weeks).

In all, 122 patients with NSCLC were evaluable for safety and 76 for clinical activity. At baseline, 60% of the 122 patients had nonsquamous histology, 96% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and 55% had received at least three prior therapies including platinum-based chemotherapy in 94%, tyrosine-kinase inhibitors in 34%, and radiotherapy in 33%.

The overall response rate was 18% in the 39 patients who were enrolled at the 10-mg/kg dose of BMS-93558, 32% in 19 patients who were given the 3-mg/kg dose, and 6% in 18 patients given the 1-mg/kg dose. The percentage of patients who were free of progression at 24 weeks was 24%, 41%, and 16%, respectively, Dr. Brahmer reported. Three NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions, but were not classified as responders for the overall response rate.

Serious adverse events occurred in 14% of the 296 patients in the entire cohort, according to Dr. Suzanne L. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore, who presented the results of the main study at the ASCO meeting.

Grade 3/4 adverse events occurred in 10 patients (8%) with NSCLC. There were three drug-related deaths in the study resulting from pneumonitis in two patients with NSCLC and one patient with colorectal cancer, said Dr. Brahmer, who presented the results for patients with NSCLC in a separate session. Investigators saw no apparent relationship between drug dose and adverse event frequency in all treated patients or NSCLC patients.

Dr. Giaccone said the severe pneumonitis was worrisome, but that there is no comparison between the toxicity of BMS-936558 and ipilimumab.

"These represent similar mechanisms, but the side effects are clearly lower with the PD-1 compound," he said, adding that randomized studies will be needed to prove that BMS-936558 is better than the standard of care.

Clinical registration trials of BMS-936558 in patients with NSCLC are planned, Dr. Brahmer said. Recruitment is already underway for a multiarm study of BMS-936558 in combination with three platinum-based doublet chemotherapy regimens in treatment-naïve, stage IIIB/IV NSCLC.

Bristol-Myers Squibb sponsored the study. Dr. Brahmer and Dr. Giaccone report no relevant disclosures.

CHICAGO – The experimental immunotherapeutic anti-PD-1 agent known as BMS-936558 appears active in non–small cell lung cancer, a malignancy notoriously resistant to immunotherapy.

Among 76 evaluable patients with advanced NSCLC who were enrolled in a multidose phase I trial, 14 patients (18%) had a response. The progression-free survival rate at 24 weeks was 26%.

Patrice Wendling/IMNG Medical Media

The responses were durable, lasting anywhere from 2 to 21 months, Dr. Julie R. Brahmer, an oncologist at Johns Hopkins Hospital in Baltimore, reported at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a fully human IgG4 antibody that blocks the programmed death–1 (PD-1) protein. PD-1 is highly expressed by regulatory T cells and tumor-infiltrating lymphocytes in many tumor types, and plays a key role – along with one of its ligands, PD-L1 – in the ability of tumor cells to evade the host’s immune system. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response, Dr. Brahmer noted.

When responses to BMS-936558 were evaluated by histology, the overall response rate was 33% (6 of 18) in patients with squamous histology, and 12.5% (7 of 56) in those with nonsquamous histology.

"Both of these responses are higher than the drugs we have for patients who fail chemotherapy," said discussant Dr. Giuseppe Giaccone of the Medical Oncology Branch at the National Cancer Institute. Moreover, there are no effective targeted agents for NSCLC patients with squamous cell histology.

He pointed out that tumor-infiltrating lymphocytes were associated with better survival in squamous cell carcinomas in a large retrospective analysis of patients with resected lung neoplasms (Ann. Thorac. Surg. 2009;87:365-71), suggesting that there are differences in immunogenicity and that squamous cell histology might be more immunogenic than other types.

Dr. Giaccone went on to highlight a recent phase II study reporting that first-line treatment with another immunomodulatory agent, ipilimumab (Yervoy), added in a phased fashion with paclitaxel (Taxol) and carboplatin chemotherapy, was superior to paclitaxel and carboplatin plus placebo in chemotherapy-naive patients with advanced NSCLC (J. Clin. Oncol. 2012;30:2046-54). Survival was much higher in patients with squamous cell vs. nonsquamous histology, which again suggested a difference between the two types with regard to immunogenicity.

Patients in the current phase I trial with advanced NSCLC and other solid tumors that had progressed after one to five systemic therapies received intravenous BMS-936558 at varying doses until disease progression or clinical deterioration or unacceptable toxicity. Patients who responded or had stable disease, or who had progressive disease but were clinically stable, were treated until they achieved a complete response, worsening progressive disease, or unacceptable toxicity for up to 12 cycles (96 weeks).

In all, 122 patients with NSCLC were evaluable for safety and 76 for clinical activity. At baseline, 60% of the 122 patients had nonsquamous histology, 96% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and 55% had received at least three prior therapies including platinum-based chemotherapy in 94%, tyrosine-kinase inhibitors in 34%, and radiotherapy in 33%.

The overall response rate was 18% in the 39 patients who were enrolled at the 10-mg/kg dose of BMS-93558, 32% in 19 patients who were given the 3-mg/kg dose, and 6% in 18 patients given the 1-mg/kg dose. The percentage of patients who were free of progression at 24 weeks was 24%, 41%, and 16%, respectively, Dr. Brahmer reported. Three NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions, but were not classified as responders for the overall response rate.

Serious adverse events occurred in 14% of the 296 patients in the entire cohort, according to Dr. Suzanne L. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore, who presented the results of the main study at the ASCO meeting.

Grade 3/4 adverse events occurred in 10 patients (8%) with NSCLC. There were three drug-related deaths in the study resulting from pneumonitis in two patients with NSCLC and one patient with colorectal cancer, said Dr. Brahmer, who presented the results for patients with NSCLC in a separate session. Investigators saw no apparent relationship between drug dose and adverse event frequency in all treated patients or NSCLC patients.

Dr. Giaccone said the severe pneumonitis was worrisome, but that there is no comparison between the toxicity of BMS-936558 and ipilimumab.

"These represent similar mechanisms, but the side effects are clearly lower with the PD-1 compound," he said, adding that randomized studies will be needed to prove that BMS-936558 is better than the standard of care.

Clinical registration trials of BMS-936558 in patients with NSCLC are planned, Dr. Brahmer said. Recruitment is already underway for a multiarm study of BMS-936558 in combination with three platinum-based doublet chemotherapy regimens in treatment-naïve, stage IIIB/IV NSCLC.

Bristol-Myers Squibb sponsored the study. Dr. Brahmer and Dr. Giaccone report no relevant disclosures.

CHICAGO – The experimental immunotherapeutic anti-PD-1 agent known as BMS-936558 appears active in non–small cell lung cancer, a malignancy notoriously resistant to immunotherapy.

Among 76 evaluable patients with advanced NSCLC who were enrolled in a multidose phase I trial, 14 patients (18%) had a response. The progression-free survival rate at 24 weeks was 26%.

Patrice Wendling/IMNG Medical Media

The responses were durable, lasting anywhere from 2 to 21 months, Dr. Julie R. Brahmer, an oncologist at Johns Hopkins Hospital in Baltimore, reported at the annual meeting of the American Society of Clinical Oncology.

BMS-936558 is a fully human IgG4 antibody that blocks the programmed death–1 (PD-1) protein. PD-1 is highly expressed by regulatory T cells and tumor-infiltrating lymphocytes in many tumor types, and plays a key role – along with one of its ligands, PD-L1 – in the ability of tumor cells to evade the host’s immune system. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response, Dr. Brahmer noted.

When responses to BMS-936558 were evaluated by histology, the overall response rate was 33% (6 of 18) in patients with squamous histology, and 12.5% (7 of 56) in those with nonsquamous histology.

"Both of these responses are higher than the drugs we have for patients who fail chemotherapy," said discussant Dr. Giuseppe Giaccone of the Medical Oncology Branch at the National Cancer Institute. Moreover, there are no effective targeted agents for NSCLC patients with squamous cell histology.

He pointed out that tumor-infiltrating lymphocytes were associated with better survival in squamous cell carcinomas in a large retrospective analysis of patients with resected lung neoplasms (Ann. Thorac. Surg. 2009;87:365-71), suggesting that there are differences in immunogenicity and that squamous cell histology might be more immunogenic than other types.

Dr. Giaccone went on to highlight a recent phase II study reporting that first-line treatment with another immunomodulatory agent, ipilimumab (Yervoy), added in a phased fashion with paclitaxel (Taxol) and carboplatin chemotherapy, was superior to paclitaxel and carboplatin plus placebo in chemotherapy-naive patients with advanced NSCLC (J. Clin. Oncol. 2012;30:2046-54). Survival was much higher in patients with squamous cell vs. nonsquamous histology, which again suggested a difference between the two types with regard to immunogenicity.

Patients in the current phase I trial with advanced NSCLC and other solid tumors that had progressed after one to five systemic therapies received intravenous BMS-936558 at varying doses until disease progression or clinical deterioration or unacceptable toxicity. Patients who responded or had stable disease, or who had progressive disease but were clinically stable, were treated until they achieved a complete response, worsening progressive disease, or unacceptable toxicity for up to 12 cycles (96 weeks).

In all, 122 patients with NSCLC were evaluable for safety and 76 for clinical activity. At baseline, 60% of the 122 patients had nonsquamous histology, 96% had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1, and 55% had received at least three prior therapies including platinum-based chemotherapy in 94%, tyrosine-kinase inhibitors in 34%, and radiotherapy in 33%.

The overall response rate was 18% in the 39 patients who were enrolled at the 10-mg/kg dose of BMS-93558, 32% in 19 patients who were given the 3-mg/kg dose, and 6% in 18 patients given the 1-mg/kg dose. The percentage of patients who were free of progression at 24 weeks was 24%, 41%, and 16%, respectively, Dr. Brahmer reported. Three NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions, but were not classified as responders for the overall response rate.

Serious adverse events occurred in 14% of the 296 patients in the entire cohort, according to Dr. Suzanne L. Topalian, director of the melanoma program and professor of surgery and oncology at Johns Hopkins University in Baltimore, who presented the results of the main study at the ASCO meeting.

Grade 3/4 adverse events occurred in 10 patients (8%) with NSCLC. There were three drug-related deaths in the study resulting from pneumonitis in two patients with NSCLC and one patient with colorectal cancer, said Dr. Brahmer, who presented the results for patients with NSCLC in a separate session. Investigators saw no apparent relationship between drug dose and adverse event frequency in all treated patients or NSCLC patients.

Dr. Giaccone said the severe pneumonitis was worrisome, but that there is no comparison between the toxicity of BMS-936558 and ipilimumab.

"These represent similar mechanisms, but the side effects are clearly lower with the PD-1 compound," he said, adding that randomized studies will be needed to prove that BMS-936558 is better than the standard of care.

Clinical registration trials of BMS-936558 in patients with NSCLC are planned, Dr. Brahmer said. Recruitment is already underway for a multiarm study of BMS-936558 in combination with three platinum-based doublet chemotherapy regimens in treatment-naïve, stage IIIB/IV NSCLC.

Bristol-Myers Squibb sponsored the study. Dr. Brahmer and Dr. Giaccone report no relevant disclosures.

CHICAGO – Researchers are beginning to unravel the genomics of squamous cell lung cancer, revealing a disease characterized by complex genomes with frequent and unique rearrangements.

Exome and RNA sequence analyses of 178 patients identified 48,690 nonsilent mutations in total, Dr. Ramaswamy Govindan reported at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

"This is not a disease like CML [chronic myeloid leukemia] with one mutation," he said. "This is a tobacco-related lung cancer with an average of 228 nonsilent mutations per tumor."

Squamous cell lung cancer was found to have 8.3 somatic mutations/megabase, far surpassing, for example, the 0.5 mutations/megabase found in acute myeloid leukemia. The average number of mutations was 360/tumor.

"It’s quite significant the amount of mutational burden," Dr. Govindan remarked. "Granted many of them are passenger mutations, but still it’s a fairly disordered genome."

Dr. Govindan and his fellow researchers with the Cancer Genome Atlas (TCGA) Lung Cancer Project are attempting to characterize the poorly understood genomic and epigenomic landscape of lung squamous cell carcinoma (LSCC), and to identify potential therapeutic targets. No molecularly targeted therapy has been approved for use in LSCC, which accounts for roughly 30% of lung cancer deaths or 45,000 deaths/year in the United States.

The researchers hope to sequence about 1,000 lung cancers in the next year, with data presented on 178 LSCC patients, most of whom smoked (96%), were male (74%), and had early stage I/II disease (76%). Their median age was 68 years.

The tumor protein 53 (TP53) gene was almost universally altered in the cohort, along with frequent loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) function, said Dr. Govindan, an oncologist/hematologist and professor of medicine with Washington University School of Medicine in St. Louis. Other significantly mutated genes were phosphatase and tensin homlog (PTEN), Kelch-like ECH-associated protein 1 (KEAP1), nuclear factor-erythroid 2 related factor 2 (NFE2L2), human leukocyte antigen-A (HLA-A) and phosphoinositide-3-kinase catalytic alpha (PIK3CA).

Therapeutic targets were identified in 127 patients or roughly three-fourths of patients with LSCC. "So it’s really rich in targets," he said.

Most of the samples had distinct genes that are significant in terms of therapy and that are altered in a mutually exclusive fashion. Targets include the fibroblast growth factor receptors (FGFR), phosphoinositide-3 (p13) kinase pathway (47%), epidermal growth factor receptor (EGFR)/erythroblastic leukemia viral oncogene homolog 2 (ErbB-2), and the cyclin-cyclin dependant kinase complexes.

Dr. Govindan recommended that existing drugs should be studied in patients with squamous cell lung cancer, but cautioned that, "This doesn’t necessarily mean a drug that is currently inhibiting a p13 kinase will work in squamous cell lung cancer. That requires well-coordinated clinical trials."

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said the research has identified several existing drug targets that should be tested in clinical trials. He pointed to drugs such as the experimental FGFR inhibitor BGJ398 for patients with FGFR1 amplification, p13K inhibitors for PIK3CA mutations, sunitinib (Sutent) for platelet-derived growth factor receptor–alpha amplification or mutation and dasatinib (Sprycel) to target discoidin domain receptor 2 (DDR2) mutations. A response to dasatinib and erlotinib was recently reported in a patient with squamous cell lung cancer harboring a DDR2 mutation (Cancer Discov. 2011;1:78-89), with a phase II trial planned in patients with advanced tumors harboring this mutation (NCT01514864).

The researchers also conducted whole genome sequencing on 19 tumors, detecting an average of 165 rearrangements/tumor. This is far more than has been seen in the TCGA database for breast or colon cancer, Dr. Govindan said.

The analysis also identified frequent loss of CDKN2A function through multiple mechanisms: homozygous deletion in 30%, methylation in 21%, and mutation in 17%. More important, the mechanisms are complimentary, and there is somatic rearrangement resulting in loss of the CDKN2A locus, Dr. Govindan said. The findings are significant because, although CDKN2A loss may result in the same type of phenotype, tumor response to a specific therapy may differ based on the inactivation mechanism.

"Alterations in CDKN2A are significant and we should really look at this in terms of therapy," he said later in the presentation.

mRNA expression profiling confirmed a recent report that lung squamous cell carcinoma is composed of four biologically distinct mRNA expression subtypes, suggesting the need for different therapies (Clin. Cancer Res. 2010;16:4864-75).

In the current analysis, the classical subtype was present in 36% of samples and enriched with p13K alterations, hypermethylation and the highest rate of tobacco use. In contrast, the basal subtype (25%) was characterized by neurofibromin 1 loss, the secretory (24%) by platelet-derived growth factor (PDGF) receptor-alpha alterations and the primitive subtype (15%) with PTEN and retinoblastoma 1 mutations.

Pathway alterations in LSCC fell into two major categories. Not surprisingly, the squamous differentiation pathway was altered in 44% of patients, but the oxidative stress response was also found to be altered in 34% of patients and 62% of those with the classical mRNA subtype. Three mutually exclusive mutations were lost within this pathway: KEAP1 in 12%, NFE2L2 in 19% and cullin 3 in 7%.

Citing the role of oxidative stress in chemotherapy resistance, Dr. Mitsudomi said, "This is really an important discovery."

Finally, Dr. Govindan said the lung cancer community is witnessing a revolution." We are at the dawn of a new era where we are going to study the cancer genomes in its entirety as we have never done before.

"We used to see the alterations in the cancer genes through a key hole and now we can actually have this panoramic view of this through this comprehensive approach."

The full paper on the TCGA Lung Cancer Project findings is expected to be published shortly and will be deposited in a public database, Dr. Govindan said.

Dr. Govindan reports a consulting or advisory role with Bayer, Boehringer Ingelheim, and Merck Serono. The Cancer Genome Atlas is supported by the National Institutes of Health. Dr. Mitsudomi reports a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer and honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

CHICAGO – Researchers are beginning to unravel the genomics of squamous cell lung cancer, revealing a disease characterized by complex genomes with frequent and unique rearrangements.

Exome and RNA sequence analyses of 178 patients identified 48,690 nonsilent mutations in total, Dr. Ramaswamy Govindan reported at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

"This is not a disease like CML [chronic myeloid leukemia] with one mutation," he said. "This is a tobacco-related lung cancer with an average of 228 nonsilent mutations per tumor."

Squamous cell lung cancer was found to have 8.3 somatic mutations/megabase, far surpassing, for example, the 0.5 mutations/megabase found in acute myeloid leukemia. The average number of mutations was 360/tumor.

"It’s quite significant the amount of mutational burden," Dr. Govindan remarked. "Granted many of them are passenger mutations, but still it’s a fairly disordered genome."

Dr. Govindan and his fellow researchers with the Cancer Genome Atlas (TCGA) Lung Cancer Project are attempting to characterize the poorly understood genomic and epigenomic landscape of lung squamous cell carcinoma (LSCC), and to identify potential therapeutic targets. No molecularly targeted therapy has been approved for use in LSCC, which accounts for roughly 30% of lung cancer deaths or 45,000 deaths/year in the United States.

The researchers hope to sequence about 1,000 lung cancers in the next year, with data presented on 178 LSCC patients, most of whom smoked (96%), were male (74%), and had early stage I/II disease (76%). Their median age was 68 years.

The tumor protein 53 (TP53) gene was almost universally altered in the cohort, along with frequent loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) function, said Dr. Govindan, an oncologist/hematologist and professor of medicine with Washington University School of Medicine in St. Louis. Other significantly mutated genes were phosphatase and tensin homlog (PTEN), Kelch-like ECH-associated protein 1 (KEAP1), nuclear factor-erythroid 2 related factor 2 (NFE2L2), human leukocyte antigen-A (HLA-A) and phosphoinositide-3-kinase catalytic alpha (PIK3CA).

Therapeutic targets were identified in 127 patients or roughly three-fourths of patients with LSCC. "So it’s really rich in targets," he said.

Most of the samples had distinct genes that are significant in terms of therapy and that are altered in a mutually exclusive fashion. Targets include the fibroblast growth factor receptors (FGFR), phosphoinositide-3 (p13) kinase pathway (47%), epidermal growth factor receptor (EGFR)/erythroblastic leukemia viral oncogene homolog 2 (ErbB-2), and the cyclin-cyclin dependant kinase complexes.

Dr. Govindan recommended that existing drugs should be studied in patients with squamous cell lung cancer, but cautioned that, "This doesn’t necessarily mean a drug that is currently inhibiting a p13 kinase will work in squamous cell lung cancer. That requires well-coordinated clinical trials."

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said the research has identified several existing drug targets that should be tested in clinical trials. He pointed to drugs such as the experimental FGFR inhibitor BGJ398 for patients with FGFR1 amplification, p13K inhibitors for PIK3CA mutations, sunitinib (Sutent) for platelet-derived growth factor receptor–alpha amplification or mutation and dasatinib (Sprycel) to target discoidin domain receptor 2 (DDR2) mutations. A response to dasatinib and erlotinib was recently reported in a patient with squamous cell lung cancer harboring a DDR2 mutation (Cancer Discov. 2011;1:78-89), with a phase II trial planned in patients with advanced tumors harboring this mutation (NCT01514864).

The researchers also conducted whole genome sequencing on 19 tumors, detecting an average of 165 rearrangements/tumor. This is far more than has been seen in the TCGA database for breast or colon cancer, Dr. Govindan said.

The analysis also identified frequent loss of CDKN2A function through multiple mechanisms: homozygous deletion in 30%, methylation in 21%, and mutation in 17%. More important, the mechanisms are complimentary, and there is somatic rearrangement resulting in loss of the CDKN2A locus, Dr. Govindan said. The findings are significant because, although CDKN2A loss may result in the same type of phenotype, tumor response to a specific therapy may differ based on the inactivation mechanism.

"Alterations in CDKN2A are significant and we should really look at this in terms of therapy," he said later in the presentation.

mRNA expression profiling confirmed a recent report that lung squamous cell carcinoma is composed of four biologically distinct mRNA expression subtypes, suggesting the need for different therapies (Clin. Cancer Res. 2010;16:4864-75).

In the current analysis, the classical subtype was present in 36% of samples and enriched with p13K alterations, hypermethylation and the highest rate of tobacco use. In contrast, the basal subtype (25%) was characterized by neurofibromin 1 loss, the secretory (24%) by platelet-derived growth factor (PDGF) receptor-alpha alterations and the primitive subtype (15%) with PTEN and retinoblastoma 1 mutations.

Pathway alterations in LSCC fell into two major categories. Not surprisingly, the squamous differentiation pathway was altered in 44% of patients, but the oxidative stress response was also found to be altered in 34% of patients and 62% of those with the classical mRNA subtype. Three mutually exclusive mutations were lost within this pathway: KEAP1 in 12%, NFE2L2 in 19% and cullin 3 in 7%.

Citing the role of oxidative stress in chemotherapy resistance, Dr. Mitsudomi said, "This is really an important discovery."

Finally, Dr. Govindan said the lung cancer community is witnessing a revolution." We are at the dawn of a new era where we are going to study the cancer genomes in its entirety as we have never done before.

"We used to see the alterations in the cancer genes through a key hole and now we can actually have this panoramic view of this through this comprehensive approach."

The full paper on the TCGA Lung Cancer Project findings is expected to be published shortly and will be deposited in a public database, Dr. Govindan said.

Dr. Govindan reports a consulting or advisory role with Bayer, Boehringer Ingelheim, and Merck Serono. The Cancer Genome Atlas is supported by the National Institutes of Health. Dr. Mitsudomi reports a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer and honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

CHICAGO – Researchers are beginning to unravel the genomics of squamous cell lung cancer, revealing a disease characterized by complex genomes with frequent and unique rearrangements.

Exome and RNA sequence analyses of 178 patients identified 48,690 nonsilent mutations in total, Dr. Ramaswamy Govindan reported at the annual meeting of the American Society of Clinical Oncology.

Patrice Wendling/IMNG Medical Media

"This is not a disease like CML [chronic myeloid leukemia] with one mutation," he said. "This is a tobacco-related lung cancer with an average of 228 nonsilent mutations per tumor."

Squamous cell lung cancer was found to have 8.3 somatic mutations/megabase, far surpassing, for example, the 0.5 mutations/megabase found in acute myeloid leukemia. The average number of mutations was 360/tumor.

"It’s quite significant the amount of mutational burden," Dr. Govindan remarked. "Granted many of them are passenger mutations, but still it’s a fairly disordered genome."

Dr. Govindan and his fellow researchers with the Cancer Genome Atlas (TCGA) Lung Cancer Project are attempting to characterize the poorly understood genomic and epigenomic landscape of lung squamous cell carcinoma (LSCC), and to identify potential therapeutic targets. No molecularly targeted therapy has been approved for use in LSCC, which accounts for roughly 30% of lung cancer deaths or 45,000 deaths/year in the United States.

The researchers hope to sequence about 1,000 lung cancers in the next year, with data presented on 178 LSCC patients, most of whom smoked (96%), were male (74%), and had early stage I/II disease (76%). Their median age was 68 years.

The tumor protein 53 (TP53) gene was almost universally altered in the cohort, along with frequent loss of cyclin-dependent kinase inhibitor 2A (CDKN2A) function, said Dr. Govindan, an oncologist/hematologist and professor of medicine with Washington University School of Medicine in St. Louis. Other significantly mutated genes were phosphatase and tensin homlog (PTEN), Kelch-like ECH-associated protein 1 (KEAP1), nuclear factor-erythroid 2 related factor 2 (NFE2L2), human leukocyte antigen-A (HLA-A) and phosphoinositide-3-kinase catalytic alpha (PIK3CA).

Therapeutic targets were identified in 127 patients or roughly three-fourths of patients with LSCC. "So it’s really rich in targets," he said.

Most of the samples had distinct genes that are significant in terms of therapy and that are altered in a mutually exclusive fashion. Targets include the fibroblast growth factor receptors (FGFR), phosphoinositide-3 (p13) kinase pathway (47%), epidermal growth factor receptor (EGFR)/erythroblastic leukemia viral oncogene homolog 2 (ErbB-2), and the cyclin-cyclin dependant kinase complexes.

Dr. Govindan recommended that existing drugs should be studied in patients with squamous cell lung cancer, but cautioned that, "This doesn’t necessarily mean a drug that is currently inhibiting a p13 kinase will work in squamous cell lung cancer. That requires well-coordinated clinical trials."

Discussant Dr. Tetsuya Mitsudomi, chief of thoracic surgery at Aichi Cancer Center Hospital in Nagoya, Japan, said the research has identified several existing drug targets that should be tested in clinical trials. He pointed to drugs such as the experimental FGFR inhibitor BGJ398 for patients with FGFR1 amplification, p13K inhibitors for PIK3CA mutations, sunitinib (Sutent) for platelet-derived growth factor receptor–alpha amplification or mutation and dasatinib (Sprycel) to target discoidin domain receptor 2 (DDR2) mutations. A response to dasatinib and erlotinib was recently reported in a patient with squamous cell lung cancer harboring a DDR2 mutation (Cancer Discov. 2011;1:78-89), with a phase II trial planned in patients with advanced tumors harboring this mutation (NCT01514864).

The researchers also conducted whole genome sequencing on 19 tumors, detecting an average of 165 rearrangements/tumor. This is far more than has been seen in the TCGA database for breast or colon cancer, Dr. Govindan said.

The analysis also identified frequent loss of CDKN2A function through multiple mechanisms: homozygous deletion in 30%, methylation in 21%, and mutation in 17%. More important, the mechanisms are complimentary, and there is somatic rearrangement resulting in loss of the CDKN2A locus, Dr. Govindan said. The findings are significant because, although CDKN2A loss may result in the same type of phenotype, tumor response to a specific therapy may differ based on the inactivation mechanism.

"Alterations in CDKN2A are significant and we should really look at this in terms of therapy," he said later in the presentation.

mRNA expression profiling confirmed a recent report that lung squamous cell carcinoma is composed of four biologically distinct mRNA expression subtypes, suggesting the need for different therapies (Clin. Cancer Res. 2010;16:4864-75).

In the current analysis, the classical subtype was present in 36% of samples and enriched with p13K alterations, hypermethylation and the highest rate of tobacco use. In contrast, the basal subtype (25%) was characterized by neurofibromin 1 loss, the secretory (24%) by platelet-derived growth factor (PDGF) receptor-alpha alterations and the primitive subtype (15%) with PTEN and retinoblastoma 1 mutations.

Pathway alterations in LSCC fell into two major categories. Not surprisingly, the squamous differentiation pathway was altered in 44% of patients, but the oxidative stress response was also found to be altered in 34% of patients and 62% of those with the classical mRNA subtype. Three mutually exclusive mutations were lost within this pathway: KEAP1 in 12%, NFE2L2 in 19% and cullin 3 in 7%.

Citing the role of oxidative stress in chemotherapy resistance, Dr. Mitsudomi said, "This is really an important discovery."

Finally, Dr. Govindan said the lung cancer community is witnessing a revolution." We are at the dawn of a new era where we are going to study the cancer genomes in its entirety as we have never done before.

"We used to see the alterations in the cancer genes through a key hole and now we can actually have this panoramic view of this through this comprehensive approach."

The full paper on the TCGA Lung Cancer Project findings is expected to be published shortly and will be deposited in a public database, Dr. Govindan said.

Dr. Govindan reports a consulting or advisory role with Bayer, Boehringer Ingelheim, and Merck Serono. The Cancer Genome Atlas is supported by the National Institutes of Health. Dr. Mitsudomi reports a consulting/advisory role with Boehringer Ingelheim, Kyowa Hakko Kirin, Lilly, and Pfizer and honoraria from AstraZeneca, Chugai Pharma, Lilly, and Roche.

CHICAGO – Vitamin D₃ can relieve the aches and pains associated with aromatase inhibitor therapy for breast cancer, according to the results of a randomized, double-blind, placebo-controlled trial.

Six months of vitamin D at 30,000 IU per week proved safe and was associated with "less worsening" of musculoskeletal events and fewer overall adverse quality of life events in women starting adjuvant letrozole (Femara) for hormone receptor–positive breast cancer, Dr. Qamar J. Khan reported at the annual meeting of the American Society of Clinical Oncology.

© Kaspri/Fotolia.com

Aromatase inhibitors are often discontinued prematurely because of new or worsening musculoskeletal pain reported in as many as half of women and fatigue in 15%-30%, said Dr. Khan of the University of Kansas Medical Center in Kansas City.

Vitamin D deficiency is thought to contribute to musculoskeletal symptoms, he said, explaining the rationale for the study. It is prevalent in breast cancer patients who have these aches and pains, and in women receiving adjuvant chemotherapy, even with supplementation. A similar syndrome is seen in people with severe vitamin D deficiency, he noted.

A prior pilot study conducted by the investigators suggested that vitamin D at 50,000 IU/wk for 12 weeks may be effective in reducing these symptoms (Breast Cancer Res. 2010;119:111-8).

The current double-blind VITAL (Vitamin D for Arthralgias From Letrozole) trial evenly randomized 160 postmenopausal women with stage I-III hormone receptor–positive invasive breast cancer and a serum vitamin D level of 40 ng/mL or less. All patients received letrozole 2.5 mg daily and the standard daily recommended daily allowance (RDA) of vitamin D 600 IU and calcium 1,200 mg. One cohort also received 30,000 IU of oral vitamin D₃ weekly for 24 weeks; the other was given a placebo.

The two arms were well matched with regard to age, race, body mass index, vitamin D level at baseline, adjuvant chemotherapy, and radiation therapy.

The per-protocol primary end point was the incidence of a musculoskeletal event, defined as worsening of pain using a simple pain intensity scale, worsening disability from musculoskeletal pain using the Health Assessment Questionnaire II, or discontinuation of letrozole because of pain at 6 months. The primary end point also was measured, substituting the quantitative Brief Pain Inventory for the simple pain intensity scale, Dr. Khan said.

Thirteen patients did not complete the study for reasons unrelated to study agents and/or musculoskeletal events, leaving 147 evaluable for efficacy.

At 6 months, 37% of women receiving 30,000 IU vitamin D weekly experienced a per-protocol musculoskeletal event, compared with 51% on placebo (P = .069), based on the simple scale. When the more robust Brief Pain Inventory was used, 61% of controls and 38% of those on vitamin D reported a musculoskeletal event, a difference that reached statistical significance (P = .008), he said.

A significantly higher proportion of women on placebo also had an adverse quality of life event, defined as a musculoskeletal event plus worsening of fatigue (72% vs. 42%; P less than .001).

The median vitamin D level at baseline was 25.1 ng/mL in the control arm and 22.5 ng/mL in the vitamin D group. It hovered at 32 ng/mL at 12 weeks and 31 ng/mL at 24 weeks in the control group, but rose to 53 ng/mL at 12 weeks and 57 ng/mL at 24 weeks in the vitamin D arm (P = .001 at both 12 and 24 weeks).

Baseline levels had little influence on the final level achieved. The sharp rise followed by relatively little gain in the active treatment arm suggests a plateau in the effect of continued vitamin D supplementation, Dr. Khan observed.

One patient in the control arm developed mild hypercalcemia, and three patients in the control arm discontinued early because of a musculoskeletal adverse event. There were no severe adverse events.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) Medical Center, said that the trial used well-validated measures and showed no discernable toxicity with 30,000 IU weekly, which is beyond the current RDA. "Therefore it may be promising for helping with these musculoskeletal symptoms and possibly fatigue," she said.

Dr. Mustian asked whether the time needed to achieve a benefit poses a potential problem in terms of patient adherence and whether data are available on the sustainability of the improvements in musculoskeletal symptoms and fatigue.

Dr. Khan said that aromatase inhibitor–induced adverse events tend to peak at about 6 months and that only one study has looked at using higher doses of vitamin D beyond 6 months. The observation that the effect of vitamin D supplementation plateaus at 3-6 months, however, is consistent with other studies.

"After you load the body with vitamin D and ... you keep on giving the same dose, the body just maintains the levels," he said.

Dr. Khan said that additional studies are needed to address long-term sustainability, and that the investigators have proposed a trial to the Southwest Oncology Group for the same intervention for 1-2 years to study a longer-term effect.

Dr. Khan reports honoraria from Abraxis BioScience and Genentech, and research funding from Abraxis and Novartis Roche/Genentech. His coauthors and Dr. Mustian report no disclosures.

CHICAGO – Vitamin D₃ can relieve the aches and pains associated with aromatase inhibitor therapy for breast cancer, according to the results of a randomized, double-blind, placebo-controlled trial.

Six months of vitamin D at 30,000 IU per week proved safe and was associated with "less worsening" of musculoskeletal events and fewer overall adverse quality of life events in women starting adjuvant letrozole (Femara) for hormone receptor–positive breast cancer, Dr. Qamar J. Khan reported at the annual meeting of the American Society of Clinical Oncology.

© Kaspri/Fotolia.com

Aromatase inhibitors are often discontinued prematurely because of new or worsening musculoskeletal pain reported in as many as half of women and fatigue in 15%-30%, said Dr. Khan of the University of Kansas Medical Center in Kansas City.

Vitamin D deficiency is thought to contribute to musculoskeletal symptoms, he said, explaining the rationale for the study. It is prevalent in breast cancer patients who have these aches and pains, and in women receiving adjuvant chemotherapy, even with supplementation. A similar syndrome is seen in people with severe vitamin D deficiency, he noted.

A prior pilot study conducted by the investigators suggested that vitamin D at 50,000 IU/wk for 12 weeks may be effective in reducing these symptoms (Breast Cancer Res. 2010;119:111-8).

The current double-blind VITAL (Vitamin D for Arthralgias From Letrozole) trial evenly randomized 160 postmenopausal women with stage I-III hormone receptor–positive invasive breast cancer and a serum vitamin D level of 40 ng/mL or less. All patients received letrozole 2.5 mg daily and the standard daily recommended daily allowance (RDA) of vitamin D 600 IU and calcium 1,200 mg. One cohort also received 30,000 IU of oral vitamin D₃ weekly for 24 weeks; the other was given a placebo.

The two arms were well matched with regard to age, race, body mass index, vitamin D level at baseline, adjuvant chemotherapy, and radiation therapy.

The per-protocol primary end point was the incidence of a musculoskeletal event, defined as worsening of pain using a simple pain intensity scale, worsening disability from musculoskeletal pain using the Health Assessment Questionnaire II, or discontinuation of letrozole because of pain at 6 months. The primary end point also was measured, substituting the quantitative Brief Pain Inventory for the simple pain intensity scale, Dr. Khan said.

Thirteen patients did not complete the study for reasons unrelated to study agents and/or musculoskeletal events, leaving 147 evaluable for efficacy.

At 6 months, 37% of women receiving 30,000 IU vitamin D weekly experienced a per-protocol musculoskeletal event, compared with 51% on placebo (P = .069), based on the simple scale. When the more robust Brief Pain Inventory was used, 61% of controls and 38% of those on vitamin D reported a musculoskeletal event, a difference that reached statistical significance (P = .008), he said.

A significantly higher proportion of women on placebo also had an adverse quality of life event, defined as a musculoskeletal event plus worsening of fatigue (72% vs. 42%; P less than .001).

The median vitamin D level at baseline was 25.1 ng/mL in the control arm and 22.5 ng/mL in the vitamin D group. It hovered at 32 ng/mL at 12 weeks and 31 ng/mL at 24 weeks in the control group, but rose to 53 ng/mL at 12 weeks and 57 ng/mL at 24 weeks in the vitamin D arm (P = .001 at both 12 and 24 weeks).

Baseline levels had little influence on the final level achieved. The sharp rise followed by relatively little gain in the active treatment arm suggests a plateau in the effect of continued vitamin D supplementation, Dr. Khan observed.

One patient in the control arm developed mild hypercalcemia, and three patients in the control arm discontinued early because of a musculoskeletal adverse event. There were no severe adverse events.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) Medical Center, said that the trial used well-validated measures and showed no discernable toxicity with 30,000 IU weekly, which is beyond the current RDA. "Therefore it may be promising for helping with these musculoskeletal symptoms and possibly fatigue," she said.

Dr. Mustian asked whether the time needed to achieve a benefit poses a potential problem in terms of patient adherence and whether data are available on the sustainability of the improvements in musculoskeletal symptoms and fatigue.

Dr. Khan said that aromatase inhibitor–induced adverse events tend to peak at about 6 months and that only one study has looked at using higher doses of vitamin D beyond 6 months. The observation that the effect of vitamin D supplementation plateaus at 3-6 months, however, is consistent with other studies.

"After you load the body with vitamin D and ... you keep on giving the same dose, the body just maintains the levels," he said.

Dr. Khan said that additional studies are needed to address long-term sustainability, and that the investigators have proposed a trial to the Southwest Oncology Group for the same intervention for 1-2 years to study a longer-term effect.

Dr. Khan reports honoraria from Abraxis BioScience and Genentech, and research funding from Abraxis and Novartis Roche/Genentech. His coauthors and Dr. Mustian report no disclosures.

CHICAGO – Vitamin D₃ can relieve the aches and pains associated with aromatase inhibitor therapy for breast cancer, according to the results of a randomized, double-blind, placebo-controlled trial.

Six months of vitamin D at 30,000 IU per week proved safe and was associated with "less worsening" of musculoskeletal events and fewer overall adverse quality of life events in women starting adjuvant letrozole (Femara) for hormone receptor–positive breast cancer, Dr. Qamar J. Khan reported at the annual meeting of the American Society of Clinical Oncology.

© Kaspri/Fotolia.com

Aromatase inhibitors are often discontinued prematurely because of new or worsening musculoskeletal pain reported in as many as half of women and fatigue in 15%-30%, said Dr. Khan of the University of Kansas Medical Center in Kansas City.

Vitamin D deficiency is thought to contribute to musculoskeletal symptoms, he said, explaining the rationale for the study. It is prevalent in breast cancer patients who have these aches and pains, and in women receiving adjuvant chemotherapy, even with supplementation. A similar syndrome is seen in people with severe vitamin D deficiency, he noted.

A prior pilot study conducted by the investigators suggested that vitamin D at 50,000 IU/wk for 12 weeks may be effective in reducing these symptoms (Breast Cancer Res. 2010;119:111-8).

The current double-blind VITAL (Vitamin D for Arthralgias From Letrozole) trial evenly randomized 160 postmenopausal women with stage I-III hormone receptor–positive invasive breast cancer and a serum vitamin D level of 40 ng/mL or less. All patients received letrozole 2.5 mg daily and the standard daily recommended daily allowance (RDA) of vitamin D 600 IU and calcium 1,200 mg. One cohort also received 30,000 IU of oral vitamin D₃ weekly for 24 weeks; the other was given a placebo.

The two arms were well matched with regard to age, race, body mass index, vitamin D level at baseline, adjuvant chemotherapy, and radiation therapy.

The per-protocol primary end point was the incidence of a musculoskeletal event, defined as worsening of pain using a simple pain intensity scale, worsening disability from musculoskeletal pain using the Health Assessment Questionnaire II, or discontinuation of letrozole because of pain at 6 months. The primary end point also was measured, substituting the quantitative Brief Pain Inventory for the simple pain intensity scale, Dr. Khan said.

Thirteen patients did not complete the study for reasons unrelated to study agents and/or musculoskeletal events, leaving 147 evaluable for efficacy.

At 6 months, 37% of women receiving 30,000 IU vitamin D weekly experienced a per-protocol musculoskeletal event, compared with 51% on placebo (P = .069), based on the simple scale. When the more robust Brief Pain Inventory was used, 61% of controls and 38% of those on vitamin D reported a musculoskeletal event, a difference that reached statistical significance (P = .008), he said.

A significantly higher proportion of women on placebo also had an adverse quality of life event, defined as a musculoskeletal event plus worsening of fatigue (72% vs. 42%; P less than .001).

The median vitamin D level at baseline was 25.1 ng/mL in the control arm and 22.5 ng/mL in the vitamin D group. It hovered at 32 ng/mL at 12 weeks and 31 ng/mL at 24 weeks in the control group, but rose to 53 ng/mL at 12 weeks and 57 ng/mL at 24 weeks in the vitamin D arm (P = .001 at both 12 and 24 weeks).

Baseline levels had little influence on the final level achieved. The sharp rise followed by relatively little gain in the active treatment arm suggests a plateau in the effect of continued vitamin D supplementation, Dr. Khan observed.

One patient in the control arm developed mild hypercalcemia, and three patients in the control arm discontinued early because of a musculoskeletal adverse event. There were no severe adverse events.

Discussant Karen Mustian, Ph.D., of the University of Rochester (N.Y.) Medical Center, said that the trial used well-validated measures and showed no discernable toxicity with 30,000 IU weekly, which is beyond the current RDA. "Therefore it may be promising for helping with these musculoskeletal symptoms and possibly fatigue," she said.

Dr. Mustian asked whether the time needed to achieve a benefit poses a potential problem in terms of patient adherence and whether data are available on the sustainability of the improvements in musculoskeletal symptoms and fatigue.

Dr. Khan said that aromatase inhibitor–induced adverse events tend to peak at about 6 months and that only one study has looked at using higher doses of vitamin D beyond 6 months. The observation that the effect of vitamin D supplementation plateaus at 3-6 months, however, is consistent with other studies.

"After you load the body with vitamin D and ... you keep on giving the same dose, the body just maintains the levels," he said.

Dr. Khan said that additional studies are needed to address long-term sustainability, and that the investigators have proposed a trial to the Southwest Oncology Group for the same intervention for 1-2 years to study a longer-term effect.

Dr. Khan reports honoraria from Abraxis BioScience and Genentech, and research funding from Abraxis and Novartis Roche/Genentech. His coauthors and Dr. Mustian report no disclosures.

CHICAGO – Lapatinib was not superior to trastuzumab when used as a component of neoadjuvant therapy for operable HER2-positive breast cancer in a randomized cooperative group trial. And neither was a combination of both drugs in the population overall.

About 50%-60% of the 529 patients studied had a pathological complete response (pCR) whether they received trastuzumab (Herceptin) only, lapatinib (Tykerb) only, or lapatinib plus trastuzumab, each in addition to standard chemotherapy in the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-41 trial, investigators reported.

However, patients whose tumors had a high level of HER2 overexpression on immunohistochemistry, scored as 3+ staining, were more likely to have a pCR if they received lapatinib plus trastuzumab than if they received trastuzumab alone, Dr. Andre Robidoux told attendees at the annual meeting of the American Society of Clinical Oncology.

Of note, the rate of grade 3 or worse diarrhea was higher with lapatinib alone or in combination, the investigators found. And patients in those groups were less likely to complete their treatment.

"Combined HER2-targeted therapy produced a numerically higher pCR percentage than single-agent HER2-directed therapy, but the difference was not statistically significant," said Dr. Robidoux of the Centre Hospitalier de l’Université de Montréal

"Unplanned analysis based on immunohistochemical staining intensity suggests that combined HER2-targeted therapy may be of greatest value in patients with tumors with a high degree of protein overexpression," he added.

Dual Blockade Supported

Discussant Dr. Gunter von Minckwitz of the German Breast Group and the University of Frankfurt noted that neoadjuvant trastuzumab therapy increases the likelihood of residual ductal carcinoma in situ (DCIS) at surgery, which is a negative prognostic factor for disease-free survival (J. Clin. Oncol. 2012;30:901-3). "So maybe the NSABP investigators should also analyze their data for an even more pure pCR definition," he proposed.

"We have seen now a series of studies either combining lapatinib and trastuzumab or combining trastuzumab and pertuzumab [Perjeta] showing higher pCR rates compared to patients who got only one of the anti-HER2 treatments," he maintained. "So this is the way we have to go. ... Dual blockade appears to be the most promising approach for the future."

"We have to wait, of course, to see how far the neoadjuvant results are predicting the outcome of adjuvant treatment; therefore, ALTTO and APHINITY are crucial," Dr. von Minckwitz added, referring to two trials.

"However, I believe the results from the neoadjuvant setting are quite consistent with the results that are now obtained in other settings – the adjuvant and metastatic settings. Therefore, this might open a regulatory path for conditional approval of agents in early development," as recently proposed by the Food and Drug Administration (N. Engl. J. Med. 2012 May 30).

Giving background on NSABP B-41, Dr. Robidoux noted that doxorubicin (Adriamycin) plus cyclophosphamide, followed by weekly paclitaxel plus trastuzumab, has been a standard neoadjuvant therapy for HER2-positive breast cancer since 2005. But lapatinib, an oral dual tyrosine kinase inhibitor of HER2 and the epidermal growth factor receptor (EGFR), has a different mechanism of action and shows synergy with trastuzumab.

"The next logical step was to evaluate the addition of a second agent that interrupts HER2 signaling through a different mechanism than trastuzumab," he said.

PCR Rates Indistinguishable

Women enrolled in the trial had a palpable tumor measuring at least 2 cm, a left ventricular ejection fraction of at least 50%, and HER2-positive disease, defined as gene amplification by fluorescence in situ hybridization (FISH) or a score of 3+ by immunohistochemistry.

All women received four cycles of doxorubicin plus cyclophosphamide. Thereafter, they received weekly paclitaxel plus trastuzumab only (as a control), plus lapatinib only, or plus both. They then underwent surgery and received trastuzumab postoperatively.

The main results showed that the rate of clinical complete response with lapatinib alone (69.9%) was lower than that with trastuzumab alone (82%) (P = .014). But it did not differ significantly between trastuzumab and lapatinib plus trastuzumab (76.8%).

The rates of pCR in the breast with lapatinib alone (53.2%) or lapatinib combined with trastuzumab (62%) were statistically indistinguishable from that seen with trastuzumab alone (52.5%).

This pattern was the same in subgroups having hormone receptor–positive and negative disease. However, in a finding that Dr. Robidoux called "intriguing," the pCR rate among those with 3+ immunohistochemical staining for HER2 was higher with lapatinib plus trastuzumab (71%) than with trastuzumab alone (54.7%) (P = .006).

The overall rate of grade 3 or worse toxicity was 50% with trastuzumab alone, 62% with lapatinib alone, and 61% with lapatinib plus trastuzumab. Grade 3 or worse diarrhea was by far more common in both lapatinib groups (P less than .001), but grade 3 or worse febrile neutropenia and hepatotoxicity were similarly common.

The rate of New York Heart Association class III or IV congestive heart failure was 4% with trastuzumab alone, 4% with lapatinib alone, and 1% with the combination, differences that were not statistically significant.

Patients in the trastuzumab group were more likely to complete their therapy (78%) than their counterparts in the lapatinib group (68%) and in the combination group (63%) (P = .01).

About half of patients were able to have breast-conserving surgery, whether they received trastuzumab alone (54%), lapatinib alone (46%), or both drugs (50%).

Dr. Robidoux disclosed that he is a consultant to GlaxoSmithKline and receives honoraria and research funding from GlaxoSmithKline and Roche. Dr. von Minckwitz disclosed no relevant conflicts of interest.

CHICAGO – Lapatinib was not superior to trastuzumab when used as a component of neoadjuvant therapy for operable HER2-positive breast cancer in a randomized cooperative group trial. And neither was a combination of both drugs in the population overall.

About 50%-60% of the 529 patients studied had a pathological complete response (pCR) whether they received trastuzumab (Herceptin) only, lapatinib (Tykerb) only, or lapatinib plus trastuzumab, each in addition to standard chemotherapy in the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-41 trial, investigators reported.

However, patients whose tumors had a high level of HER2 overexpression on immunohistochemistry, scored as 3+ staining, were more likely to have a pCR if they received lapatinib plus trastuzumab than if they received trastuzumab alone, Dr. Andre Robidoux told attendees at the annual meeting of the American Society of Clinical Oncology.

Of note, the rate of grade 3 or worse diarrhea was higher with lapatinib alone or in combination, the investigators found. And patients in those groups were less likely to complete their treatment.

"Combined HER2-targeted therapy produced a numerically higher pCR percentage than single-agent HER2-directed therapy, but the difference was not statistically significant," said Dr. Robidoux of the Centre Hospitalier de l’Université de Montréal

"Unplanned analysis based on immunohistochemical staining intensity suggests that combined HER2-targeted therapy may be of greatest value in patients with tumors with a high degree of protein overexpression," he added.

Dual Blockade Supported

Discussant Dr. Gunter von Minckwitz of the German Breast Group and the University of Frankfurt noted that neoadjuvant trastuzumab therapy increases the likelihood of residual ductal carcinoma in situ (DCIS) at surgery, which is a negative prognostic factor for disease-free survival (J. Clin. Oncol. 2012;30:901-3). "So maybe the NSABP investigators should also analyze their data for an even more pure pCR definition," he proposed.

"We have seen now a series of studies either combining lapatinib and trastuzumab or combining trastuzumab and pertuzumab [Perjeta] showing higher pCR rates compared to patients who got only one of the anti-HER2 treatments," he maintained. "So this is the way we have to go. ... Dual blockade appears to be the most promising approach for the future."

"We have to wait, of course, to see how far the neoadjuvant results are predicting the outcome of adjuvant treatment; therefore, ALTTO and APHINITY are crucial," Dr. von Minckwitz added, referring to two trials.

"However, I believe the results from the neoadjuvant setting are quite consistent with the results that are now obtained in other settings – the adjuvant and metastatic settings. Therefore, this might open a regulatory path for conditional approval of agents in early development," as recently proposed by the Food and Drug Administration (N. Engl. J. Med. 2012 May 30).

Giving background on NSABP B-41, Dr. Robidoux noted that doxorubicin (Adriamycin) plus cyclophosphamide, followed by weekly paclitaxel plus trastuzumab, has been a standard neoadjuvant therapy for HER2-positive breast cancer since 2005. But lapatinib, an oral dual tyrosine kinase inhibitor of HER2 and the epidermal growth factor receptor (EGFR), has a different mechanism of action and shows synergy with trastuzumab.

"The next logical step was to evaluate the addition of a second agent that interrupts HER2 signaling through a different mechanism than trastuzumab," he said.

PCR Rates Indistinguishable

Women enrolled in the trial had a palpable tumor measuring at least 2 cm, a left ventricular ejection fraction of at least 50%, and HER2-positive disease, defined as gene amplification by fluorescence in situ hybridization (FISH) or a score of 3+ by immunohistochemistry.

All women received four cycles of doxorubicin plus cyclophosphamide. Thereafter, they received weekly paclitaxel plus trastuzumab only (as a control), plus lapatinib only, or plus both. They then underwent surgery and received trastuzumab postoperatively.

The main results showed that the rate of clinical complete response with lapatinib alone (69.9%) was lower than that with trastuzumab alone (82%) (P = .014). But it did not differ significantly between trastuzumab and lapatinib plus trastuzumab (76.8%).

The rates of pCR in the breast with lapatinib alone (53.2%) or lapatinib combined with trastuzumab (62%) were statistically indistinguishable from that seen with trastuzumab alone (52.5%).

This pattern was the same in subgroups having hormone receptor–positive and negative disease. However, in a finding that Dr. Robidoux called "intriguing," the pCR rate among those with 3+ immunohistochemical staining for HER2 was higher with lapatinib plus trastuzumab (71%) than with trastuzumab alone (54.7%) (P = .006).

The overall rate of grade 3 or worse toxicity was 50% with trastuzumab alone, 62% with lapatinib alone, and 61% with lapatinib plus trastuzumab. Grade 3 or worse diarrhea was by far more common in both lapatinib groups (P less than .001), but grade 3 or worse febrile neutropenia and hepatotoxicity were similarly common.

The rate of New York Heart Association class III or IV congestive heart failure was 4% with trastuzumab alone, 4% with lapatinib alone, and 1% with the combination, differences that were not statistically significant.

Patients in the trastuzumab group were more likely to complete their therapy (78%) than their counterparts in the lapatinib group (68%) and in the combination group (63%) (P = .01).

About half of patients were able to have breast-conserving surgery, whether they received trastuzumab alone (54%), lapatinib alone (46%), or both drugs (50%).

Dr. Robidoux disclosed that he is a consultant to GlaxoSmithKline and receives honoraria and research funding from GlaxoSmithKline and Roche. Dr. von Minckwitz disclosed no relevant conflicts of interest.

CHICAGO – Lapatinib was not superior to trastuzumab when used as a component of neoadjuvant therapy for operable HER2-positive breast cancer in a randomized cooperative group trial. And neither was a combination of both drugs in the population overall.

About 50%-60% of the 529 patients studied had a pathological complete response (pCR) whether they received trastuzumab (Herceptin) only, lapatinib (Tykerb) only, or lapatinib plus trastuzumab, each in addition to standard chemotherapy in the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-41 trial, investigators reported.

However, patients whose tumors had a high level of HER2 overexpression on immunohistochemistry, scored as 3+ staining, were more likely to have a pCR if they received lapatinib plus trastuzumab than if they received trastuzumab alone, Dr. Andre Robidoux told attendees at the annual meeting of the American Society of Clinical Oncology.

Of note, the rate of grade 3 or worse diarrhea was higher with lapatinib alone or in combination, the investigators found. And patients in those groups were less likely to complete their treatment.

"Combined HER2-targeted therapy produced a numerically higher pCR percentage than single-agent HER2-directed therapy, but the difference was not statistically significant," said Dr. Robidoux of the Centre Hospitalier de l’Université de Montréal

"Unplanned analysis based on immunohistochemical staining intensity suggests that combined HER2-targeted therapy may be of greatest value in patients with tumors with a high degree of protein overexpression," he added.

Dual Blockade Supported

Discussant Dr. Gunter von Minckwitz of the German Breast Group and the University of Frankfurt noted that neoadjuvant trastuzumab therapy increases the likelihood of residual ductal carcinoma in situ (DCIS) at surgery, which is a negative prognostic factor for disease-free survival (J. Clin. Oncol. 2012;30:901-3). "So maybe the NSABP investigators should also analyze their data for an even more pure pCR definition," he proposed.

"We have seen now a series of studies either combining lapatinib and trastuzumab or combining trastuzumab and pertuzumab [Perjeta] showing higher pCR rates compared to patients who got only one of the anti-HER2 treatments," he maintained. "So this is the way we have to go. ... Dual blockade appears to be the most promising approach for the future."

"We have to wait, of course, to see how far the neoadjuvant results are predicting the outcome of adjuvant treatment; therefore, ALTTO and APHINITY are crucial," Dr. von Minckwitz added, referring to two trials.

"However, I believe the results from the neoadjuvant setting are quite consistent with the results that are now obtained in other settings – the adjuvant and metastatic settings. Therefore, this might open a regulatory path for conditional approval of agents in early development," as recently proposed by the Food and Drug Administration (N. Engl. J. Med. 2012 May 30).

Giving background on NSABP B-41, Dr. Robidoux noted that doxorubicin (Adriamycin) plus cyclophosphamide, followed by weekly paclitaxel plus trastuzumab, has been a standard neoadjuvant therapy for HER2-positive breast cancer since 2005. But lapatinib, an oral dual tyrosine kinase inhibitor of HER2 and the epidermal growth factor receptor (EGFR), has a different mechanism of action and shows synergy with trastuzumab.

"The next logical step was to evaluate the addition of a second agent that interrupts HER2 signaling through a different mechanism than trastuzumab," he said.

PCR Rates Indistinguishable

Women enrolled in the trial had a palpable tumor measuring at least 2 cm, a left ventricular ejection fraction of at least 50%, and HER2-positive disease, defined as gene amplification by fluorescence in situ hybridization (FISH) or a score of 3+ by immunohistochemistry.

All women received four cycles of doxorubicin plus cyclophosphamide. Thereafter, they received weekly paclitaxel plus trastuzumab only (as a control), plus lapatinib only, or plus both. They then underwent surgery and received trastuzumab postoperatively.

The main results showed that the rate of clinical complete response with lapatinib alone (69.9%) was lower than that with trastuzumab alone (82%) (P = .014). But it did not differ significantly between trastuzumab and lapatinib plus trastuzumab (76.8%).

The rates of pCR in the breast with lapatinib alone (53.2%) or lapatinib combined with trastuzumab (62%) were statistically indistinguishable from that seen with trastuzumab alone (52.5%).

This pattern was the same in subgroups having hormone receptor–positive and negative disease. However, in a finding that Dr. Robidoux called "intriguing," the pCR rate among those with 3+ immunohistochemical staining for HER2 was higher with lapatinib plus trastuzumab (71%) than with trastuzumab alone (54.7%) (P = .006).

The overall rate of grade 3 or worse toxicity was 50% with trastuzumab alone, 62% with lapatinib alone, and 61% with lapatinib plus trastuzumab. Grade 3 or worse diarrhea was by far more common in both lapatinib groups (P less than .001), but grade 3 or worse febrile neutropenia and hepatotoxicity were similarly common.

The rate of New York Heart Association class III or IV congestive heart failure was 4% with trastuzumab alone, 4% with lapatinib alone, and 1% with the combination, differences that were not statistically significant.

Patients in the trastuzumab group were more likely to complete their therapy (78%) than their counterparts in the lapatinib group (68%) and in the combination group (63%) (P = .01).

About half of patients were able to have breast-conserving surgery, whether they received trastuzumab alone (54%), lapatinib alone (46%), or both drugs (50%).

Dr. Robidoux disclosed that he is a consultant to GlaxoSmithKline and receives honoraria and research funding from GlaxoSmithKline and Roche. Dr. von Minckwitz disclosed no relevant conflicts of interest.

CHICAGO  – Radiation therapy dramatically improves local control in ductal carcinoma in situ, even in cases having favorable features, investigators reported.

The randomized Radiation Therapy Oncology Group (RTOG) 9804 trial was conducted among 585 women who had "good-risk" ductal carcinoma in situ (DCIS), meaning small, asymptomatic tumors of low grade and with adequate resection margins after lumpectomy.

The main results showed that women had a significant 86% relative reduction in the risk of local failure if they received radiation therapy instead of observation. But the absolute 5-year rate of local failure was only about 3%, even without this intervention.

"We were able, using standard pathology methods and our Web-based RTOG pathology tool, to define good-risk or low-risk DCIS patients who had an extremely low event rate even with observation," said lead investigator Dr. Beryl McCormick at the annual meeting of the American Society of Clinical Oncology.

Nonetheless, "for this good-risk disease, the addition of radiation significantly reduced the risk of local failure. Clearly, we are expecting to follow this group out longer," added Dr. McCormick, a radiation oncologist and chief of the external beam radiotherapy service at Memorial Sloan-Kettering Cancer Center in New York.

"The study was a positive study," commented discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C. "The reasons for that are debatable. On this analysis, there was a lower recurrence rate in the excision-only group than had been predicted, but what drove the positive findings was the much lower rate in the radiation therapy group."

Dr. Hwang speculated that the use of tamoxifen by about two-thirds of women may have contributed to the low rate of local recurrence seen even in the absence of radiation therapy.

"Further follow-up is required, because many of these patients [had] a short follow-up that may explain why we saw such low recurrence risks in this study," she proposed.

Women with DCIS who were above age 26 were eligible for RTOG 9804 if they had no symptoms (their tumors had been found mammographically or incidentally), had only low or intermediate tumor grade, had a tumor size of 2.5 cm or less, and had a resection margin width of at least 3 mm.

The 585 study participants were randomly assigned in balanced fashion to observation or radiation therapy, each with or without tamoxifen. (Overall, 62% received the drug.) Radiation therapy began within 12 weeks of final surgery, and consisted of 42.5-50.4 Gy, with no boost.

The main trial results showed that the actuarial 5-year rate of local failure (invasive or noninvasive) in the treated breast was 3.2% in the observation group and 0.4% in the radiation therapy group, corresponding to an 86% reduction in risk (hazard ratio, 0.14; P = .002), Dr. McCormick reported.

In the radiation therapy group, there were no local failures in the same quadrant as the original tumor; in contrast, in the observation group, two-thirds of the failures were in the same quadrant.

The two groups were statistically indistinguishable with respect to the rate of contralateral breast events, disease-free survival, and overall survival.

The rate of acute grade 3 or worse nonhematologic toxicities was similar in the observation group and radiation therapy group (4.0% vs. 4.2%, respectively), although lower-grade toxicities were more common in the latter. The rate of late grade 3 or worse radiation therapy toxicity was 0.7% in the group given this therapy.

Dr. McCormick disclosed no relevant conflicts of interest. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.

CHICAGO  – Radiation therapy dramatically improves local control in ductal carcinoma in situ, even in cases having favorable features, investigators reported.

The randomized Radiation Therapy Oncology Group (RTOG) 9804 trial was conducted among 585 women who had "good-risk" ductal carcinoma in situ (DCIS), meaning small, asymptomatic tumors of low grade and with adequate resection margins after lumpectomy.

The main results showed that women had a significant 86% relative reduction in the risk of local failure if they received radiation therapy instead of observation. But the absolute 5-year rate of local failure was only about 3%, even without this intervention.

"We were able, using standard pathology methods and our Web-based RTOG pathology tool, to define good-risk or low-risk DCIS patients who had an extremely low event rate even with observation," said lead investigator Dr. Beryl McCormick at the annual meeting of the American Society of Clinical Oncology.

Nonetheless, "for this good-risk disease, the addition of radiation significantly reduced the risk of local failure. Clearly, we are expecting to follow this group out longer," added Dr. McCormick, a radiation oncologist and chief of the external beam radiotherapy service at Memorial Sloan-Kettering Cancer Center in New York.

"The study was a positive study," commented discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C. "The reasons for that are debatable. On this analysis, there was a lower recurrence rate in the excision-only group than had been predicted, but what drove the positive findings was the much lower rate in the radiation therapy group."

Dr. Hwang speculated that the use of tamoxifen by about two-thirds of women may have contributed to the low rate of local recurrence seen even in the absence of radiation therapy.

"Further follow-up is required, because many of these patients [had] a short follow-up that may explain why we saw such low recurrence risks in this study," she proposed.

Women with DCIS who were above age 26 were eligible for RTOG 9804 if they had no symptoms (their tumors had been found mammographically or incidentally), had only low or intermediate tumor grade, had a tumor size of 2.5 cm or less, and had a resection margin width of at least 3 mm.

The 585 study participants were randomly assigned in balanced fashion to observation or radiation therapy, each with or without tamoxifen. (Overall, 62% received the drug.) Radiation therapy began within 12 weeks of final surgery, and consisted of 42.5-50.4 Gy, with no boost.

The main trial results showed that the actuarial 5-year rate of local failure (invasive or noninvasive) in the treated breast was 3.2% in the observation group and 0.4% in the radiation therapy group, corresponding to an 86% reduction in risk (hazard ratio, 0.14; P = .002), Dr. McCormick reported.

In the radiation therapy group, there were no local failures in the same quadrant as the original tumor; in contrast, in the observation group, two-thirds of the failures were in the same quadrant.

The two groups were statistically indistinguishable with respect to the rate of contralateral breast events, disease-free survival, and overall survival.

The rate of acute grade 3 or worse nonhematologic toxicities was similar in the observation group and radiation therapy group (4.0% vs. 4.2%, respectively), although lower-grade toxicities were more common in the latter. The rate of late grade 3 or worse radiation therapy toxicity was 0.7% in the group given this therapy.

Dr. McCormick disclosed no relevant conflicts of interest. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.

CHICAGO  – Radiation therapy dramatically improves local control in ductal carcinoma in situ, even in cases having favorable features, investigators reported.

The randomized Radiation Therapy Oncology Group (RTOG) 9804 trial was conducted among 585 women who had "good-risk" ductal carcinoma in situ (DCIS), meaning small, asymptomatic tumors of low grade and with adequate resection margins after lumpectomy.

The main results showed that women had a significant 86% relative reduction in the risk of local failure if they received radiation therapy instead of observation. But the absolute 5-year rate of local failure was only about 3%, even without this intervention.

"We were able, using standard pathology methods and our Web-based RTOG pathology tool, to define good-risk or low-risk DCIS patients who had an extremely low event rate even with observation," said lead investigator Dr. Beryl McCormick at the annual meeting of the American Society of Clinical Oncology.

Nonetheless, "for this good-risk disease, the addition of radiation significantly reduced the risk of local failure. Clearly, we are expecting to follow this group out longer," added Dr. McCormick, a radiation oncologist and chief of the external beam radiotherapy service at Memorial Sloan-Kettering Cancer Center in New York.

"The study was a positive study," commented discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C. "The reasons for that are debatable. On this analysis, there was a lower recurrence rate in the excision-only group than had been predicted, but what drove the positive findings was the much lower rate in the radiation therapy group."

Dr. Hwang speculated that the use of tamoxifen by about two-thirds of women may have contributed to the low rate of local recurrence seen even in the absence of radiation therapy.

"Further follow-up is required, because many of these patients [had] a short follow-up that may explain why we saw such low recurrence risks in this study," she proposed.

Women with DCIS who were above age 26 were eligible for RTOG 9804 if they had no symptoms (their tumors had been found mammographically or incidentally), had only low or intermediate tumor grade, had a tumor size of 2.5 cm or less, and had a resection margin width of at least 3 mm.

The 585 study participants were randomly assigned in balanced fashion to observation or radiation therapy, each with or without tamoxifen. (Overall, 62% received the drug.) Radiation therapy began within 12 weeks of final surgery, and consisted of 42.5-50.4 Gy, with no boost.

The main trial results showed that the actuarial 5-year rate of local failure (invasive or noninvasive) in the treated breast was 3.2% in the observation group and 0.4% in the radiation therapy group, corresponding to an 86% reduction in risk (hazard ratio, 0.14; P = .002), Dr. McCormick reported.

In the radiation therapy group, there were no local failures in the same quadrant as the original tumor; in contrast, in the observation group, two-thirds of the failures were in the same quadrant.

The two groups were statistically indistinguishable with respect to the rate of contralateral breast events, disease-free survival, and overall survival.

The rate of acute grade 3 or worse nonhematologic toxicities was similar in the observation group and radiation therapy group (4.0% vs. 4.2%, respectively), although lower-grade toxicities were more common in the latter. The rate of late grade 3 or worse radiation therapy toxicity was 0.7% in the group given this therapy.

Dr. McCormick disclosed no relevant conflicts of interest. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.

CHICAGO – The new DCIS score, an offshoot of the Oncotype DX recurrence score, independently predicts the risk of ipsilateral recurrence or invasive disease in patients with ductal carcinoma in situ, according to a subgroup analysis from the prospective validation study.

The score correlated only moderately, poorly, or not at all with measures such as menopausal status and histologic grade among 327 patients with ductal carcinoma in situ (DCIS) treated with wide local excision and without radiation therapy, investigators reported.

And even after such measures were taken into account, each 50-point increase in the 100-point score was significantly associated with more than a doubling of the 10-year risk of recurrence or invasive disease in the same breast.

"The DCIS score provides independent information on ipsilateral breast risk beyond clinical and pathologic variables," lead author Dr. Sunil S. Badve said at the annual meeting of the American Society of Clinical Oncology.

"One can use the DCIS score to select patients with ... a clinically good prognosis who may have a higher DCIS score and may have a slightly [greater] risk than one would have estimated by traditional criteria," added Dr. Badve, a professor in the department of pathology and laboratory medicine and the department of internal medicine, and director of the Translational Genomics Core at Indiana University, Indianapolis.

"So particularly for the subset with a clinically good prognosis, we may be able to dissect which patients really might have a better prognosis and which patients may need to be more cautious."

Discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C., called particular attention to the weak association between nuclear grade and DCIS Score.

"This is a very important point to make and a response to the criticism that’s often heard that the DCIS score or the Oncotype score may just be a surrogate – and a very expensive one – for proliferative index or Ki-67," she commented.

Next-generation sequencing and advances in epigenomics, proteomics, and molecular characterization of stroma are likely to make it possible to further risk-stratify DCIS in the future, according to Dr. Hwang.

"But none of this is important unless we can implement it into treatment of patients. So how this is implemented in our everyday practice will be very important to analyze – whether it impacts decision making, and whether it gives patients satisfaction with the decisions they make will also be very important to look at," she added.

"Finally, in this increasingly resource-constrained environment, cost-effectiveness issues will also be very important to analyze as we go forward," she noted.

Study analyses were based on a subset of women from the E5194 trial, a prospective study to validate the DCIS score, which contains 12 of the 21 genes included in the Oncotype DX recurrence score used in estrogen receptor–positive early-stage breast cancer.

All of the women had DCIS treated with wide local excision. They had a median age of 61 years and a median tumor size of 7 mm. Twenty-nine percent received tamoxifen. The median duration of follow-up was 8.8 years.

Results showed that the DCIS score was only moderately correlated with histologic grade (r = 0.41-0.46) and with the percentage of cells showing comedo necrosis (r = 0.49), and was poorly correlated with tumor size (r = 0.18), Dr. Badve reported. And there was no correlation with age, menopausal status, DCIS histologic pattern, or margin status.

In a multivariate analysis, each 50-point increase in DCIS score was associated with more than a doubling of the risk of a recurrence of DCIS or the occurrence of invasive disease in the ipsilateral breast (hazard ratio, 2.41; P = .02).

In addition, tumor size was an independent positive predictor of risk (HR for each 5-mm increase, 1.52; P = .01), and postmenopausal status was an independent negative predictor (HR, 0.49; P = .02).

Dr. Badve disclosed that he is a consultant to Genomic Health, which makes the assay. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.

CHICAGO – The new DCIS score, an offshoot of the Oncotype DX recurrence score, independently predicts the risk of ipsilateral recurrence or invasive disease in patients with ductal carcinoma in situ, according to a subgroup analysis from the prospective validation study.

The score correlated only moderately, poorly, or not at all with measures such as menopausal status and histologic grade among 327 patients with ductal carcinoma in situ (DCIS) treated with wide local excision and without radiation therapy, investigators reported.

And even after such measures were taken into account, each 50-point increase in the 100-point score was significantly associated with more than a doubling of the 10-year risk of recurrence or invasive disease in the same breast.

"The DCIS score provides independent information on ipsilateral breast risk beyond clinical and pathologic variables," lead author Dr. Sunil S. Badve said at the annual meeting of the American Society of Clinical Oncology.

"One can use the DCIS score to select patients with ... a clinically good prognosis who may have a higher DCIS score and may have a slightly [greater] risk than one would have estimated by traditional criteria," added Dr. Badve, a professor in the department of pathology and laboratory medicine and the department of internal medicine, and director of the Translational Genomics Core at Indiana University, Indianapolis.

"So particularly for the subset with a clinically good prognosis, we may be able to dissect which patients really might have a better prognosis and which patients may need to be more cautious."

Discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C., called particular attention to the weak association between nuclear grade and DCIS Score.

"This is a very important point to make and a response to the criticism that’s often heard that the DCIS score or the Oncotype score may just be a surrogate – and a very expensive one – for proliferative index or Ki-67," she commented.

Next-generation sequencing and advances in epigenomics, proteomics, and molecular characterization of stroma are likely to make it possible to further risk-stratify DCIS in the future, according to Dr. Hwang.

"But none of this is important unless we can implement it into treatment of patients. So how this is implemented in our everyday practice will be very important to analyze – whether it impacts decision making, and whether it gives patients satisfaction with the decisions they make will also be very important to look at," she added.

"Finally, in this increasingly resource-constrained environment, cost-effectiveness issues will also be very important to analyze as we go forward," she noted.

Study analyses were based on a subset of women from the E5194 trial, a prospective study to validate the DCIS score, which contains 12 of the 21 genes included in the Oncotype DX recurrence score used in estrogen receptor–positive early-stage breast cancer.

All of the women had DCIS treated with wide local excision. They had a median age of 61 years and a median tumor size of 7 mm. Twenty-nine percent received tamoxifen. The median duration of follow-up was 8.8 years.

Results showed that the DCIS score was only moderately correlated with histologic grade (r = 0.41-0.46) and with the percentage of cells showing comedo necrosis (r = 0.49), and was poorly correlated with tumor size (r = 0.18), Dr. Badve reported. And there was no correlation with age, menopausal status, DCIS histologic pattern, or margin status.

In a multivariate analysis, each 50-point increase in DCIS score was associated with more than a doubling of the risk of a recurrence of DCIS or the occurrence of invasive disease in the ipsilateral breast (hazard ratio, 2.41; P = .02).

In addition, tumor size was an independent positive predictor of risk (HR for each 5-mm increase, 1.52; P = .01), and postmenopausal status was an independent negative predictor (HR, 0.49; P = .02).

Dr. Badve disclosed that he is a consultant to Genomic Health, which makes the assay. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.

CHICAGO – The new DCIS score, an offshoot of the Oncotype DX recurrence score, independently predicts the risk of ipsilateral recurrence or invasive disease in patients with ductal carcinoma in situ, according to a subgroup analysis from the prospective validation study.

The score correlated only moderately, poorly, or not at all with measures such as menopausal status and histologic grade among 327 patients with ductal carcinoma in situ (DCIS) treated with wide local excision and without radiation therapy, investigators reported.

And even after such measures were taken into account, each 50-point increase in the 100-point score was significantly associated with more than a doubling of the 10-year risk of recurrence or invasive disease in the same breast.

"The DCIS score provides independent information on ipsilateral breast risk beyond clinical and pathologic variables," lead author Dr. Sunil S. Badve said at the annual meeting of the American Society of Clinical Oncology.

"One can use the DCIS score to select patients with ... a clinically good prognosis who may have a higher DCIS score and may have a slightly [greater] risk than one would have estimated by traditional criteria," added Dr. Badve, a professor in the department of pathology and laboratory medicine and the department of internal medicine, and director of the Translational Genomics Core at Indiana University, Indianapolis.

"So particularly for the subset with a clinically good prognosis, we may be able to dissect which patients really might have a better prognosis and which patients may need to be more cautious."

Discussant Dr. Eun-Sil Shelley Hwang of Duke University Medical Center in Durham, N.C., called particular attention to the weak association between nuclear grade and DCIS Score.

"This is a very important point to make and a response to the criticism that’s often heard that the DCIS score or the Oncotype score may just be a surrogate – and a very expensive one – for proliferative index or Ki-67," she commented.

Next-generation sequencing and advances in epigenomics, proteomics, and molecular characterization of stroma are likely to make it possible to further risk-stratify DCIS in the future, according to Dr. Hwang.

"But none of this is important unless we can implement it into treatment of patients. So how this is implemented in our everyday practice will be very important to analyze – whether it impacts decision making, and whether it gives patients satisfaction with the decisions they make will also be very important to look at," she added.

"Finally, in this increasingly resource-constrained environment, cost-effectiveness issues will also be very important to analyze as we go forward," she noted.

Study analyses were based on a subset of women from the E5194 trial, a prospective study to validate the DCIS score, which contains 12 of the 21 genes included in the Oncotype DX recurrence score used in estrogen receptor–positive early-stage breast cancer.

All of the women had DCIS treated with wide local excision. They had a median age of 61 years and a median tumor size of 7 mm. Twenty-nine percent received tamoxifen. The median duration of follow-up was 8.8 years.

Results showed that the DCIS score was only moderately correlated with histologic grade (r = 0.41-0.46) and with the percentage of cells showing comedo necrosis (r = 0.49), and was poorly correlated with tumor size (r = 0.18), Dr. Badve reported. And there was no correlation with age, menopausal status, DCIS histologic pattern, or margin status.

In a multivariate analysis, each 50-point increase in DCIS score was associated with more than a doubling of the risk of a recurrence of DCIS or the occurrence of invasive disease in the ipsilateral breast (hazard ratio, 2.41; P = .02).

In addition, tumor size was an independent positive predictor of risk (HR for each 5-mm increase, 1.52; P = .01), and postmenopausal status was an independent negative predictor (HR, 0.49; P = .02).

Dr. Badve disclosed that he is a consultant to Genomic Health, which makes the assay. Dr. Hwang disclosed that she is a consultant to Genomic Health and receives research funding from Merck and Novartis.

CHICAGO – Some patients will go to great lengths – literally – to receive proton beam radiotherapy for prostate cancer, but there is still little evidence to date to support its use over intensity-modulated radiotherapy in this population, investigators noted at the annual meeting of the American Society of Clinical Oncology.

Although some patients traveled cross-country to be treated at one of six proton beam therapy (PBT) centers, the only significant difference in adverse event outcomes between the costlier proton therapy and the more widely available intensity-modulated radiotherapy (IMRT) was lower 6-month genitourinary toxicity with PBT (5.9% vs. 9.5%; odds ratio, 0.60; P = .03), reported Dr. James B. Yu, a radiation oncologist at Yale University in New Haven, Conn., and colleagues.

"We found that the rate of complications was transiently better for proton therapy, but at 1 year there was no difference between that and IMRT," Dr. Yu said in an interview. He reported the 12-month rate of genitourinary complications as statistically similar, at 18.8% with PBT and 17.5% with IMRT.

There were no significant differences between the two types of therapy in gastrointestinal or other toxicities at either 6 or 12 months.

The Yale investigators obtained data on all Medicare claims in 2008 and 2009 from the Medicare Chronic Condition Warehouse database. Looking for both patterns of care and clinical outcomes, they identified a total of 27,647 men (aged 66-94 years) who received either PBT or IMRT.

Patients All Over the Map

They also found that the 421 men (1.5% of the total cohort) who underwent PBT came from all over the U.S. map, and that more of them sought treatment at centers 75 miles or farther from where they lived (5.7%, compared with 4.9% treated at centers within 75 miles of home).

Curiously, some patients traveled across the entire country even when there was a proton facility in their backyard. For example, several patients flew from California, where there is a proton therapy center at Loma Linda University, to the University of Florida in Jacksonville, whereas others traveled from Boston, where Massachusetts General Hospital has a proton beam center, to California.

"We’re not really sure why they did this, but our hypothesis is that there are two tiers of health care in this country, with some folks who can and are willing to fly across the country for treatment, and others who go down the street for their care," Dr. Yu said.

Patients treated with PBT tended to be younger and healthier, and have a higher socioeconomic status, the investigators found.

Findings in Line With Other Studies

Dr. Jason A. Efstathiou, a radiation oncologist at Massachusetts General Hospital, which has been delivering proton therapy since the 1940s, says that the findings are in line with those of other comparative studies, some showing a modest early benefit in terms of adverse events for proton beams, and others showing an advantage for IMRT over proton therapy or conformal radiation in patients with prostate cancer.

"There are results out there supporting differences, largely modest differences, between radiation therapy types, but they’re kind of all over the map," he said in an interview.

For example, he and colleagues presented data from a prospective study at the 2012 ASCO Genitourinary Cancers Symposium showing that in patient-reported quality of life domains, "PBT appears to be associated with lower gastrointestinal and urinary toxicity early after treatment, with similar late outcomes," they wrote.

In a different study, published in April 2012 in JAMA, investigators at the University of North Carolina in Chapel Hill found that "among patients with nonmetastatic prostate cancer, the use of IMRT compared with conformal radiation therapy was associated with less gastrointestinal morbidity and fewer hip fractures, but more erectile dysfunction; IMRT compared with proton therapy was associated with less gastrointestinal morbidity" (JAMA 2012;307:1611-20).

To get a better handle on this complex issue, Massachusetts General Hospital, in partnership with the University of Pennsylvania, is embarking on a randomized study of the comparative efficacy and safety of PBT vs. IMRT. The study will look at 6-month efficacy outcomes, cost effectiveness and toxicities at 2 years, and survival and other end points out to 10 years. Dr. Efstathiou is the principal investigator of that study. He was not involved in the study by Dr.Yu and his colleagues.

The current study was conducted with assistance from the Centers for Medicare and Medicaid Services. Dr. Yu and Dr. Efstathiou reported having no relevant disclosures.

CHICAGO – Some patients will go to great lengths – literally – to receive proton beam radiotherapy for prostate cancer, but there is still little evidence to date to support its use over intensity-modulated radiotherapy in this population, investigators noted at the annual meeting of the American Society of Clinical Oncology.

Although some patients traveled cross-country to be treated at one of six proton beam therapy (PBT) centers, the only significant difference in adverse event outcomes between the costlier proton therapy and the more widely available intensity-modulated radiotherapy (IMRT) was lower 6-month genitourinary toxicity with PBT (5.9% vs. 9.5%; odds ratio, 0.60; P = .03), reported Dr. James B. Yu, a radiation oncologist at Yale University in New Haven, Conn., and colleagues.

"We found that the rate of complications was transiently better for proton therapy, but at 1 year there was no difference between that and IMRT," Dr. Yu said in an interview. He reported the 12-month rate of genitourinary complications as statistically similar, at 18.8% with PBT and 17.5% with IMRT.

There were no significant differences between the two types of therapy in gastrointestinal or other toxicities at either 6 or 12 months.

The Yale investigators obtained data on all Medicare claims in 2008 and 2009 from the Medicare Chronic Condition Warehouse database. Looking for both patterns of care and clinical outcomes, they identified a total of 27,647 men (aged 66-94 years) who received either PBT or IMRT.

Patients All Over the Map

They also found that the 421 men (1.5% of the total cohort) who underwent PBT came from all over the U.S. map, and that more of them sought treatment at centers 75 miles or farther from where they lived (5.7%, compared with 4.9% treated at centers within 75 miles of home).

Curiously, some patients traveled across the entire country even when there was a proton facility in their backyard. For example, several patients flew from California, where there is a proton therapy center at Loma Linda University, to the University of Florida in Jacksonville, whereas others traveled from Boston, where Massachusetts General Hospital has a proton beam center, to California.

"We’re not really sure why they did this, but our hypothesis is that there are two tiers of health care in this country, with some folks who can and are willing to fly across the country for treatment, and others who go down the street for their care," Dr. Yu said.

Patients treated with PBT tended to be younger and healthier, and have a higher socioeconomic status, the investigators found.

Findings in Line With Other Studies

Dr. Jason A. Efstathiou, a radiation oncologist at Massachusetts General Hospital, which has been delivering proton therapy since the 1940s, says that the findings are in line with those of other comparative studies, some showing a modest early benefit in terms of adverse events for proton beams, and others showing an advantage for IMRT over proton therapy or conformal radiation in patients with prostate cancer.

"There are results out there supporting differences, largely modest differences, between radiation therapy types, but they’re kind of all over the map," he said in an interview.

For example, he and colleagues presented data from a prospective study at the 2012 ASCO Genitourinary Cancers Symposium showing that in patient-reported quality of life domains, "PBT appears to be associated with lower gastrointestinal and urinary toxicity early after treatment, with similar late outcomes," they wrote.

In a different study, published in April 2012 in JAMA, investigators at the University of North Carolina in Chapel Hill found that "among patients with nonmetastatic prostate cancer, the use of IMRT compared with conformal radiation therapy was associated with less gastrointestinal morbidity and fewer hip fractures, but more erectile dysfunction; IMRT compared with proton therapy was associated with less gastrointestinal morbidity" (JAMA 2012;307:1611-20).

To get a better handle on this complex issue, Massachusetts General Hospital, in partnership with the University of Pennsylvania, is embarking on a randomized study of the comparative efficacy and safety of PBT vs. IMRT. The study will look at 6-month efficacy outcomes, cost effectiveness and toxicities at 2 years, and survival and other end points out to 10 years. Dr. Efstathiou is the principal investigator of that study. He was not involved in the study by Dr.Yu and his colleagues.

The current study was conducted with assistance from the Centers for Medicare and Medicaid Services. Dr. Yu and Dr. Efstathiou reported having no relevant disclosures.

CHICAGO – Some patients will go to great lengths – literally – to receive proton beam radiotherapy for prostate cancer, but there is still little evidence to date to support its use over intensity-modulated radiotherapy in this population, investigators noted at the annual meeting of the American Society of Clinical Oncology.

Although some patients traveled cross-country to be treated at one of six proton beam therapy (PBT) centers, the only significant difference in adverse event outcomes between the costlier proton therapy and the more widely available intensity-modulated radiotherapy (IMRT) was lower 6-month genitourinary toxicity with PBT (5.9% vs. 9.5%; odds ratio, 0.60; P = .03), reported Dr. James B. Yu, a radiation oncologist at Yale University in New Haven, Conn., and colleagues.

"We found that the rate of complications was transiently better for proton therapy, but at 1 year there was no difference between that and IMRT," Dr. Yu said in an interview. He reported the 12-month rate of genitourinary complications as statistically similar, at 18.8% with PBT and 17.5% with IMRT.

There were no significant differences between the two types of therapy in gastrointestinal or other toxicities at either 6 or 12 months.

The Yale investigators obtained data on all Medicare claims in 2008 and 2009 from the Medicare Chronic Condition Warehouse database. Looking for both patterns of care and clinical outcomes, they identified a total of 27,647 men (aged 66-94 years) who received either PBT or IMRT.

Patients All Over the Map

They also found that the 421 men (1.5% of the total cohort) who underwent PBT came from all over the U.S. map, and that more of them sought treatment at centers 75 miles or farther from where they lived (5.7%, compared with 4.9% treated at centers within 75 miles of home).

Curiously, some patients traveled across the entire country even when there was a proton facility in their backyard. For example, several patients flew from California, where there is a proton therapy center at Loma Linda University, to the University of Florida in Jacksonville, whereas others traveled from Boston, where Massachusetts General Hospital has a proton beam center, to California.

"We’re not really sure why they did this, but our hypothesis is that there are two tiers of health care in this country, with some folks who can and are willing to fly across the country for treatment, and others who go down the street for their care," Dr. Yu said.

Patients treated with PBT tended to be younger and healthier, and have a higher socioeconomic status, the investigators found.

Findings in Line With Other Studies

Dr. Jason A. Efstathiou, a radiation oncologist at Massachusetts General Hospital, which has been delivering proton therapy since the 1940s, says that the findings are in line with those of other comparative studies, some showing a modest early benefit in terms of adverse events for proton beams, and others showing an advantage for IMRT over proton therapy or conformal radiation in patients with prostate cancer.

"There are results out there supporting differences, largely modest differences, between radiation therapy types, but they’re kind of all over the map," he said in an interview.

For example, he and colleagues presented data from a prospective study at the 2012 ASCO Genitourinary Cancers Symposium showing that in patient-reported quality of life domains, "PBT appears to be associated with lower gastrointestinal and urinary toxicity early after treatment, with similar late outcomes," they wrote.

In a different study, published in April 2012 in JAMA, investigators at the University of North Carolina in Chapel Hill found that "among patients with nonmetastatic prostate cancer, the use of IMRT compared with conformal radiation therapy was associated with less gastrointestinal morbidity and fewer hip fractures, but more erectile dysfunction; IMRT compared with proton therapy was associated with less gastrointestinal morbidity" (JAMA 2012;307:1611-20).

To get a better handle on this complex issue, Massachusetts General Hospital, in partnership with the University of Pennsylvania, is embarking on a randomized study of the comparative efficacy and safety of PBT vs. IMRT. The study will look at 6-month efficacy outcomes, cost effectiveness and toxicities at 2 years, and survival and other end points out to 10 years. Dr. Efstathiou is the principal investigator of that study. He was not involved in the study by Dr.Yu and his colleagues.

The current study was conducted with assistance from the Centers for Medicare and Medicaid Services. Dr. Yu and Dr. Efstathiou reported having no relevant disclosures.

CHICAGO – Lower doses of the experimental agent cabozantinib may maintain efficacy with improved tolerability in men with metastatic castration-resistant prostate cancer, a dose-finding study suggests.

Cabozantinib, an oral inhibitor of MET and VEGFR-2 (vascular endothelial growth factor receptor–2), produced responses in 76% of men with metastatic castration-resistant prostate cancer (CRPC) in a previous phase II discontinuation trial. At the daily dose of 100 mg, however, 51% of patients required dose reductions and 10% stopped using the drug completely because of significant toxicities.

Based on the results, the study was amended to add a nonrandomized cohort exploring two daily dose levels: 100 mg in 93 men and 40 mg in 51 men, all of whom had CRPC with bone metastases despite prior docetaxel chemotherapy, as well as radiographic progression within 6 months of prior taxane therapy.

Lower Dose, Less Toxicity

A separate dose-finding study was also initiated, exploring 20-mg and 40-mg doses among 36 men with CRPC and bone metastases.

Patrice Wendling/IMNG Medical Media

In this study, a bone scan response was achieved in 16 of 24 patients (67%) receiving cabozantinib 40 mg, Dr. Richard J. Lee reported in a poster at the annual meeting of the American Society of Clinical Oncology. The median change in bone lesion area was –62%. Response was assessed using a Food and Drug Administration–approved, computer-aided detection system, and was defined as at least a 30% decrease in total bone scan lesion area.

The 40-mg-dose was also associated with better tolerability than that previously reported for 100 mg daily, according to Dr. Lee of the cancer center at Massachusetts General Hospital in Boston. No dose reductions or delays were required through the first 12 weeks of therapy, although two patients stopped therapy because of fatigue or weight loss/anorexia at weeks 19 and 36.

Cabozantinib 20 mg daily was less active than the 40-mg dose, with only 1 of 10 evaluable patients achieving a response at week 6. Five patients were escalated to 40 mg daily and three (60%) achieved a bone scan response at week 12.

Investigators observed substantial reductions in circulating tumor cells (CTCs) – an increasingly important measure of tumor burden in prostate cancer – that seem to correlate with bone scan results, Dr. Lee said in an interview. After 24 weeks of therapy, 58% of 12 evaluable patients converted to less than 5 CTCs per 7.5 mL of blood.

Overall, lower-dose cabozantinib was very well tolerated, he said. One patient on daily 20-mg and two patients on daily 40-mg doses discontinued treatment because of a venous thromboembolic event. Dr. Lee noted that it’s hard to say whether the VTEs were drug related in patients with such heavily pretreated, advanced disease. At baseline, 44% of patients had received prior chemotherapy and 28% had soft tissue disease.

Activity and Toxicity Persist at 100 mg

Results from the 100-mg cohort of the amended phase II study were reported in a separate oral presentation at the meeting, with complete or partial bone scan responses achieved in 67% of men.

Patrice Wendling/IMNG Medical Media

Evidence of tumor regression occurred in 80% of patients, pain scores were reduced by a median of 46% of patients, and 56% decreased or discontinued narcotics, said Dr. Matthew R. Smith, director of the genitourinary malignancies program at the cancer center of the Massachusetts General Hospital.

The median duration of response was 5.4 months, and activity occurred regardless of prior abiraterone (Zytiga) and/or cabazitaxel (Jevtana) therapy. Among 62 evaluable patients, 39% converted to less than 5 CTCs per 7.5 mL of blood.

Still, 84% of patients who were treated with 100 mg daily experienced at least one dose reduction because of an adverse event. Grade 3 fatigue and diarrhea occurred in 26% and 11% of patients, respectively, with grade 4 venous thrombosis in 5%. One patient with extensive liver disease had a portal vein thrombosis and died of liver failure, he said.

Discussant Dr. Karim Fizazi of the Institut de Cancérologie Gustave Roussy in Villejuif, France, called the bone scan improvement and pain effect impressive, and said that the 39% CTC conversion rate is a very important finding. The rest of the results were mainly confirmation of last year’s data, he said.

Randomized Trials Started

Two phase III studies have recently been initiated. COMET-1 is comparing 60-mg daily cabozantinib vs. twice-daily 5-mg prednisone in metastatic CRPC that progressed after docetaxel and abiraterone (Zytiga) and/or MDV3100. COMET-2 is comparing cabozantinib vs. mitoxantrone (Novantrone) plus prednisone in previously treated, symptomatic CRPC.

Cabozantinib is also being studied in a variety of other cancers, including heavily pretreated, refractory renal cell carcinoma and medullary thyroid cancer.

Exelixis sponsored both trials. Dr. Lee reported no conflicts. Dr. Smith and several of his coauthors reported a consultant/advisory role with and research funding from Exelixis. Dr. Fizazi reported a consultant/advisory role with OncoGenex and Exelixis.

CHICAGO – Lower doses of the experimental agent cabozantinib may maintain efficacy with improved tolerability in men with metastatic castration-resistant prostate cancer, a dose-finding study suggests.

Cabozantinib, an oral inhibitor of MET and VEGFR-2 (vascular endothelial growth factor receptor–2), produced responses in 76% of men with metastatic castration-resistant prostate cancer (CRPC) in a previous phase II discontinuation trial. At the daily dose of 100 mg, however, 51% of patients required dose reductions and 10% stopped using the drug completely because of significant toxicities.

Based on the results, the study was amended to add a nonrandomized cohort exploring two daily dose levels: 100 mg in 93 men and 40 mg in 51 men, all of whom had CRPC with bone metastases despite prior docetaxel chemotherapy, as well as radiographic progression within 6 months of prior taxane therapy.

Lower Dose, Less Toxicity

A separate dose-finding study was also initiated, exploring 20-mg and 40-mg doses among 36 men with CRPC and bone metastases.

Patrice Wendling/IMNG Medical Media

In this study, a bone scan response was achieved in 16 of 24 patients (67%) receiving cabozantinib 40 mg, Dr. Richard J. Lee reported in a poster at the annual meeting of the American Society of Clinical Oncology. The median change in bone lesion area was –62%. Response was assessed using a Food and Drug Administration–approved, computer-aided detection system, and was defined as at least a 30% decrease in total bone scan lesion area.

The 40-mg-dose was also associated with better tolerability than that previously reported for 100 mg daily, according to Dr. Lee of the cancer center at Massachusetts General Hospital in Boston. No dose reductions or delays were required through the first 12 weeks of therapy, although two patients stopped therapy because of fatigue or weight loss/anorexia at weeks 19 and 36.

Cabozantinib 20 mg daily was less active than the 40-mg dose, with only 1 of 10 evaluable patients achieving a response at week 6. Five patients were escalated to 40 mg daily and three (60%) achieved a bone scan response at week 12.

Investigators observed substantial reductions in circulating tumor cells (CTCs) – an increasingly important measure of tumor burden in prostate cancer – that seem to correlate with bone scan results, Dr. Lee said in an interview. After 24 weeks of therapy, 58% of 12 evaluable patients converted to less than 5 CTCs per 7.5 mL of blood.

Overall, lower-dose cabozantinib was very well tolerated, he said. One patient on daily 20-mg and two patients on daily 40-mg doses discontinued treatment because of a venous thromboembolic event. Dr. Lee noted that it’s hard to say whether the VTEs were drug related in patients with such heavily pretreated, advanced disease. At baseline, 44% of patients had received prior chemotherapy and 28% had soft tissue disease.

Activity and Toxicity Persist at 100 mg

Results from the 100-mg cohort of the amended phase II study were reported in a separate oral presentation at the meeting, with complete or partial bone scan responses achieved in 67% of men.

Patrice Wendling/IMNG Medical Media

Evidence of tumor regression occurred in 80% of patients, pain scores were reduced by a median of 46% of patients, and 56% decreased or discontinued narcotics, said Dr. Matthew R. Smith, director of the genitourinary malignancies program at the cancer center of the Massachusetts General Hospital.

The median duration of response was 5.4 months, and activity occurred regardless of prior abiraterone (Zytiga) and/or cabazitaxel (Jevtana) therapy. Among 62 evaluable patients, 39% converted to less than 5 CTCs per 7.5 mL of blood.

Still, 84% of patients who were treated with 100 mg daily experienced at least one dose reduction because of an adverse event. Grade 3 fatigue and diarrhea occurred in 26% and 11% of patients, respectively, with grade 4 venous thrombosis in 5%. One patient with extensive liver disease had a portal vein thrombosis and died of liver failure, he said.

Discussant Dr. Karim Fizazi of the Institut de Cancérologie Gustave Roussy in Villejuif, France, called the bone scan improvement and pain effect impressive, and said that the 39% CTC conversion rate is a very important finding. The rest of the results were mainly confirmation of last year’s data, he said.

Randomized Trials Started

Two phase III studies have recently been initiated. COMET-1 is comparing 60-mg daily cabozantinib vs. twice-daily 5-mg prednisone in metastatic CRPC that progressed after docetaxel and abiraterone (Zytiga) and/or MDV3100. COMET-2 is comparing cabozantinib vs. mitoxantrone (Novantrone) plus prednisone in previously treated, symptomatic CRPC.

Cabozantinib is also being studied in a variety of other cancers, including heavily pretreated, refractory renal cell carcinoma and medullary thyroid cancer.

Exelixis sponsored both trials. Dr. Lee reported no conflicts. Dr. Smith and several of his coauthors reported a consultant/advisory role with and research funding from Exelixis. Dr. Fizazi reported a consultant/advisory role with OncoGenex and Exelixis.

CHICAGO – Lower doses of the experimental agent cabozantinib may maintain efficacy with improved tolerability in men with metastatic castration-resistant prostate cancer, a dose-finding study suggests.

Cabozantinib, an oral inhibitor of MET and VEGFR-2 (vascular endothelial growth factor receptor–2), produced responses in 76% of men with metastatic castration-resistant prostate cancer (CRPC) in a previous phase II discontinuation trial. At the daily dose of 100 mg, however, 51% of patients required dose reductions and 10% stopped using the drug completely because of significant toxicities.

Based on the results, the study was amended to add a nonrandomized cohort exploring two daily dose levels: 100 mg in 93 men and 40 mg in 51 men, all of whom had CRPC with bone metastases despite prior docetaxel chemotherapy, as well as radiographic progression within 6 months of prior taxane therapy.

Lower Dose, Less Toxicity

A separate dose-finding study was also initiated, exploring 20-mg and 40-mg doses among 36 men with CRPC and bone metastases.

Patrice Wendling/IMNG Medical Media

In this study, a bone scan response was achieved in 16 of 24 patients (67%) receiving cabozantinib 40 mg, Dr. Richard J. Lee reported in a poster at the annual meeting of the American Society of Clinical Oncology. The median change in bone lesion area was –62%. Response was assessed using a Food and Drug Administration–approved, computer-aided detection system, and was defined as at least a 30% decrease in total bone scan lesion area.

The 40-mg-dose was also associated with better tolerability than that previously reported for 100 mg daily, according to Dr. Lee of the cancer center at Massachusetts General Hospital in Boston. No dose reductions or delays were required through the first 12 weeks of therapy, although two patients stopped therapy because of fatigue or weight loss/anorexia at weeks 19 and 36.

Cabozantinib 20 mg daily was less active than the 40-mg dose, with only 1 of 10 evaluable patients achieving a response at week 6. Five patients were escalated to 40 mg daily and three (60%) achieved a bone scan response at week 12.

Investigators observed substantial reductions in circulating tumor cells (CTCs) – an increasingly important measure of tumor burden in prostate cancer – that seem to correlate with bone scan results, Dr. Lee said in an interview. After 24 weeks of therapy, 58% of 12 evaluable patients converted to less than 5 CTCs per 7.5 mL of blood.

Overall, lower-dose cabozantinib was very well tolerated, he said. One patient on daily 20-mg and two patients on daily 40-mg doses discontinued treatment because of a venous thromboembolic event. Dr. Lee noted that it’s hard to say whether the VTEs were drug related in patients with such heavily pretreated, advanced disease. At baseline, 44% of patients had received prior chemotherapy and 28% had soft tissue disease.

Activity and Toxicity Persist at 100 mg

Results from the 100-mg cohort of the amended phase II study were reported in a separate oral presentation at the meeting, with complete or partial bone scan responses achieved in 67% of men.

Patrice Wendling/IMNG Medical Media

Evidence of tumor regression occurred in 80% of patients, pain scores were reduced by a median of 46% of patients, and 56% decreased or discontinued narcotics, said Dr. Matthew R. Smith, director of the genitourinary malignancies program at the cancer center of the Massachusetts General Hospital.

The median duration of response was 5.4 months, and activity occurred regardless of prior abiraterone (Zytiga) and/or cabazitaxel (Jevtana) therapy. Among 62 evaluable patients, 39% converted to less than 5 CTCs per 7.5 mL of blood.

Still, 84% of patients who were treated with 100 mg daily experienced at least one dose reduction because of an adverse event. Grade 3 fatigue and diarrhea occurred in 26% and 11% of patients, respectively, with grade 4 venous thrombosis in 5%. One patient with extensive liver disease had a portal vein thrombosis and died of liver failure, he said.

Discussant Dr. Karim Fizazi of the Institut de Cancérologie Gustave Roussy in Villejuif, France, called the bone scan improvement and pain effect impressive, and said that the 39% CTC conversion rate is a very important finding. The rest of the results were mainly confirmation of last year’s data, he said.

Randomized Trials Started

Two phase III studies have recently been initiated. COMET-1 is comparing 60-mg daily cabozantinib vs. twice-daily 5-mg prednisone in metastatic CRPC that progressed after docetaxel and abiraterone (Zytiga) and/or MDV3100. COMET-2 is comparing cabozantinib vs. mitoxantrone (Novantrone) plus prednisone in previously treated, symptomatic CRPC.

Cabozantinib is also being studied in a variety of other cancers, including heavily pretreated, refractory renal cell carcinoma and medullary thyroid cancer.

Exelixis sponsored both trials. Dr. Lee reported no conflicts. Dr. Smith and several of his coauthors reported a consultant/advisory role with and research funding from Exelixis. Dr. Fizazi reported a consultant/advisory role with OncoGenex and Exelixis.