Sharon Worcester

BARCELONA – Adding veliparib to frontline chemotherapy and maintenance therapy significantly extended progression-free survival in women with high-grade serous epithelial ovarian cancer (HGSC) in the phase 3 VELIA/GOG-3005 trial.

The benefit associated with the oral poly (ADP-ribose) polymerase (PARP) inhibitor was seen in all women with newly diagnosed HGSC included in the randomized, placebo-controlled trial, regardless of BRCA mutation (BRCAm) status or homologous recombination deficiency (HRD) status, Robert L. Coleman, MD, reported at the European Society for Medical Oncology Congress.

Of 1,140 patients enrolled in the international, multicenter trial, 26% had a BRCAm and 55% were HRD positive. In the intent-to-treat population, median progression-free survival (PFS) was 23.5 months in 382 patients who received carboplatin/paclitaxel (CP) plus veliparib followed by veliparib maintenance (veliparib group 1) versus 17.3 months in 375 patients treated with CP alone followed by placebo maintenance (the control group) (hazard ratio, 0.68), according to Dr. Coleman, professor and Ann Rife Cox Chair in Gynecology in the department of gynecologic oncology and reproductive medicine in the division of surgery at the University of Texas MD Anderson Cancer Center, Houston.

Among 200 patients with a deleterious BRCAm, including 108 in the veliparib 1 group and 92 in the control group, median PFS was 34.7 and 22.0 months, respectively (HR, 0.44), and among 421 patients with HRD and BRCAm, including 214 in the veliparib 1 group and 207 in the control group, median PFS was 31.9 versus 20.5 months (HR, 0.57).

In the non-HRD population of 249 patients (125 in the veliparib 1 arm and 124 in the control arm), median PFS was 15.0 and 11.5 months, respectively.

The PFS for an additional group of 383 patients treated with CP plus veliparib followed by placebo maintenance (veliparib group 2) didn’t differ significantly from either the veliparib 1 or the control group (HR, 1.07 vs. the control group in the intent-to-treat population), and the PFS rates were also similar for the BRCAm and HRD-positive patients in the veliparib 2 group and control group, he noted, explaining that the main focus of his presentation was the primary study endpoint of median PFS in the veliparib 1 versus control group.

The overall response rates at the end of treatment in the intent-to-treat populations were 84% in the veliparib 1 group, 74% in the control group, and 79% in the veliparib 2 group, Dr. Coleman said, adding that response rates were numerically higher in both veliparib-containing arms.

Additional analyses, including overall survival, will be reported at a future date, he noted.

Study participants were adults with a mean age of 62 years who had previously untreated stage III-IV HGSC. Treatment included six cycles of CP at 21-day intervals, with paclitaxel given either weekly or every 3 weeks following primary cytoreduction or neoadjuvant chemotherapy with interval cytoreduction. The veliparib dose when given with CP was 150 mg twice daily, and the veliparib maintenance dose was 400 mg twice daily for 30 cycles.

Relative CP dose intensities were similar between arms, and grade 3-4 adverse events were similar in the veliparib 1 and control groups during CP – with the exception of thrombocytopenia, which occurred in 27% and 8% of patients in the groups, respectively. During maintenance, the rates of any grade 3-4 adverse events were higher in the veliparib 1 group versus the control group (45% vs. 32%), but serious adverse event rates were similar in the groups (17% and 19%).

Observed toxicities were consistent with the known veliparib safety profile, Dr. Coleman said.

The findings are notable, as PARP inhibitors have proven effective in ovarian cancer, but their use in combination with chemotherapy has been challenging because of hematologic toxicity, he added, explaining, however, that veliparib has not only been shown to have single agent activity in germline BRCAm recurrent ovarian cancer patients, but also has binding characteristics – namely increased protein poly ADP-ribosylation and decreased PARP trapping – that could allow for its use in combination with chemotherapy.

VELIA/GOG-3005 is the first randomized trial designed to enroll only untreated patients with advanced-stage HGSC regardless of BRCA status, surgical management, or response to treatment, and the findings suggest that veliparib can be safely administered with CP and should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer, he concluded.

In an ESMO press release, Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, said that this trial, along with others such as the SOLO-1 trial, the PAOLA-1/ENGOT-Ov25 trial, and the PRIMA/ENGOT-OV26/GOG-3012 trial, which each looked at integrating PARP inhibitors into first-line treatment, represents “a milestone for patients.”

“After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression free survival and hopefully we will improve long-term outcome,” she said.

The study was sponsored by AbbVie. Dr. Coleman and Dr. Oaknin reported relationships with numerous pharmaceutical companies.

SOURCE: Coleman RL et al. ESMO 2019, Abstract LBA3-PR.

BARCELONA – Adding veliparib to frontline chemotherapy and maintenance therapy significantly extended progression-free survival in women with high-grade serous epithelial ovarian cancer (HGSC) in the phase 3 VELIA/GOG-3005 trial.

The benefit associated with the oral poly (ADP-ribose) polymerase (PARP) inhibitor was seen in all women with newly diagnosed HGSC included in the randomized, placebo-controlled trial, regardless of BRCA mutation (BRCAm) status or homologous recombination deficiency (HRD) status, Robert L. Coleman, MD, reported at the European Society for Medical Oncology Congress.

Of 1,140 patients enrolled in the international, multicenter trial, 26% had a BRCAm and 55% were HRD positive. In the intent-to-treat population, median progression-free survival (PFS) was 23.5 months in 382 patients who received carboplatin/paclitaxel (CP) plus veliparib followed by veliparib maintenance (veliparib group 1) versus 17.3 months in 375 patients treated with CP alone followed by placebo maintenance (the control group) (hazard ratio, 0.68), according to Dr. Coleman, professor and Ann Rife Cox Chair in Gynecology in the department of gynecologic oncology and reproductive medicine in the division of surgery at the University of Texas MD Anderson Cancer Center, Houston.

Among 200 patients with a deleterious BRCAm, including 108 in the veliparib 1 group and 92 in the control group, median PFS was 34.7 and 22.0 months, respectively (HR, 0.44), and among 421 patients with HRD and BRCAm, including 214 in the veliparib 1 group and 207 in the control group, median PFS was 31.9 versus 20.5 months (HR, 0.57).

In the non-HRD population of 249 patients (125 in the veliparib 1 arm and 124 in the control arm), median PFS was 15.0 and 11.5 months, respectively.

The PFS for an additional group of 383 patients treated with CP plus veliparib followed by placebo maintenance (veliparib group 2) didn’t differ significantly from either the veliparib 1 or the control group (HR, 1.07 vs. the control group in the intent-to-treat population), and the PFS rates were also similar for the BRCAm and HRD-positive patients in the veliparib 2 group and control group, he noted, explaining that the main focus of his presentation was the primary study endpoint of median PFS in the veliparib 1 versus control group.

The overall response rates at the end of treatment in the intent-to-treat populations were 84% in the veliparib 1 group, 74% in the control group, and 79% in the veliparib 2 group, Dr. Coleman said, adding that response rates were numerically higher in both veliparib-containing arms.

Additional analyses, including overall survival, will be reported at a future date, he noted.

Study participants were adults with a mean age of 62 years who had previously untreated stage III-IV HGSC. Treatment included six cycles of CP at 21-day intervals, with paclitaxel given either weekly or every 3 weeks following primary cytoreduction or neoadjuvant chemotherapy with interval cytoreduction. The veliparib dose when given with CP was 150 mg twice daily, and the veliparib maintenance dose was 400 mg twice daily for 30 cycles.

Relative CP dose intensities were similar between arms, and grade 3-4 adverse events were similar in the veliparib 1 and control groups during CP – with the exception of thrombocytopenia, which occurred in 27% and 8% of patients in the groups, respectively. During maintenance, the rates of any grade 3-4 adverse events were higher in the veliparib 1 group versus the control group (45% vs. 32%), but serious adverse event rates were similar in the groups (17% and 19%).

Observed toxicities were consistent with the known veliparib safety profile, Dr. Coleman said.

The findings are notable, as PARP inhibitors have proven effective in ovarian cancer, but their use in combination with chemotherapy has been challenging because of hematologic toxicity, he added, explaining, however, that veliparib has not only been shown to have single agent activity in germline BRCAm recurrent ovarian cancer patients, but also has binding characteristics – namely increased protein poly ADP-ribosylation and decreased PARP trapping – that could allow for its use in combination with chemotherapy.

VELIA/GOG-3005 is the first randomized trial designed to enroll only untreated patients with advanced-stage HGSC regardless of BRCA status, surgical management, or response to treatment, and the findings suggest that veliparib can be safely administered with CP and should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer, he concluded.

In an ESMO press release, Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, said that this trial, along with others such as the SOLO-1 trial, the PAOLA-1/ENGOT-Ov25 trial, and the PRIMA/ENGOT-OV26/GOG-3012 trial, which each looked at integrating PARP inhibitors into first-line treatment, represents “a milestone for patients.”

“After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression free survival and hopefully we will improve long-term outcome,” she said.

The study was sponsored by AbbVie. Dr. Coleman and Dr. Oaknin reported relationships with numerous pharmaceutical companies.

SOURCE: Coleman RL et al. ESMO 2019, Abstract LBA3-PR.

BARCELONA – Adding veliparib to frontline chemotherapy and maintenance therapy significantly extended progression-free survival in women with high-grade serous epithelial ovarian cancer (HGSC) in the phase 3 VELIA/GOG-3005 trial.

The benefit associated with the oral poly (ADP-ribose) polymerase (PARP) inhibitor was seen in all women with newly diagnosed HGSC included in the randomized, placebo-controlled trial, regardless of BRCA mutation (BRCAm) status or homologous recombination deficiency (HRD) status, Robert L. Coleman, MD, reported at the European Society for Medical Oncology Congress.

Of 1,140 patients enrolled in the international, multicenter trial, 26% had a BRCAm and 55% were HRD positive. In the intent-to-treat population, median progression-free survival (PFS) was 23.5 months in 382 patients who received carboplatin/paclitaxel (CP) plus veliparib followed by veliparib maintenance (veliparib group 1) versus 17.3 months in 375 patients treated with CP alone followed by placebo maintenance (the control group) (hazard ratio, 0.68), according to Dr. Coleman, professor and Ann Rife Cox Chair in Gynecology in the department of gynecologic oncology and reproductive medicine in the division of surgery at the University of Texas MD Anderson Cancer Center, Houston.

Among 200 patients with a deleterious BRCAm, including 108 in the veliparib 1 group and 92 in the control group, median PFS was 34.7 and 22.0 months, respectively (HR, 0.44), and among 421 patients with HRD and BRCAm, including 214 in the veliparib 1 group and 207 in the control group, median PFS was 31.9 versus 20.5 months (HR, 0.57).

In the non-HRD population of 249 patients (125 in the veliparib 1 arm and 124 in the control arm), median PFS was 15.0 and 11.5 months, respectively.

The PFS for an additional group of 383 patients treated with CP plus veliparib followed by placebo maintenance (veliparib group 2) didn’t differ significantly from either the veliparib 1 or the control group (HR, 1.07 vs. the control group in the intent-to-treat population), and the PFS rates were also similar for the BRCAm and HRD-positive patients in the veliparib 2 group and control group, he noted, explaining that the main focus of his presentation was the primary study endpoint of median PFS in the veliparib 1 versus control group.

The overall response rates at the end of treatment in the intent-to-treat populations were 84% in the veliparib 1 group, 74% in the control group, and 79% in the veliparib 2 group, Dr. Coleman said, adding that response rates were numerically higher in both veliparib-containing arms.

Additional analyses, including overall survival, will be reported at a future date, he noted.

Study participants were adults with a mean age of 62 years who had previously untreated stage III-IV HGSC. Treatment included six cycles of CP at 21-day intervals, with paclitaxel given either weekly or every 3 weeks following primary cytoreduction or neoadjuvant chemotherapy with interval cytoreduction. The veliparib dose when given with CP was 150 mg twice daily, and the veliparib maintenance dose was 400 mg twice daily for 30 cycles.

Relative CP dose intensities were similar between arms, and grade 3-4 adverse events were similar in the veliparib 1 and control groups during CP – with the exception of thrombocytopenia, which occurred in 27% and 8% of patients in the groups, respectively. During maintenance, the rates of any grade 3-4 adverse events were higher in the veliparib 1 group versus the control group (45% vs. 32%), but serious adverse event rates were similar in the groups (17% and 19%).

Observed toxicities were consistent with the known veliparib safety profile, Dr. Coleman said.

The findings are notable, as PARP inhibitors have proven effective in ovarian cancer, but their use in combination with chemotherapy has been challenging because of hematologic toxicity, he added, explaining, however, that veliparib has not only been shown to have single agent activity in germline BRCAm recurrent ovarian cancer patients, but also has binding characteristics – namely increased protein poly ADP-ribosylation and decreased PARP trapping – that could allow for its use in combination with chemotherapy.

VELIA/GOG-3005 is the first randomized trial designed to enroll only untreated patients with advanced-stage HGSC regardless of BRCA status, surgical management, or response to treatment, and the findings suggest that veliparib can be safely administered with CP and should be considered a new treatment option for women with newly diagnosed, advanced-stage serous ovarian cancer, he concluded.

In an ESMO press release, Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, said that this trial, along with others such as the SOLO-1 trial, the PAOLA-1/ENGOT-Ov25 trial, and the PRIMA/ENGOT-OV26/GOG-3012 trial, which each looked at integrating PARP inhibitors into first-line treatment, represents “a milestone for patients.”

“After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression free survival and hopefully we will improve long-term outcome,” she said.

The study was sponsored by AbbVie. Dr. Coleman and Dr. Oaknin reported relationships with numerous pharmaceutical companies.

SOURCE: Coleman RL et al. ESMO 2019, Abstract LBA3-PR.

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

[email protected]

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Checkpoint inhibition with nivolumab led to a clinically meaningful, but not statistically significant, improvement in overall survival, compared with sorafenib for the first-line treatment of advanced hepatocellular carcinoma (HCC) in the phase 3 CheckMate 459 study.

Median overall survival (OS), the primary study endpoint, was 16.4 months in 371 patients randomized to receive the programmed death-1 (PD-1) inhibitor nivolumab, and 14.7 months in 372 patients who received the tyrosine kinase inhibitor sorafenib – the current standard for advanced HCC therapy (hazard ratio, 0.85; P = .0752), Thomas Yau, MD, reported at the European Society for Medical Oncology Congress.

The median OS seen with nivolumab is the longest ever reported in a first-line phase 3 HCC trial, but the difference between the arms did not meet the predefined threshold for statistical significance (HR, 0.84 and P = .419). However, clinical benefit was observed across predefined subgroups of patients, including those with hepatitis infection and those with vascular invasion and/or extrahepatic spread, said Dr. Yau of the University of Hong Kong.

The overall response rates (ORR) were 15% and 7% in the nivolumab and sorafenib arms, with 14 and 5 patients in each group experiencing a complete response (CR), respectively, he said.

At 12 and 24 months, the OS rates in the groups were 59.7% vs. 55.1%, and 36.5% vs. 33.1%, respectively. Median progression-free survival (PFS) was similar in the groups, at 3.7 and 3.8 months, respectively, and analysis by baseline tumor programmed death-ligand 1 (PD-L1) expression showed that ORR was 28% vs. 9% with PD-L1 expression of 1% or greater in the groups, respectively, and 12% vs. 7% among those with PD-L1 expression less than 1%.

Additionally, nivolumab had a more tolerable safety profile; grade 3/4 treatment-related adverse events were reported in 22% and 49% of patients in the groups, respectively, and led to discontinuation in 4% and 8%, respectively. No new safety signals were observed, Dr. Yau said.

Participants in the multicenter study were systemic therapy–naive adults with advanced disease. They were randomized 1:1 to receive intravenous nivolumab at a dose of 240 mg every 2 weeks or oral sorafenib at a dose of 400 mg twice daily, and were followed for at least 22.8 months.

“These results are important in the treatment of hepatocellular carcinoma, as there have been no significant advances over sorafenib in the first-line setting in more than a decade,” Dr. Yau said in an ESMO press release. “HCC is often diagnosed in the advanced stage, where effective treatment options are limited. The encouraging efficacy and favorable safety profile seen with nivolumab demonstrates the potential benefit of immunotherapy as a first-line treatment for patients with this aggressive cancer.”

He further noted that the OS benefit seen in this study is “particularly impactful considering the high frequency of subsequent use of systemic therapy, including immunotherapy, in the sorafenib arm,” and that the OS impact is bolstered by patient-reported outcomes suggesting improved quality of life in the nivolumab arm.

Nevertheless, the fact that CheckMate 459 did not meet its primary OS endpoint means the findings are unlikely to change the current standard of care, according to Angela Lamarca, MD, PhD, consultant medical oncologist and honorary senior lecturer at the Christie NHS Foundation Trust, University of Manchester (England).

She added, however, that the findings do underscore a potential role for immunotherapy in the first-line treatment of advanced HCC and noted that the clinically meaningful improvement in response rates with nivolumab, along with the checkpoint inhibitor’s favorable safety profile in this study, raise the possibility of its selection in this setting.

“In a hypothetical scenario in which both options ... were available and reimbursed, and if quality of life was shown to be better with nivolumab ... clinicians and patients may favor the option with a more tolerable safety profile,” she said in the press release.

She added, however, that at this point conclusions should be made cautiously and the high cost of immunotherapy should be considered.

Dr. Lamarca also highlighted the finding that patients with high PD-L1 expression had an increased response rate only in the nivolumab arm. This suggests a potential role for PD-L1 expression as a predictive biomarker in advanced HCC, but more research is needed to better understand how to select patients for immunotherapy, she said, adding that the lack of a reliable biomarker may have contributed to the study’s failure to show improved OS with nivolumab.

“In addition, the study design with a ‘high’ predefined threshold of statistical significance is generating confusion in the community, with potentially beneficial therapies generating statistically negative studies,” she noted.

CheckMate 459 was funded by Bristol-Myers Squibb. Dr. Yau is an advisor and/or consultant to Bristol-Myers Squibb, and reported honoraria from the company to his institution. Dr. Lamarca reported honoraria, consultation fees, travel funding, and/or education funding from Eisai, Nutricia, Ipsen, Pfizer, Bayer, AAA, Sirtex, Delcath, Novartis, and Mylan, as well as participation in company-sponsored speaker bureaus for Pfizer, Ipsen, Merck, and Incyte.

SOURCE: Yau T et al. ESMO 2019, Abstract LBA38-PR
 

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

BARCELONA – Niraparib significantly improves progression-free survival when given after first-line chemotherapy in patients with advanced ovarian cancer, according to “potentially practice-changing” results from the phase 3 PRIMA/ENGOT-OV26/GOG-3012 study.

Sharon Worcester/MDedge News

Overall progression-free survival (PFS) in 484 patients randomized to receive the poly-ADP ribose polymerase inhibitor (PARPi) niraparib was 13.8 months, compared with 8.2 months in 244 patients who received placebo (hazard ratio, 0.62), Antonio González-Martin, MD, PhD, reported at the European Society for Medical Oncology Congress.

The findings were published simultaneously online in the New England Journal of Medicine (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1910962).

In patients at high risk for progression based on homologous recombination deficiency (HRd) – defined by certain tumor factors or the presence of BRCA mutation (BRCAm), PFS was 21.9 vs. 10.4 months in the treatment (n = 245) vs. placebo (n = 125) groups, respectively (HR, 0.43), said Dr. González-Martin of Grupo Español de Investigación en Cáncer de Ovario (GEICO), medical oncology department, Clínica Universidad de Navarra, Madrid.

“At 18 months, which means approximately 2 years after the initiation of chemotherapy, 42% of patients treated with niraparib remained alive and progression free,” he said, adding that 59% of the HRd patients remained alive and progression free at 18 months.

Exploratory analyses showed that the niraparib benefits occurred across all prespecified patient subgroups, including those aged 65 and older vs. those under age 65, those with stage III vs. stage IV disease at diagnosis, those receiving vs. not receiving neoadjuvant chemotherapy, those with complete response (CR) vs. partial response (PR) as their best response to platinum chemotherapy, and those with HRd who had BRCAm vs. BRCA wild type (BRCAwt) tumors, he said.

The hazard ratios for the HRd BRCAm vs. BRCAwt tumors were 0.40 and 0.50, respectively.

“So the benefit of niraparib in the HRd tumor is not driven only by the BRCA-mutated patients,” he said. “Importantly, we also saw benefit in the group of patients with tumors that were [homologous recombination] proficient (HRp), with a reduction in the risk of progression of 32%.”

For the key secondary endpoint of overall survival, a preplanned interim analysis showed that 84% vs. 77% in the niraparib and placebo groups, respectively, were alive at 2 years; in the HRd and HRp groups, those rates were 91% vs. 85% and 81% vs. 59%, respectively.

Participants in the double-blind trial had newly diagnosed, advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer; their mean age was 62 years; and they had experienced a CR (69%) or PR (31%) to first-line platinum-based chemotherapy. Overall, 35% had stage IV disease and 67% received neoadjuvant chemotherapy. They were randomized 2:1 to once-daily niraparib at a starting dose of 300 mg or 200 mg depending on body weight and platelet count, with those weighing 77 kg or greater and with platelet count of 150,000/mcL or less starting at the higher dose, and those weighing less than 77 kg and/or with platelet count less than 150,000/mcL starting at the lower dose.

All subgroups showed a sustained and durable treatment effect, and although most patients experienced treatment-related adverse events (TRAEs), those were “manageable with dose interruption or dose reduction,” Dr. González-Martin said.

Discontinuations due to TRAEs occurred in 12% vs. 2.5% in the treatment vs. placebo groups, and this was consistent with prior niraparib experience, he said, adding that no niraparib-related deaths were reported and no new safety signals were identified.

The findings are notable, because the recurrence rate after standard first-line platinum-based chemotherapy in women with advanced ovarian cancer is estimated at up to 85%, and while certain subgroups of patients have options for maintenance therapy, there remains a high unmet need for others, he explained.

For example olaparib is an option, but only for tumors with BRCA mutation, and bevacizumab can be used, but “may be limited due to safety concerns in some patients and also due to limited data from randomized trials in the neoadjuvant setting,” he said.

As a result, surveillance after chemotherapy is the approach used for many patients, he added.

Niraparib is the first oral PARPi approved for maintenance in patients with recurrent ovarian cancer, regardless of BRCA mutation status; in the NOVA study, it demonstrated efficacy after platinum chemotherapy in all biomarker populations, and in the QUADRA study it showed benefit in patients who received at least three prior therapies.

The current study was designed to test the efficacy and safety of niraparib therapy after response to platinum-based chemotherapy in patients with newly diagnosed advanced ovarian cancer, including those at high risk of relapse.

“Niraparib is the first PARP inhibitor that has demonstrated benefit after front-line platinum-based chemotherapy across all the biomarker subgroups, regardless of BRCA status, consistent with data from the recurrent setting,” Dr. González-Martin said, adding that patients with ovarian cancer at the highest risk of early disease progression obtained significant benefit. “What does this mean for our patients and our practice? Based on these results, niraparib after first-line platinum chemotherapy should be considered a new standard of care.”

Invited discussant Ana Oaknin, MD, PhD, head of the gynecologic cancer program at Vall d’Hebron Institute of Oncology, Vall d’Hebron University Hospital, Barcelona, called the findings “striking” and noted that they, along with those from the PAOLA-1/ENGOT-Ov25 trial demonstrating a PFS benefit with the addition of olaparib to bevacizumab maintenance therapy after first-line platinum-based chemotherapy in advanced ovarian cancer, represent important advances.

“We are witnessing a paradigm shift in the first-line treatment of advanced ovarian cancer patients,” she said.

Are the findings of these trials clinically meaningful enough to justify the addition of PARPi maintenance therapy after first-line chemotherapy therapy as a new standard of care?

“Yes, but while the benefit is clinically meaningful in the overall population, we should consider PFS outcomes according to the biomarker status in the selection of optimal therapy; companion diagnostic tests will be needed,” she said.

The PRIMA/ENGOT-OV26/GOG-3012 study was sponsored by TESARO. Dr. González-Martin reported relationships with numerous pharmaceutical companies.

[email protected]

SOURCE: González-Martin A et al. ESMO 2019: Abstract LBA1.

BARCELONA – Ivosidenib, a first-in-class, oral, small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) protein, significantly improved progression-free survival, compared with placebo, for the treatment of advanced cholangiocarcinoma in the global, randomized, phase 3 ClarIDHy trial.

A trend toward favorable overall survival was also seen in the pivotal double-blind trial, Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) in 124 patients randomized to receive 500 mg of ivosidenib (IVO) once daily was 2.7 months, compared with 1.4 months in 61 patients who received placebo (hazard ratio, 0.37).

The primary study endpoint – PFS by central review – was reached, Dr. Abou-Alfa said, noting that the PFS rates at 6 and 12 months were 32% and 22% in the IVO arm, whereas none of the patients in the placebo arm were progression-free for 6 or more months.

Although the 1.3-month difference in PFS between the treatment and placebo arms “may seem short and some people may question whether this is clinically meaningful,” this outcome actually represents an important breakthrough for patients with a disease that has few treatment options, Angela Lamarca, MD, PhD, of the Christie NHS Foundation Trust, Manchester, England, explained in a press release about the study.

“A treatment that increases the chance of being free from progression by 32% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families,” said Dr. Lamarca, representing the ESMO Press & Media Affairs Committee.

Indeed, the overall response rate in the IVO arm was 2.4%, representing three partial responses, and the stable disease rate was 50.8%. The overall response rate and stable disease rates in the placebo arm were 0% and 28%, Dr. Abou-Alfa said.

Median overall survival in the intent-to-treat population, including the 57% of placebo arm patients who crossed over to the treatment arm at the time of radiographic progression as allowed by study protocol, was 10.8 months, compared with 9.7 months in the placebo arm, respectively (HR, 0.69), Dr. Abou-Alfa said.

Crossover-adjusted overall survival was 6 months for the placebo arm (HR, 0.46) as assessed using rank-preserving structural failure time analysis, which suggested that the overall survival benefit would have been statistically significant had there been no crossover.

Study subjects had unresectable or metastatic mIDH1 cholangiocarcinoma, good performance status, and measurable disease. They had a median age of 62 years, and 68 were men. Most had intrahepatic disease (91%) and metastatic disease (92%), and 43% had two prior therapies, he noted.

They were randomized 2:1 to the treatment and placebo arms, respectively.

Since IVO targets mIDH1, which occurs in about 20% of patients with cholangiocarcinoma and results in production of the oncogenesis-promoting oncometabolite D-2-hydroxyglutarate, and since the IVO has shown encouraging activity in smaller prior studies, ClarIDHy was designed to evaluate it in the advanced mIDH1 cholangiocarcinoma setting because patients with this aggressive disease have generally poor prognosis and few treatment options beyond chemotherapy, he explained.

In addition to providing significant, clinically meaningful survival benefit, the treatment also was generally well tolerated, he noted.

Treatment-emergent adverse events occurring in more than 15% of patients in the IVO arm included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade 3 or higher adverse events were reported in 46% and 36% of the IVO and placebo patients, respectively.

The findings are notable, in part because of the unmet need and also because this is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma, he said, concluding that “these pivotal data demonstrate the clinical relevance and benefit of ivosidenib in mIDH1 cholangiocarcinoma ... [and] establish the role for genomic testing in this rare cancer with a high unmet need.”

He also said studies should investigate IVO in the first-line setting for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.

In the ESMO press release, Chris Verslype, MD, of University Hospital Leuven (Belgium) called the findings of this study unprecedented given the lack of treatment options in those who fail systemic therapy, which has led to very limited survival.

The findings are “very likely to change clinical practice” and “will, for sure, drive the further development of targeted therapy for the disease,” he said.

Despite being limited by the requirement that patients have good performance status after prior chemotherapy (which means the findings may not be representative of all patients), ClarIDHy is “still a strong study because of the randomization to placebo.”

“It showed a real effect,” he said.

ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa reported both personal and institutional relationships with industry. These include advisory /consulting roles and research grants/funding from numerous pharmaceutical companies.

SOURCE: Abou-Alfa GK et al. ESMO 2019, Abstract LBA10-PR.

BARCELONA – Ivosidenib, a first-in-class, oral, small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) protein, significantly improved progression-free survival, compared with placebo, for the treatment of advanced cholangiocarcinoma in the global, randomized, phase 3 ClarIDHy trial.

A trend toward favorable overall survival was also seen in the pivotal double-blind trial, Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) in 124 patients randomized to receive 500 mg of ivosidenib (IVO) once daily was 2.7 months, compared with 1.4 months in 61 patients who received placebo (hazard ratio, 0.37).

The primary study endpoint – PFS by central review – was reached, Dr. Abou-Alfa said, noting that the PFS rates at 6 and 12 months were 32% and 22% in the IVO arm, whereas none of the patients in the placebo arm were progression-free for 6 or more months.

Although the 1.3-month difference in PFS between the treatment and placebo arms “may seem short and some people may question whether this is clinically meaningful,” this outcome actually represents an important breakthrough for patients with a disease that has few treatment options, Angela Lamarca, MD, PhD, of the Christie NHS Foundation Trust, Manchester, England, explained in a press release about the study.

“A treatment that increases the chance of being free from progression by 32% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families,” said Dr. Lamarca, representing the ESMO Press & Media Affairs Committee.

Indeed, the overall response rate in the IVO arm was 2.4%, representing three partial responses, and the stable disease rate was 50.8%. The overall response rate and stable disease rates in the placebo arm were 0% and 28%, Dr. Abou-Alfa said.

Median overall survival in the intent-to-treat population, including the 57% of placebo arm patients who crossed over to the treatment arm at the time of radiographic progression as allowed by study protocol, was 10.8 months, compared with 9.7 months in the placebo arm, respectively (HR, 0.69), Dr. Abou-Alfa said.

Crossover-adjusted overall survival was 6 months for the placebo arm (HR, 0.46) as assessed using rank-preserving structural failure time analysis, which suggested that the overall survival benefit would have been statistically significant had there been no crossover.

Study subjects had unresectable or metastatic mIDH1 cholangiocarcinoma, good performance status, and measurable disease. They had a median age of 62 years, and 68 were men. Most had intrahepatic disease (91%) and metastatic disease (92%), and 43% had two prior therapies, he noted.

They were randomized 2:1 to the treatment and placebo arms, respectively.

Since IVO targets mIDH1, which occurs in about 20% of patients with cholangiocarcinoma and results in production of the oncogenesis-promoting oncometabolite D-2-hydroxyglutarate, and since the IVO has shown encouraging activity in smaller prior studies, ClarIDHy was designed to evaluate it in the advanced mIDH1 cholangiocarcinoma setting because patients with this aggressive disease have generally poor prognosis and few treatment options beyond chemotherapy, he explained.

In addition to providing significant, clinically meaningful survival benefit, the treatment also was generally well tolerated, he noted.

Treatment-emergent adverse events occurring in more than 15% of patients in the IVO arm included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade 3 or higher adverse events were reported in 46% and 36% of the IVO and placebo patients, respectively.

The findings are notable, in part because of the unmet need and also because this is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma, he said, concluding that “these pivotal data demonstrate the clinical relevance and benefit of ivosidenib in mIDH1 cholangiocarcinoma ... [and] establish the role for genomic testing in this rare cancer with a high unmet need.”

He also said studies should investigate IVO in the first-line setting for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.

In the ESMO press release, Chris Verslype, MD, of University Hospital Leuven (Belgium) called the findings of this study unprecedented given the lack of treatment options in those who fail systemic therapy, which has led to very limited survival.

The findings are “very likely to change clinical practice” and “will, for sure, drive the further development of targeted therapy for the disease,” he said.

Despite being limited by the requirement that patients have good performance status after prior chemotherapy (which means the findings may not be representative of all patients), ClarIDHy is “still a strong study because of the randomization to placebo.”

“It showed a real effect,” he said.

ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa reported both personal and institutional relationships with industry. These include advisory /consulting roles and research grants/funding from numerous pharmaceutical companies.

SOURCE: Abou-Alfa GK et al. ESMO 2019, Abstract LBA10-PR.

BARCELONA – Ivosidenib, a first-in-class, oral, small-molecule inhibitor of the mutant isocitrate dehydrogenase 1 (mIDH1) protein, significantly improved progression-free survival, compared with placebo, for the treatment of advanced cholangiocarcinoma in the global, randomized, phase 3 ClarIDHy trial.

A trend toward favorable overall survival was also seen in the pivotal double-blind trial, Ghassan K. Abou-Alfa, MD, of Memorial Sloan-Kettering Cancer Center, New York, reported at the European Society for Medical Oncology Congress.

Median progression-free survival (PFS) in 124 patients randomized to receive 500 mg of ivosidenib (IVO) once daily was 2.7 months, compared with 1.4 months in 61 patients who received placebo (hazard ratio, 0.37).

The primary study endpoint – PFS by central review – was reached, Dr. Abou-Alfa said, noting that the PFS rates at 6 and 12 months were 32% and 22% in the IVO arm, whereas none of the patients in the placebo arm were progression-free for 6 or more months.

Although the 1.3-month difference in PFS between the treatment and placebo arms “may seem short and some people may question whether this is clinically meaningful,” this outcome actually represents an important breakthrough for patients with a disease that has few treatment options, Angela Lamarca, MD, PhD, of the Christie NHS Foundation Trust, Manchester, England, explained in a press release about the study.

“A treatment that increases the chance of being free from progression by 32% at 6 months after starting treatment and that prolongs survival from 6 months with placebo to 10.8 months with ivosidenib, after adjusting for crossover, is definitely meaningful for our patients with cholangiocarcinoma and their families,” said Dr. Lamarca, representing the ESMO Press & Media Affairs Committee.

Indeed, the overall response rate in the IVO arm was 2.4%, representing three partial responses, and the stable disease rate was 50.8%. The overall response rate and stable disease rates in the placebo arm were 0% and 28%, Dr. Abou-Alfa said.

Median overall survival in the intent-to-treat population, including the 57% of placebo arm patients who crossed over to the treatment arm at the time of radiographic progression as allowed by study protocol, was 10.8 months, compared with 9.7 months in the placebo arm, respectively (HR, 0.69), Dr. Abou-Alfa said.

Crossover-adjusted overall survival was 6 months for the placebo arm (HR, 0.46) as assessed using rank-preserving structural failure time analysis, which suggested that the overall survival benefit would have been statistically significant had there been no crossover.

Study subjects had unresectable or metastatic mIDH1 cholangiocarcinoma, good performance status, and measurable disease. They had a median age of 62 years, and 68 were men. Most had intrahepatic disease (91%) and metastatic disease (92%), and 43% had two prior therapies, he noted.

They were randomized 2:1 to the treatment and placebo arms, respectively.

Since IVO targets mIDH1, which occurs in about 20% of patients with cholangiocarcinoma and results in production of the oncogenesis-promoting oncometabolite D-2-hydroxyglutarate, and since the IVO has shown encouraging activity in smaller prior studies, ClarIDHy was designed to evaluate it in the advanced mIDH1 cholangiocarcinoma setting because patients with this aggressive disease have generally poor prognosis and few treatment options beyond chemotherapy, he explained.

In addition to providing significant, clinically meaningful survival benefit, the treatment also was generally well tolerated, he noted.

Treatment-emergent adverse events occurring in more than 15% of patients in the IVO arm included nausea (32.1%), diarrhea (28.8%), fatigue (23.7%), cough (19.2%), abdominal pain (18.6%), ascites (18.6%), decreased appetite (17.3%), anemia (16.0%), and vomiting (16.0%). Grade 3 or higher adverse events were reported in 46% and 36% of the IVO and placebo patients, respectively.

The findings are notable, in part because of the unmet need and also because this is the first pivotal study demonstrating the clinical benefit of targeting mIDH1 in patients with advanced mIDH1 cholangiocarcinoma, he said, concluding that “these pivotal data demonstrate the clinical relevance and benefit of ivosidenib in mIDH1 cholangiocarcinoma ... [and] establish the role for genomic testing in this rare cancer with a high unmet need.”

He also said studies should investigate IVO in the first-line setting for IDH1-mutated cholangiocarcinoma, in addition to its use in combination therapy and as adjuvant therapy.

In the ESMO press release, Chris Verslype, MD, of University Hospital Leuven (Belgium) called the findings of this study unprecedented given the lack of treatment options in those who fail systemic therapy, which has led to very limited survival.

The findings are “very likely to change clinical practice” and “will, for sure, drive the further development of targeted therapy for the disease,” he said.

Despite being limited by the requirement that patients have good performance status after prior chemotherapy (which means the findings may not be representative of all patients), ClarIDHy is “still a strong study because of the randomization to placebo.”

“It showed a real effect,” he said.

ClarIDHy was funded by Agios Pharmaceuticals. Dr. Abou-Alfa reported both personal and institutional relationships with industry. These include advisory /consulting roles and research grants/funding from numerous pharmaceutical companies.

SOURCE: Abou-Alfa GK et al. ESMO 2019, Abstract LBA10-PR.

BARCELONA – Adding the CDK4/6 inhibitor abemaciclib to fulvestrant significantly improves overall survival in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer patients who progressed on prior endocrine therapy, according to findings from the phase 3 MONARCH 2 trial.

At a median follow-up of 47.7 months, overall survival – a secondary study endpoint – was 46.7 months in 446 patients randomized to receive abemaciclib and fulvestrant, compared with 37.3 months in 223 patients who received placebo and fulvestrant (hazard ratio, 0.757), George W. Sledge, MD, reported at the European Society for Medical Oncology Congress.

The overall survival benefit was consistent across stratification factors, which included site of metastasis (visceral, bone, or other) and resistance to prior endocrine therapy (primary versus secondary), but it was most pronounced in patients with visceral disease (HR, 0.675) and primary resistance to prior endocrine therapy (HR, 0.686), said Dr. Sledge, a professor of medicine at Stanford (Calif.) Medical Center.

Progression-free survival, the primary study endpoint, was 16.4 and 9.3 months at the previously reported 2-year follow-up in the treatment and placebo groups, respectively, and the current analysis showed progression-free survival to be “highly consistent” with those findings (16.9 vs. 9.3 months; HR, 0.563), he said.

“Of note, and of interest for further follow-up, a landmark analysis at 3 years shows that approximately three times as many patients on the abemaciclib arm remained progression free, compared to the control arm,” he added, also noting that time from randomization to postdiscontinuation chemotherapy was prolonged with abemaciclib, compared with placebo (50.2 vs. 22.1 months; HR, 0.625).

“A highly significant result,” he said.

At the 47.7 month follow-up, 17% and 4% of patients in the treatment and placebo groups, respectively, remained on treatment.

An additional exploratory analysis showed that 5.8% of patients receiving abemaciclib crossed over to another CDK4/6 inhibitor after discontinuation of therapy, compared with 17.0% of those in the placebo group.

“CDK4/6 inhibitors have emerged as standard-of-care treatment for patients with HR+, HER2– breast cancer,” he said, noting that abemaciclib is a selective CDK4/6 inhibitor with continuous, twice-daily oral administration. “It is approved for monotherapy after progression on endocrine therapy and prior chemotherapy in the metastatic setting, and ... in combination with endocrine therapy in the front-line setting and after progression.”

The global, randomized, double-blind MONARCH 2 trial assessed abemaciclib + fulvestrant in women with advanced endocrine therapy–resistant HR+, HER2– advanced breast cancer, including pre- or perimenopausal women with ovarian suppression and postmenopausal women.

Study participants were randomized 2:1 to receive 500 mg of fulvestrant per label instructions plus 150 mg of abemaciclib every 12 hours or placebo.

Treatment-emergent adverse events in MONARCH 2 were consistent with those previously reported in the primary analysis, Dr. Sledge said.

“Continued follow-up of MONARCH 2 is ongoing to further characterize the overall survival benefit and to look at exploratory efficacy and correlative endpoints,” he noted.

Speaking about the findings during a press conference at the meeting, Nadia Harbeck, MD, a professor at Ludwig Maximilians University, Munich, Germany, said they have important practice-changing implications.

“We were always struggling with whether to give these drugs first or second line, and I think now if we consider the first-line survival benefit ... [first-line use] should be standard of care,” she said, referring to CDK4/6 inhibitors and to findings from MONARCH 2 and prior studies of the inhibitors, including the MONALEESA-3 trial presented at the ESMO Congress.

MONALEESA-3 showed similar overall survival results with the CDK4/6 inhibitor ribociclib in postmenopausal women with HR+, HER2– advanced breast cancer.

“The data are highly clinically meaningful; I think they are going to make a huge impact on how we treat breast cancer,” Dr. Harbeck said.

Dr. Sledge has received trial support, research grants, and travel accommodations from Eli Lilly and Company; is a board member for Tessa Therapeutics; and is a consultant for Syndax, Symphogen, and Verseau Therapeutics. Dr. Harbeck disclosed financial relationships with Agendia, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Nanostring, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. She is also director of the West German Study Group and a member of the German AGO Breast Committee.

SOURCE: Sledge G et al., ESMO 2019, Abstract LBA6-PR.

BARCELONA – Adding the CDK4/6 inhibitor abemaciclib to fulvestrant significantly improves overall survival in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer patients who progressed on prior endocrine therapy, according to findings from the phase 3 MONARCH 2 trial.

At a median follow-up of 47.7 months, overall survival – a secondary study endpoint – was 46.7 months in 446 patients randomized to receive abemaciclib and fulvestrant, compared with 37.3 months in 223 patients who received placebo and fulvestrant (hazard ratio, 0.757), George W. Sledge, MD, reported at the European Society for Medical Oncology Congress.

The overall survival benefit was consistent across stratification factors, which included site of metastasis (visceral, bone, or other) and resistance to prior endocrine therapy (primary versus secondary), but it was most pronounced in patients with visceral disease (HR, 0.675) and primary resistance to prior endocrine therapy (HR, 0.686), said Dr. Sledge, a professor of medicine at Stanford (Calif.) Medical Center.

Progression-free survival, the primary study endpoint, was 16.4 and 9.3 months at the previously reported 2-year follow-up in the treatment and placebo groups, respectively, and the current analysis showed progression-free survival to be “highly consistent” with those findings (16.9 vs. 9.3 months; HR, 0.563), he said.

“Of note, and of interest for further follow-up, a landmark analysis at 3 years shows that approximately three times as many patients on the abemaciclib arm remained progression free, compared to the control arm,” he added, also noting that time from randomization to postdiscontinuation chemotherapy was prolonged with abemaciclib, compared with placebo (50.2 vs. 22.1 months; HR, 0.625).

“A highly significant result,” he said.

At the 47.7 month follow-up, 17% and 4% of patients in the treatment and placebo groups, respectively, remained on treatment.

An additional exploratory analysis showed that 5.8% of patients receiving abemaciclib crossed over to another CDK4/6 inhibitor after discontinuation of therapy, compared with 17.0% of those in the placebo group.

“CDK4/6 inhibitors have emerged as standard-of-care treatment for patients with HR+, HER2– breast cancer,” he said, noting that abemaciclib is a selective CDK4/6 inhibitor with continuous, twice-daily oral administration. “It is approved for monotherapy after progression on endocrine therapy and prior chemotherapy in the metastatic setting, and ... in combination with endocrine therapy in the front-line setting and after progression.”

The global, randomized, double-blind MONARCH 2 trial assessed abemaciclib + fulvestrant in women with advanced endocrine therapy–resistant HR+, HER2– advanced breast cancer, including pre- or perimenopausal women with ovarian suppression and postmenopausal women.

Study participants were randomized 2:1 to receive 500 mg of fulvestrant per label instructions plus 150 mg of abemaciclib every 12 hours or placebo.

Treatment-emergent adverse events in MONARCH 2 were consistent with those previously reported in the primary analysis, Dr. Sledge said.

“Continued follow-up of MONARCH 2 is ongoing to further characterize the overall survival benefit and to look at exploratory efficacy and correlative endpoints,” he noted.

Speaking about the findings during a press conference at the meeting, Nadia Harbeck, MD, a professor at Ludwig Maximilians University, Munich, Germany, said they have important practice-changing implications.

“We were always struggling with whether to give these drugs first or second line, and I think now if we consider the first-line survival benefit ... [first-line use] should be standard of care,” she said, referring to CDK4/6 inhibitors and to findings from MONARCH 2 and prior studies of the inhibitors, including the MONALEESA-3 trial presented at the ESMO Congress.

MONALEESA-3 showed similar overall survival results with the CDK4/6 inhibitor ribociclib in postmenopausal women with HR+, HER2– advanced breast cancer.

“The data are highly clinically meaningful; I think they are going to make a huge impact on how we treat breast cancer,” Dr. Harbeck said.

Dr. Sledge has received trial support, research grants, and travel accommodations from Eli Lilly and Company; is a board member for Tessa Therapeutics; and is a consultant for Syndax, Symphogen, and Verseau Therapeutics. Dr. Harbeck disclosed financial relationships with Agendia, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Nanostring, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. She is also director of the West German Study Group and a member of the German AGO Breast Committee.

SOURCE: Sledge G et al., ESMO 2019, Abstract LBA6-PR.

BARCELONA – Adding the CDK4/6 inhibitor abemaciclib to fulvestrant significantly improves overall survival in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer patients who progressed on prior endocrine therapy, according to findings from the phase 3 MONARCH 2 trial.

At a median follow-up of 47.7 months, overall survival – a secondary study endpoint – was 46.7 months in 446 patients randomized to receive abemaciclib and fulvestrant, compared with 37.3 months in 223 patients who received placebo and fulvestrant (hazard ratio, 0.757), George W. Sledge, MD, reported at the European Society for Medical Oncology Congress.

The overall survival benefit was consistent across stratification factors, which included site of metastasis (visceral, bone, or other) and resistance to prior endocrine therapy (primary versus secondary), but it was most pronounced in patients with visceral disease (HR, 0.675) and primary resistance to prior endocrine therapy (HR, 0.686), said Dr. Sledge, a professor of medicine at Stanford (Calif.) Medical Center.

Progression-free survival, the primary study endpoint, was 16.4 and 9.3 months at the previously reported 2-year follow-up in the treatment and placebo groups, respectively, and the current analysis showed progression-free survival to be “highly consistent” with those findings (16.9 vs. 9.3 months; HR, 0.563), he said.

“Of note, and of interest for further follow-up, a landmark analysis at 3 years shows that approximately three times as many patients on the abemaciclib arm remained progression free, compared to the control arm,” he added, also noting that time from randomization to postdiscontinuation chemotherapy was prolonged with abemaciclib, compared with placebo (50.2 vs. 22.1 months; HR, 0.625).

“A highly significant result,” he said.

At the 47.7 month follow-up, 17% and 4% of patients in the treatment and placebo groups, respectively, remained on treatment.

An additional exploratory analysis showed that 5.8% of patients receiving abemaciclib crossed over to another CDK4/6 inhibitor after discontinuation of therapy, compared with 17.0% of those in the placebo group.

“CDK4/6 inhibitors have emerged as standard-of-care treatment for patients with HR+, HER2– breast cancer,” he said, noting that abemaciclib is a selective CDK4/6 inhibitor with continuous, twice-daily oral administration. “It is approved for monotherapy after progression on endocrine therapy and prior chemotherapy in the metastatic setting, and ... in combination with endocrine therapy in the front-line setting and after progression.”

The global, randomized, double-blind MONARCH 2 trial assessed abemaciclib + fulvestrant in women with advanced endocrine therapy–resistant HR+, HER2– advanced breast cancer, including pre- or perimenopausal women with ovarian suppression and postmenopausal women.

Study participants were randomized 2:1 to receive 500 mg of fulvestrant per label instructions plus 150 mg of abemaciclib every 12 hours or placebo.

Treatment-emergent adverse events in MONARCH 2 were consistent with those previously reported in the primary analysis, Dr. Sledge said.

“Continued follow-up of MONARCH 2 is ongoing to further characterize the overall survival benefit and to look at exploratory efficacy and correlative endpoints,” he noted.

Speaking about the findings during a press conference at the meeting, Nadia Harbeck, MD, a professor at Ludwig Maximilians University, Munich, Germany, said they have important practice-changing implications.

“We were always struggling with whether to give these drugs first or second line, and I think now if we consider the first-line survival benefit ... [first-line use] should be standard of care,” she said, referring to CDK4/6 inhibitors and to findings from MONARCH 2 and prior studies of the inhibitors, including the MONALEESA-3 trial presented at the ESMO Congress.

MONALEESA-3 showed similar overall survival results with the CDK4/6 inhibitor ribociclib in postmenopausal women with HR+, HER2– advanced breast cancer.

“The data are highly clinically meaningful; I think they are going to make a huge impact on how we treat breast cancer,” Dr. Harbeck said.

Dr. Sledge has received trial support, research grants, and travel accommodations from Eli Lilly and Company; is a board member for Tessa Therapeutics; and is a consultant for Syndax, Symphogen, and Verseau Therapeutics. Dr. Harbeck disclosed financial relationships with Agendia, Amgen, AstraZeneca, Celgene, Daiichi-Sankyo, Genomic Health, Lilly, MSD, Nanostring, Novartis, Odonate, Pfizer, Roche, Sandoz/Hexal, and Seattle Genetics. She is also director of the West German Study Group and a member of the German AGO Breast Committee.

SOURCE: Sledge G et al., ESMO 2019, Abstract LBA6-PR.

BARCELONA – Adding olaparib to bevacizumab as maintenance after first-line platinum-based chemotherapy for advanced ovarian cancer provided a significant and clinically meaningful progression-free survival (PFS) benefit in the phase 3 PAOLA-1/ENGOT-ov25 trial.

The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.

Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.

The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.

In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.

“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”

The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.

“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.

Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.

Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.

The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.

Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.

The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.

During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.

“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.

Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.

“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”

In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”

Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”

In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”

As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.

The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.

[email protected]

SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
 

BARCELONA – Adding olaparib to bevacizumab as maintenance after first-line platinum-based chemotherapy for advanced ovarian cancer provided a significant and clinically meaningful progression-free survival (PFS) benefit in the phase 3 PAOLA-1/ENGOT-ov25 trial.

The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.

Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.

The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.

In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.

“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”

The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.

“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.

Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.

Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.

The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.

Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.

The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.

During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.

“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.

Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.

“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”

In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”

Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”

In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”

As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.

The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.

[email protected]

SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
 

BARCELONA – Adding olaparib to bevacizumab as maintenance after first-line platinum-based chemotherapy for advanced ovarian cancer provided a significant and clinically meaningful progression-free survival (PFS) benefit in the phase 3 PAOLA-1/ENGOT-ov25 trial.

The benefit was particularly pronounced in patients with a tumor BRCA mutation (tBRCAm), and in those with homologous recombination deficiency (HRD)–positive disease, Isabelle Ray-Coquard, MD, PhD, reported at the European Society for Medical Oncology Congress.

Investigator-assessed median PFS was 22.1 months in 537 patients randomized to receive the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor olaparib plus bevacizumab maintenance, compared with 16.6 months in 269 patients who received placebo plus bevacizumab in the randomized, double-blind trial.

The difference was statistically significant (hazard ratio, 0.59; P = .0001), said Dr. Ray-Coquard, a medical oncologist at Centre Léon Bérard and a professor of medical oncology at the Université Claude Bernard, Lyon, France.

In patients with tBRCAm, the median PFS in the olaparib and placebo arms, respectively, was 37.2 vs. 21.7 months (HR, 0.31); in HRD-positive patients – inclusive of those with tBRCAm – median PFS was 37.2 vs. 17.7 months, respectively; and in HRD-positive patients without tBRCAm, median PFS was 28.1 and 16.6 months, respectively (HR, 0.43), she said.

“So PAOLA-1 met its primary endpoint of a statistically significant improvement in PFS in the [intent-to-treat] population, in favor of the olaparib arm,” Dr. Ray-Coquard said. “What does that mean? For advanced ovarian cancer ... a benefit of a median time of nearly 30 months without relapse.”

The findings of the subgroup analysis showing an even stronger association between combination olaparib and bevacizumab and improved PFS in patients with tBRCAm are similar to those reported from the SOLO1 trial of olaparib monotherapy vs. chemotherapy in newly diagnosed advanced ovarian cancer, she noted.

“It is interesting to note that our PFS in the control arm is longer than [that seen] in the SOLO1 trial, which is probably due to the use of bevacizumab” in PAOLA-1, she said.

Additionally, a “new population of patients was identified: HRD-positive [patients] without BRCA mutation,” who experienced a PFS improvement of almost 1 year with olaparib versus placebo, Dr. Ray-Coquard noted.

Patients enrolled in the international trial – the first randomized trial to explore the efficacy and safety of maintenance olaparib plus bevacizumab in this setting and in patients with or without tBRCAm – had newly diagnosed stage III-IV, high-grade serous or endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer; had undergone upfront or interval surgery; had received platinum-taxane–based chemotherapy; and had received at least three cycles of bevacizumab. They were randomized 2:1 to receive maintenance therapy with 300-mg olaparib tablets given twice daily for up to 24 months along with bevacizumab at a dose of 15 mg/kg on day 1 every 3 weeks for 15 months (including when combined with platinum-based chemotherapy), or placebo plus bevacizumab.

The current standard of care for most patients with newly diagnosed advanced ovarian cancer is surgery and platinum-based chemotherapy combined with bevacizumab, followed by bevacizumab alone for maintenance.

Patient characteristics in the two arms were well balanced, Dr. Ray-Coquard said. “The PAOLA-1 population is representative of the majority of patients with advanced ovarian cancer, as the patient selection was not restricted by surgical outcome or BRCA mutation,” she commented, adding that the safety profile of the olaparib-bevacizumab combination was generally consistent with that seen in previous trials.

The addition of olaparib did not appear to affect bevacizumab tolerability or quality of life, she noted.

During a press briefing at the congress, Susan Banerjee, MBBS, PhD, who reported the SOLO1 results at the 2018 ESMO Congress, said that “PARP inhibitors have revolutionized the treatment landscape in ovarian cancer,” and have been approved in the recurrent ovarian cancer setting.

“But if we’re really going to have a chance to increase overall survival, and hopefully [have] more women cured, we need to bring these treatments into the first-line setting,” said Dr. Banerjee, consultant medical oncologist and research lead for the gynecology unit of the Royal Marsden Hospital, NHS Foundation Trust, London.

Given these and other recent findings, answers to the key question of how to improve outcomes in the first-line setting – and in patients beyond those with BRCA mutations – are emerging and showing that more women with ovarian cancer can benefit from PARP inhibitors.

“We know now ... that we can use PARP inhibitors in the first-line setting, beyond women with BRCA mutations,” Dr. Banerjee said. “The key question, really, is ‘What about patients that don’t have HRD deficiency? We do know that patients with BRCA mutations and who are HRD-positive have the greatest benefit with either a PARP inhibitor alone or, indeed, in combination with bevacizumab.”

In an ESMO press release about the PAOLA-1 and other related data presented at the congress, Ana Oaknin, MD, of Vall D’Hebron Institute of Oncology in Barcelona, stated that “the main goal in ovarian cancer is to avoid relapse after first-line therapy because otherwise the probability of cure is quite low.”

Combination olaparib and bevacizumab for first-line maintenance therapy “should become a new standard of care for patients with advanced ovarian cancer,” she said, noting that, while the PAOLA-1/ENGOT-ov25 trial did not include patients with no response to first-line chemotherapy (who comprise a small group of ovarian cancer patients), the trial is “a significant step forward in treatment for these women.”

In the context of other positive trial findings, including those from SOLO1 and other studies of PARP inhibition in this setting, the results represent a milestone, Dr. Oaknin said. “After decades studying different chemotherapy approaches, it is the first time we have meaningfully prolonged progression-free survival, and hopefully we will improve long-term outcome.”

As for the “next priority for research in this field, Dr. Oaknin said that strategies are needed to improve the current 45% 5-year overall survival rate for ovarian cancer. “I think the next approach is to incorporate immunotherapy as part of first-line therapy; ongoing trials are expected to report in 2-3 years,” she commented.

The PAOLA-1/ENGOT-ov25 trial was funded by ARCAGY Research, AstraZeneca, and Roche. Dr. Ray-Coquard reported relationships with AstraZeneca, Clovis Oncology, Tesaro, Pharma Mar, Roche, and Genmab, including receiving honoraria, travel/accommodations/expenses, and/or research grant funding, and/or serving as an advisor or consultant. Dr. Banerjee is a lecturer and/or advisory board member for AstraZeneca, Clovis, Gamamabs, Merck Serono, Pharmamar, Seattle Genetics, Roche, and Tesaro, and has received a travel grant from Nucana. Dr. Oaknin reported having no disclosures.

[email protected]

SOURCE: Ray-Coquard I et al. ESMO 2019, Abstract LBA2. Ann Oncol. 19;30:suppl 9.
 

BARCELONA – A continuous schedule of combination cediranib and olaparib demonstrated clinical benefit in 85% of patients with platinum-resistant ovarian cancer (PROC) in the randomized, phase 2 BAROCCO (Best Approach in Recurrent Ovarian Cancer With Cediranib-Olaparib) study.

Sharon Worcester/MDedge News

The continuous treatment approach was also associated with a trend toward improved progression-free survival (PFS) versus weekly paclitaxel in heavily pretreated patients with PROC, and this was particularly true in patients with germline BRCA wild-type (gBRCAwt), with a hazard ratio for PFS of 0.63, Nicolleta Colombo, MD, reported at the European Society of Medical Oncology Congress.

Median investigator-assessed PFS was 3.1, 5.7, and 3.8 months, respectively, in 123 patients with PROC and any gBRCA status who were enrolled from multiple centers in Italy and randomized 1:1:1 to receive 80 mg/m² of weekly paclitaxel for up to 24 weeks, continuous combination therapy with 20 mg of cediranib daily and 300 mg of olaparib twice daily, or intermittent dosing with 20 mg of cediranib given 5 days per week until progression, said Dr. Colombo, director of gynecologic cancer medical treatments at Istituto Europeo di Oncologia, Milan.

The hazard ratios for PFS with continuous therapy and intermittent therapy versus paclitaxel were 0.76 and 1.08, respectively, but the former comparison was not proportional and the difference in the area under the PFS curves was assessed and found to be 1.25 months in favor of continuous therapy with cediranib and olaparib, she explained.

“Surprisingly, the intermittent regimen did not perform as well,” she noted.

Subgroup analyses showed that in patients with gBRCAwt or unknown BRCA status, median PFS was 2.1, 5.8, and 3.8 months in the paclitaxel, continuous, and intermittent groups, respectively, demonstrating a trend toward greater benefit with continuous combination therapy versus the other arms (HR, 0.63; P = .13). The area under the PFS curves showed a difference of 1.32 months in favor of continuous therapy, she said.

Similarly, a trend toward greater benefit was seen in patients who had received up to two prior lines of therapy (HR, 0.47; P = .28).

As for the secondary study endpoint of response rates, complete responses occurred in 2 of 24 evaluable paclitaxel patients, and none of 39 and 35 patients in the continuous and intermittent groups. Partial responses occurred in 6, 7, and 4 patients in the groups, respectively; stable disease occurred in 5, 26, and 18, respectively; and progressive disease occurred in 11, 6, and 13 patients, respectively.

“The [rate of] progression was much higher with paclitaxel than in the continuous and intermittent arms,” Dr. Colombo said. “So the clinical benefit was very good; it was 84.6% for the continuous arm, and 62.8% for the intermittent arm.”

Clinical benefit in the paclitaxel arm was 54.1%, and duration of response was 4.4, 6.2, and 2.7 months in the arms, respectively.

The findings are of note, as the BAROCCO study includes a difficult-to-treat population with a high unmet need, she said, explaining that 59% of patients had received three or more prior lines of therapy, and the median platinum-free interval was only 1.8 months.

“Median progression-free survival for these patients is only about 3-4 months, even after weekly paclitaxel, which is recognized as the most effective chemotherapy regimen in this patient population,” she said, noting that new therapeutic options in this setting are of great clinical interest.

Additionally, BAROCCO is the first trial of combined cediranib-olaparib in PROC to include a control arm, she noted.

Single-agent olaparib was approved by the Food and Drug Administration in 2017 for the treatment of patients with germline BRCA mutated (gBRCAm) relapsed ovarian cancer after 3 or more lines of chemotherapy, but the efficacy of the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor in gBRCAwt PROC is limited.

Findings from the CLIO trial presented in June at American Society of Clinical Oncology annual meeting showed an overall response rate (ORR) of 13% and PFS of 2.9 months in gBRCAwt patients with PROC treated with olaparib, and in the QUADRA study, the ORR in gBRCAwt PROC was just 3%

“On the other hand, olaparib activity was observed beyond BRCA-mutated tumors in the platinum-sensitive relapsed ovarian cancer patients, and was increased when combined with an antiangiogenic agent,” Dr. Colombo said. “In fact, both the trials with cediranib and olaparib, and with bevacizumab and niraparib, showed an improvement in progression-free survival, compared with a single agent.

“So there is a strong rationale for the combination and the synergistic effect of cediranib and olaparib, because molecular pharmacologic studies suggest that cediranib induces downregulation of some genes that are involved in homologous recombination, thus producing a sort of functional ‘BRCAness’ that favors the selective activity of the PARP inhibitors,” she explained.

Preclinical evidence suggests this may be related to the antiangiogenic effect of cediranib, or possibly to the inhibition of the platinum-derived growth factor signaling by cediranib.

BAROCCO was designed to assess whether the combination would provide superior PFS, compared with weekly paclitaxel, in the platinum-resistant population, and if an intermittent schedule might improve gastrointestinal tolerability, as treatment has been associated with severe diarrhea in previous trials, she said.

However, the toxicity profile of the study arms was as expected, and similar between experimental arms, with 11%, 18%, and 7% of patients in the paclitaxel, continuous, and intermittent arms discontinuing treatment because of adverse events, she noted.

Five serious adverse drug reactions occurred and two were fatal, including one in the control arm and one in the continuous arm.

Although not statistically significant, the continuous administration regimen was well tolerated, and showed “a promising trend for improved PFS,” particularly in gBRCAwt patients.

Notably, only 5% of patients in that arm experienced severe diarrhea, Dr. Colombo said, adding that “the continuous administration of cediranib and olaparib is active in PROC patients, with clinical benefit observed in 85% of cases.”

“We believe that [this combination] represents an active, feasible oral regimen, which deserves further investigation, and these results support ongoing trials investigating the same combination in platinum-resistant ovarian cancer,” she concluded.

Invited discussant Antonio Gonzalez Martin, MD, said that some of the drug-related adverse events reported in the study – which occurred in 70%-78% of patients in the three arms and included diarrhea, nausea, fatigue, and others – could have an impact on quality of life.

“It’s something that we need to study; patient-reported outcomes should be integrated in these types of trials for this very important population,” said Dr. Gonzalez-Martin, head of medical oncology at Clinica Universidad de Navarra, Madrid.

He added that the future of antiangiogenic and PARP inhibitor combinations remains to be defined in the first-line, platinum-sensitive, and platinum-resistant ovarian cancer settings.

The BAROCCO Trial was funded by AstraZeneca. Dr. Colombo has received honoraria from or been an advisor or consultant to Roche/Genentech, PharmaMar; AstraZeneca, Tesaro, Clovis Oncology, Pfizer, MSD Oncology, BioCad, and Takeda. Dr. Gonzalez-Martin has received fees, honoraria, and/or grants from Roche, AstraZeneca, Tesaro, GSK, Clovis, MSD, Pfizer, Novartis, PharmaMar, and Imugene.

[email protected]

SOURCE: Colombo N et al. ESMO 2019, Abstract LBA58. Ann Oncol. 2019;30:suppl 5.

BARCELONA – A continuous schedule of combination cediranib and olaparib demonstrated clinical benefit in 85% of patients with platinum-resistant ovarian cancer (PROC) in the randomized, phase 2 BAROCCO (Best Approach in Recurrent Ovarian Cancer With Cediranib-Olaparib) study.

Sharon Worcester/MDedge News

The continuous treatment approach was also associated with a trend toward improved progression-free survival (PFS) versus weekly paclitaxel in heavily pretreated patients with PROC, and this was particularly true in patients with germline BRCA wild-type (gBRCAwt), with a hazard ratio for PFS of 0.63, Nicolleta Colombo, MD, reported at the European Society of Medical Oncology Congress.

Median investigator-assessed PFS was 3.1, 5.7, and 3.8 months, respectively, in 123 patients with PROC and any gBRCA status who were enrolled from multiple centers in Italy and randomized 1:1:1 to receive 80 mg/m² of weekly paclitaxel for up to 24 weeks, continuous combination therapy with 20 mg of cediranib daily and 300 mg of olaparib twice daily, or intermittent dosing with 20 mg of cediranib given 5 days per week until progression, said Dr. Colombo, director of gynecologic cancer medical treatments at Istituto Europeo di Oncologia, Milan.

The hazard ratios for PFS with continuous therapy and intermittent therapy versus paclitaxel were 0.76 and 1.08, respectively, but the former comparison was not proportional and the difference in the area under the PFS curves was assessed and found to be 1.25 months in favor of continuous therapy with cediranib and olaparib, she explained.

“Surprisingly, the intermittent regimen did not perform as well,” she noted.

Subgroup analyses showed that in patients with gBRCAwt or unknown BRCA status, median PFS was 2.1, 5.8, and 3.8 months in the paclitaxel, continuous, and intermittent groups, respectively, demonstrating a trend toward greater benefit with continuous combination therapy versus the other arms (HR, 0.63; P = .13). The area under the PFS curves showed a difference of 1.32 months in favor of continuous therapy, she said.

Similarly, a trend toward greater benefit was seen in patients who had received up to two prior lines of therapy (HR, 0.47; P = .28).

As for the secondary study endpoint of response rates, complete responses occurred in 2 of 24 evaluable paclitaxel patients, and none of 39 and 35 patients in the continuous and intermittent groups. Partial responses occurred in 6, 7, and 4 patients in the groups, respectively; stable disease occurred in 5, 26, and 18, respectively; and progressive disease occurred in 11, 6, and 13 patients, respectively.

“The [rate of] progression was much higher with paclitaxel than in the continuous and intermittent arms,” Dr. Colombo said. “So the clinical benefit was very good; it was 84.6% for the continuous arm, and 62.8% for the intermittent arm.”

Clinical benefit in the paclitaxel arm was 54.1%, and duration of response was 4.4, 6.2, and 2.7 months in the arms, respectively.

The findings are of note, as the BAROCCO study includes a difficult-to-treat population with a high unmet need, she said, explaining that 59% of patients had received three or more prior lines of therapy, and the median platinum-free interval was only 1.8 months.

“Median progression-free survival for these patients is only about 3-4 months, even after weekly paclitaxel, which is recognized as the most effective chemotherapy regimen in this patient population,” she said, noting that new therapeutic options in this setting are of great clinical interest.

Additionally, BAROCCO is the first trial of combined cediranib-olaparib in PROC to include a control arm, she noted.

Single-agent olaparib was approved by the Food and Drug Administration in 2017 for the treatment of patients with germline BRCA mutated (gBRCAm) relapsed ovarian cancer after 3 or more lines of chemotherapy, but the efficacy of the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor in gBRCAwt PROC is limited.

Findings from the CLIO trial presented in June at American Society of Clinical Oncology annual meeting showed an overall response rate (ORR) of 13% and PFS of 2.9 months in gBRCAwt patients with PROC treated with olaparib, and in the QUADRA study, the ORR in gBRCAwt PROC was just 3%

“On the other hand, olaparib activity was observed beyond BRCA-mutated tumors in the platinum-sensitive relapsed ovarian cancer patients, and was increased when combined with an antiangiogenic agent,” Dr. Colombo said. “In fact, both the trials with cediranib and olaparib, and with bevacizumab and niraparib, showed an improvement in progression-free survival, compared with a single agent.

“So there is a strong rationale for the combination and the synergistic effect of cediranib and olaparib, because molecular pharmacologic studies suggest that cediranib induces downregulation of some genes that are involved in homologous recombination, thus producing a sort of functional ‘BRCAness’ that favors the selective activity of the PARP inhibitors,” she explained.

Preclinical evidence suggests this may be related to the antiangiogenic effect of cediranib, or possibly to the inhibition of the platinum-derived growth factor signaling by cediranib.

BAROCCO was designed to assess whether the combination would provide superior PFS, compared with weekly paclitaxel, in the platinum-resistant population, and if an intermittent schedule might improve gastrointestinal tolerability, as treatment has been associated with severe diarrhea in previous trials, she said.

However, the toxicity profile of the study arms was as expected, and similar between experimental arms, with 11%, 18%, and 7% of patients in the paclitaxel, continuous, and intermittent arms discontinuing treatment because of adverse events, she noted.

Five serious adverse drug reactions occurred and two were fatal, including one in the control arm and one in the continuous arm.

Although not statistically significant, the continuous administration regimen was well tolerated, and showed “a promising trend for improved PFS,” particularly in gBRCAwt patients.

Notably, only 5% of patients in that arm experienced severe diarrhea, Dr. Colombo said, adding that “the continuous administration of cediranib and olaparib is active in PROC patients, with clinical benefit observed in 85% of cases.”

“We believe that [this combination] represents an active, feasible oral regimen, which deserves further investigation, and these results support ongoing trials investigating the same combination in platinum-resistant ovarian cancer,” she concluded.

Invited discussant Antonio Gonzalez Martin, MD, said that some of the drug-related adverse events reported in the study – which occurred in 70%-78% of patients in the three arms and included diarrhea, nausea, fatigue, and others – could have an impact on quality of life.

“It’s something that we need to study; patient-reported outcomes should be integrated in these types of trials for this very important population,” said Dr. Gonzalez-Martin, head of medical oncology at Clinica Universidad de Navarra, Madrid.

He added that the future of antiangiogenic and PARP inhibitor combinations remains to be defined in the first-line, platinum-sensitive, and platinum-resistant ovarian cancer settings.

The BAROCCO Trial was funded by AstraZeneca. Dr. Colombo has received honoraria from or been an advisor or consultant to Roche/Genentech, PharmaMar; AstraZeneca, Tesaro, Clovis Oncology, Pfizer, MSD Oncology, BioCad, and Takeda. Dr. Gonzalez-Martin has received fees, honoraria, and/or grants from Roche, AstraZeneca, Tesaro, GSK, Clovis, MSD, Pfizer, Novartis, PharmaMar, and Imugene.

[email protected]

SOURCE: Colombo N et al. ESMO 2019, Abstract LBA58. Ann Oncol. 2019;30:suppl 5.

BARCELONA – A continuous schedule of combination cediranib and olaparib demonstrated clinical benefit in 85% of patients with platinum-resistant ovarian cancer (PROC) in the randomized, phase 2 BAROCCO (Best Approach in Recurrent Ovarian Cancer With Cediranib-Olaparib) study.

Sharon Worcester/MDedge News

The continuous treatment approach was also associated with a trend toward improved progression-free survival (PFS) versus weekly paclitaxel in heavily pretreated patients with PROC, and this was particularly true in patients with germline BRCA wild-type (gBRCAwt), with a hazard ratio for PFS of 0.63, Nicolleta Colombo, MD, reported at the European Society of Medical Oncology Congress.

Median investigator-assessed PFS was 3.1, 5.7, and 3.8 months, respectively, in 123 patients with PROC and any gBRCA status who were enrolled from multiple centers in Italy and randomized 1:1:1 to receive 80 mg/m² of weekly paclitaxel for up to 24 weeks, continuous combination therapy with 20 mg of cediranib daily and 300 mg of olaparib twice daily, or intermittent dosing with 20 mg of cediranib given 5 days per week until progression, said Dr. Colombo, director of gynecologic cancer medical treatments at Istituto Europeo di Oncologia, Milan.

The hazard ratios for PFS with continuous therapy and intermittent therapy versus paclitaxel were 0.76 and 1.08, respectively, but the former comparison was not proportional and the difference in the area under the PFS curves was assessed and found to be 1.25 months in favor of continuous therapy with cediranib and olaparib, she explained.

“Surprisingly, the intermittent regimen did not perform as well,” she noted.

Subgroup analyses showed that in patients with gBRCAwt or unknown BRCA status, median PFS was 2.1, 5.8, and 3.8 months in the paclitaxel, continuous, and intermittent groups, respectively, demonstrating a trend toward greater benefit with continuous combination therapy versus the other arms (HR, 0.63; P = .13). The area under the PFS curves showed a difference of 1.32 months in favor of continuous therapy, she said.

Similarly, a trend toward greater benefit was seen in patients who had received up to two prior lines of therapy (HR, 0.47; P = .28).

As for the secondary study endpoint of response rates, complete responses occurred in 2 of 24 evaluable paclitaxel patients, and none of 39 and 35 patients in the continuous and intermittent groups. Partial responses occurred in 6, 7, and 4 patients in the groups, respectively; stable disease occurred in 5, 26, and 18, respectively; and progressive disease occurred in 11, 6, and 13 patients, respectively.

“The [rate of] progression was much higher with paclitaxel than in the continuous and intermittent arms,” Dr. Colombo said. “So the clinical benefit was very good; it was 84.6% for the continuous arm, and 62.8% for the intermittent arm.”

Clinical benefit in the paclitaxel arm was 54.1%, and duration of response was 4.4, 6.2, and 2.7 months in the arms, respectively.

The findings are of note, as the BAROCCO study includes a difficult-to-treat population with a high unmet need, she said, explaining that 59% of patients had received three or more prior lines of therapy, and the median platinum-free interval was only 1.8 months.

“Median progression-free survival for these patients is only about 3-4 months, even after weekly paclitaxel, which is recognized as the most effective chemotherapy regimen in this patient population,” she said, noting that new therapeutic options in this setting are of great clinical interest.

Additionally, BAROCCO is the first trial of combined cediranib-olaparib in PROC to include a control arm, she noted.

Single-agent olaparib was approved by the Food and Drug Administration in 2017 for the treatment of patients with germline BRCA mutated (gBRCAm) relapsed ovarian cancer after 3 or more lines of chemotherapy, but the efficacy of the poly adenosine diphosphate–ribose polymerase (PARP) inhibitor in gBRCAwt PROC is limited.

Findings from the CLIO trial presented in June at American Society of Clinical Oncology annual meeting showed an overall response rate (ORR) of 13% and PFS of 2.9 months in gBRCAwt patients with PROC treated with olaparib, and in the QUADRA study, the ORR in gBRCAwt PROC was just 3%

“On the other hand, olaparib activity was observed beyond BRCA-mutated tumors in the platinum-sensitive relapsed ovarian cancer patients, and was increased when combined with an antiangiogenic agent,” Dr. Colombo said. “In fact, both the trials with cediranib and olaparib, and with bevacizumab and niraparib, showed an improvement in progression-free survival, compared with a single agent.

“So there is a strong rationale for the combination and the synergistic effect of cediranib and olaparib, because molecular pharmacologic studies suggest that cediranib induces downregulation of some genes that are involved in homologous recombination, thus producing a sort of functional ‘BRCAness’ that favors the selective activity of the PARP inhibitors,” she explained.

Preclinical evidence suggests this may be related to the antiangiogenic effect of cediranib, or possibly to the inhibition of the platinum-derived growth factor signaling by cediranib.

BAROCCO was designed to assess whether the combination would provide superior PFS, compared with weekly paclitaxel, in the platinum-resistant population, and if an intermittent schedule might improve gastrointestinal tolerability, as treatment has been associated with severe diarrhea in previous trials, she said.

However, the toxicity profile of the study arms was as expected, and similar between experimental arms, with 11%, 18%, and 7% of patients in the paclitaxel, continuous, and intermittent arms discontinuing treatment because of adverse events, she noted.

Five serious adverse drug reactions occurred and two were fatal, including one in the control arm and one in the continuous arm.

Although not statistically significant, the continuous administration regimen was well tolerated, and showed “a promising trend for improved PFS,” particularly in gBRCAwt patients.

Notably, only 5% of patients in that arm experienced severe diarrhea, Dr. Colombo said, adding that “the continuous administration of cediranib and olaparib is active in PROC patients, with clinical benefit observed in 85% of cases.”

“We believe that [this combination] represents an active, feasible oral regimen, which deserves further investigation, and these results support ongoing trials investigating the same combination in platinum-resistant ovarian cancer,” she concluded.

Invited discussant Antonio Gonzalez Martin, MD, said that some of the drug-related adverse events reported in the study – which occurred in 70%-78% of patients in the three arms and included diarrhea, nausea, fatigue, and others – could have an impact on quality of life.

“It’s something that we need to study; patient-reported outcomes should be integrated in these types of trials for this very important population,” said Dr. Gonzalez-Martin, head of medical oncology at Clinica Universidad de Navarra, Madrid.

He added that the future of antiangiogenic and PARP inhibitor combinations remains to be defined in the first-line, platinum-sensitive, and platinum-resistant ovarian cancer settings.

The BAROCCO Trial was funded by AstraZeneca. Dr. Colombo has received honoraria from or been an advisor or consultant to Roche/Genentech, PharmaMar; AstraZeneca, Tesaro, Clovis Oncology, Pfizer, MSD Oncology, BioCad, and Takeda. Dr. Gonzalez-Martin has received fees, honoraria, and/or grants from Roche, AstraZeneca, Tesaro, GSK, Clovis, MSD, Pfizer, Novartis, PharmaMar, and Imugene.

[email protected]

SOURCE: Colombo N et al. ESMO 2019, Abstract LBA58. Ann Oncol. 2019;30:suppl 5.

EDINBURGH – Lenalidomide maintenance therapy after chemoimmunotherapy in high-risk chronic lymphocytic leukemia (CLL) improved progression- and event-free survival, but not overall survival, and was associated with three unexpected cases of B-cell acute lymphoblastic leukemia (B-ALL), according to 4-year follow-up in the German, phase 3 CLLM1 study.

Given these findings, and in particular the B-ALL cases, lenalidomide cannot be generally recommended as maintenance therapy in high-risk CLL, Moritz Fürstenau, MD, of the University of Cologne, reported in a poster at the International Workshop on Chronic Lymphocytic Leukemia.

At a median follow-up of 47.6 months, median progression-free survival (PFS) by investigator assessment was 54.7 months in 60 patients randomized to receive lenalidomide maintenance therapy, compared with 23.2 months for 29 who received placebo (hazard ratio, 0.22), and median event-free survival (EFS) was 46.2 months vs. 14.6 months in the groups, respectively (hazard ratio, 0.24), Dr. Fürstenau said during an oral poster presentation at the conference.

“So ... after 4 years of observation, we still see improvement in PFS, EFS, and time to next treatment,” he said, also noting that minimal residual disease (MRD) negativity was achieved by eight patients in the lenalidomide group, and in none of the patients in the placebo group.

However, overall survival was 79% and 87% in the lenalidomide and placebo groups, respectively (HR, 1.53). In total, 12 patients died, including 9 in the lenalidomide group from fatal infections, concomitant disease, CLL progression, or unknown causes. Three patients in the placebo group died from CLL progression or fatal infection.

In the lenalidomide group, hematological and solid tumor second primary malignancies were reported in three and four patients, respectively (5% and 7%), compared with zero and two patients, respectively (0% and 7%), in the placebo group.

The CLLM1 study of the German CLL Study Group evaluated maintenance with lenalidomide vs. placebo in patients with high risk of progression after first-line chemoimmunotherapy. Previously reported results also favored lenalidomide maintenance for PFS, but not OS, Dr. Fürstenau said, adding that the study was unblinded at a median follow-up of 17.9 months, and in November 2017 treatment was stopped when two cases of B-ALL were observed. A third case was reported in 2018.

The current analysis includes data available through December 2018, and the findings warrant further investigation to analyze the unexpectedly high incidence of B-ALL, he said.

The CLLM1 study was funded by Celgene.

[email protected]

EDINBURGH – Lenalidomide maintenance therapy after chemoimmunotherapy in high-risk chronic lymphocytic leukemia (CLL) improved progression- and event-free survival, but not overall survival, and was associated with three unexpected cases of B-cell acute lymphoblastic leukemia (B-ALL), according to 4-year follow-up in the German, phase 3 CLLM1 study.

Given these findings, and in particular the B-ALL cases, lenalidomide cannot be generally recommended as maintenance therapy in high-risk CLL, Moritz Fürstenau, MD, of the University of Cologne, reported in a poster at the International Workshop on Chronic Lymphocytic Leukemia.

At a median follow-up of 47.6 months, median progression-free survival (PFS) by investigator assessment was 54.7 months in 60 patients randomized to receive lenalidomide maintenance therapy, compared with 23.2 months for 29 who received placebo (hazard ratio, 0.22), and median event-free survival (EFS) was 46.2 months vs. 14.6 months in the groups, respectively (hazard ratio, 0.24), Dr. Fürstenau said during an oral poster presentation at the conference.

“So ... after 4 years of observation, we still see improvement in PFS, EFS, and time to next treatment,” he said, also noting that minimal residual disease (MRD) negativity was achieved by eight patients in the lenalidomide group, and in none of the patients in the placebo group.

However, overall survival was 79% and 87% in the lenalidomide and placebo groups, respectively (HR, 1.53). In total, 12 patients died, including 9 in the lenalidomide group from fatal infections, concomitant disease, CLL progression, or unknown causes. Three patients in the placebo group died from CLL progression or fatal infection.

In the lenalidomide group, hematological and solid tumor second primary malignancies were reported in three and four patients, respectively (5% and 7%), compared with zero and two patients, respectively (0% and 7%), in the placebo group.

The CLLM1 study of the German CLL Study Group evaluated maintenance with lenalidomide vs. placebo in patients with high risk of progression after first-line chemoimmunotherapy. Previously reported results also favored lenalidomide maintenance for PFS, but not OS, Dr. Fürstenau said, adding that the study was unblinded at a median follow-up of 17.9 months, and in November 2017 treatment was stopped when two cases of B-ALL were observed. A third case was reported in 2018.

The current analysis includes data available through December 2018, and the findings warrant further investigation to analyze the unexpectedly high incidence of B-ALL, he said.

The CLLM1 study was funded by Celgene.

[email protected]

EDINBURGH – Lenalidomide maintenance therapy after chemoimmunotherapy in high-risk chronic lymphocytic leukemia (CLL) improved progression- and event-free survival, but not overall survival, and was associated with three unexpected cases of B-cell acute lymphoblastic leukemia (B-ALL), according to 4-year follow-up in the German, phase 3 CLLM1 study.

Given these findings, and in particular the B-ALL cases, lenalidomide cannot be generally recommended as maintenance therapy in high-risk CLL, Moritz Fürstenau, MD, of the University of Cologne, reported in a poster at the International Workshop on Chronic Lymphocytic Leukemia.

At a median follow-up of 47.6 months, median progression-free survival (PFS) by investigator assessment was 54.7 months in 60 patients randomized to receive lenalidomide maintenance therapy, compared with 23.2 months for 29 who received placebo (hazard ratio, 0.22), and median event-free survival (EFS) was 46.2 months vs. 14.6 months in the groups, respectively (hazard ratio, 0.24), Dr. Fürstenau said during an oral poster presentation at the conference.

“So ... after 4 years of observation, we still see improvement in PFS, EFS, and time to next treatment,” he said, also noting that minimal residual disease (MRD) negativity was achieved by eight patients in the lenalidomide group, and in none of the patients in the placebo group.

However, overall survival was 79% and 87% in the lenalidomide and placebo groups, respectively (HR, 1.53). In total, 12 patients died, including 9 in the lenalidomide group from fatal infections, concomitant disease, CLL progression, or unknown causes. Three patients in the placebo group died from CLL progression or fatal infection.

In the lenalidomide group, hematological and solid tumor second primary malignancies were reported in three and four patients, respectively (5% and 7%), compared with zero and two patients, respectively (0% and 7%), in the placebo group.

The CLLM1 study of the German CLL Study Group evaluated maintenance with lenalidomide vs. placebo in patients with high risk of progression after first-line chemoimmunotherapy. Previously reported results also favored lenalidomide maintenance for PFS, but not OS, Dr. Fürstenau said, adding that the study was unblinded at a median follow-up of 17.9 months, and in November 2017 treatment was stopped when two cases of B-ALL were observed. A third case was reported in 2018.

The current analysis includes data available through December 2018, and the findings warrant further investigation to analyze the unexpectedly high incidence of B-ALL, he said.

The CLLM1 study was funded by Celgene.

[email protected]

BARCELONA – First-line flat-dose nivolumab plus weight-based ipilimumab was safe and showed encouraging clinical activity both in general and in patients with poor performance status and comorbidities in the multicenter CheckMate 817 study of patients with advanced non–small cell lung cancer.

Sharon Worcester/MDedge News

The treatment-related adverse event (TRAE) rate in 139 patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 2, for example, was 63%, compared with 77% in 391 patients with good ECOG PS (score of 0-1), and the rates of grade 3-4 AEs in the groups, respectively, were 26% and 35%, Fabrice Barlesi, MD, reported at the World Conference on Lung Cancer.

In 59 patients with ECOG PS of 0-1 plus either asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV infection, the overall TRAE and grade 3-4 TRAE rates were 78% and 34%.

The combined TRAE and grade 3-4 TRAE rates in the two “special populations” cohorts were 67% and 28%, respectively, Dr. Barlesi, of Aix-Marseille Universite and Assistance Publique Hôpitaux de Marseille, France, said at the conference, which was sponsored by the International Association for the Study of Lung Cancer.

The overall response rate (ORR) in the ECOG PS-2 and PS-01+comorbidity groups was 19% and 37%, respectively, compared with 36% in the good PS cohort, and median duration of response in the three groups was 14.2 months, 9.7 months, and at least 18 months (median not reached), respectively.

The 1-year PFS rates were 25%, 27%, and 35% respectively, and median PFS was 3.6, 4.2, and 5.8, he said.

Among the 198 special population patients, those with PD-L1 expression of 50% or greater, 1% or greater, or less than 1% had 1-yr PFS rates of 46%, 24%, and 29% (median, 9.6, 3.2, and 3.9 months), and in those with 10 or greater mut/Mb and less than 10 mut/Mb, they were 42% and 17% (median, 8.3 and 2.8 months), respectively.

The single-arm, nonrandomized CheckMate 817 study evaluated the programmed death-ligand 1 (PD-L1) inhibitor nivolumab at a flat dose of 240 mg given intravenously every 2 weeks plus the CTLA-4 inhibitor ipilimumab at 1 mg/kg IV every 6 weeks, with treatment until disease progression or unacceptable toxicity for up to 2 years. Participants had stage IV non–small cell lung cancer (NSCLC), had received no prior systemic therapy, and had no known sensitizing EGFR or ALK alterations.

“Nivolumab and ipilimumab are immune checkpoint inhibitors with distinct ... but complementary mechanisms of action,” Dr. Barlesi said, adding that in combination they have demonstrated clinical benefit vs. chemotherapy in the first-line treatment of NSCLC.

However, data are limited on safety and efficacy of immunotherapy in patients with advanced NSCLC with other comorbidities such as brain metastases, kidney and renal disease, and HIV, as such patients – despite comprising the majority of NSCLC patients at presentation – are typically ineligible for trial registration, he explained, adding that CheckMate 817 is a multicohort, nonrandomized, phase 3b study evaluating the safety and efficacy of nivolumab plus ipilimumab in such patients.

The findings show a safety profile “clearly comparable” to that observed in prior studies using weight-based nivolumab, he noted.

“Nivolumab plus ipilimumab showed clearly encouraging clinical activity in this special population, with an overall response rate of 24%,” he said. “As expected, unfortunately, the outcomes in these special populations were affected by poor performance status, however, despite the poor performance status or comorbidities, those patients were shown to achieve durable responses ... with [an overall] duration of response at 1 year, of 57%.”

CheckMate 817 was sponsored by Bristol-Myers Squibb. Dr. Barlesi disclosed financial relationships with Abbvie, ACEA, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, and Takeda.

SOURCE: Barlesi F et al. WCLC 2019: Abstract OA04.02.

BARCELONA – First-line flat-dose nivolumab plus weight-based ipilimumab was safe and showed encouraging clinical activity both in general and in patients with poor performance status and comorbidities in the multicenter CheckMate 817 study of patients with advanced non–small cell lung cancer.

Sharon Worcester/MDedge News

The treatment-related adverse event (TRAE) rate in 139 patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 2, for example, was 63%, compared with 77% in 391 patients with good ECOG PS (score of 0-1), and the rates of grade 3-4 AEs in the groups, respectively, were 26% and 35%, Fabrice Barlesi, MD, reported at the World Conference on Lung Cancer.

In 59 patients with ECOG PS of 0-1 plus either asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV infection, the overall TRAE and grade 3-4 TRAE rates were 78% and 34%.

The combined TRAE and grade 3-4 TRAE rates in the two “special populations” cohorts were 67% and 28%, respectively, Dr. Barlesi, of Aix-Marseille Universite and Assistance Publique Hôpitaux de Marseille, France, said at the conference, which was sponsored by the International Association for the Study of Lung Cancer.

The overall response rate (ORR) in the ECOG PS-2 and PS-01+comorbidity groups was 19% and 37%, respectively, compared with 36% in the good PS cohort, and median duration of response in the three groups was 14.2 months, 9.7 months, and at least 18 months (median not reached), respectively.

The 1-year PFS rates were 25%, 27%, and 35% respectively, and median PFS was 3.6, 4.2, and 5.8, he said.

Among the 198 special population patients, those with PD-L1 expression of 50% or greater, 1% or greater, or less than 1% had 1-yr PFS rates of 46%, 24%, and 29% (median, 9.6, 3.2, and 3.9 months), and in those with 10 or greater mut/Mb and less than 10 mut/Mb, they were 42% and 17% (median, 8.3 and 2.8 months), respectively.

The single-arm, nonrandomized CheckMate 817 study evaluated the programmed death-ligand 1 (PD-L1) inhibitor nivolumab at a flat dose of 240 mg given intravenously every 2 weeks plus the CTLA-4 inhibitor ipilimumab at 1 mg/kg IV every 6 weeks, with treatment until disease progression or unacceptable toxicity for up to 2 years. Participants had stage IV non–small cell lung cancer (NSCLC), had received no prior systemic therapy, and had no known sensitizing EGFR or ALK alterations.

“Nivolumab and ipilimumab are immune checkpoint inhibitors with distinct ... but complementary mechanisms of action,” Dr. Barlesi said, adding that in combination they have demonstrated clinical benefit vs. chemotherapy in the first-line treatment of NSCLC.

However, data are limited on safety and efficacy of immunotherapy in patients with advanced NSCLC with other comorbidities such as brain metastases, kidney and renal disease, and HIV, as such patients – despite comprising the majority of NSCLC patients at presentation – are typically ineligible for trial registration, he explained, adding that CheckMate 817 is a multicohort, nonrandomized, phase 3b study evaluating the safety and efficacy of nivolumab plus ipilimumab in such patients.

The findings show a safety profile “clearly comparable” to that observed in prior studies using weight-based nivolumab, he noted.

“Nivolumab plus ipilimumab showed clearly encouraging clinical activity in this special population, with an overall response rate of 24%,” he said. “As expected, unfortunately, the outcomes in these special populations were affected by poor performance status, however, despite the poor performance status or comorbidities, those patients were shown to achieve durable responses ... with [an overall] duration of response at 1 year, of 57%.”

CheckMate 817 was sponsored by Bristol-Myers Squibb. Dr. Barlesi disclosed financial relationships with Abbvie, ACEA, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, and Takeda.

SOURCE: Barlesi F et al. WCLC 2019: Abstract OA04.02.

BARCELONA – First-line flat-dose nivolumab plus weight-based ipilimumab was safe and showed encouraging clinical activity both in general and in patients with poor performance status and comorbidities in the multicenter CheckMate 817 study of patients with advanced non–small cell lung cancer.

Sharon Worcester/MDedge News

The treatment-related adverse event (TRAE) rate in 139 patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 2, for example, was 63%, compared with 77% in 391 patients with good ECOG PS (score of 0-1), and the rates of grade 3-4 AEs in the groups, respectively, were 26% and 35%, Fabrice Barlesi, MD, reported at the World Conference on Lung Cancer.

In 59 patients with ECOG PS of 0-1 plus either asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV infection, the overall TRAE and grade 3-4 TRAE rates were 78% and 34%.

The combined TRAE and grade 3-4 TRAE rates in the two “special populations” cohorts were 67% and 28%, respectively, Dr. Barlesi, of Aix-Marseille Universite and Assistance Publique Hôpitaux de Marseille, France, said at the conference, which was sponsored by the International Association for the Study of Lung Cancer.

The overall response rate (ORR) in the ECOG PS-2 and PS-01+comorbidity groups was 19% and 37%, respectively, compared with 36% in the good PS cohort, and median duration of response in the three groups was 14.2 months, 9.7 months, and at least 18 months (median not reached), respectively.

The 1-year PFS rates were 25%, 27%, and 35% respectively, and median PFS was 3.6, 4.2, and 5.8, he said.

Among the 198 special population patients, those with PD-L1 expression of 50% or greater, 1% or greater, or less than 1% had 1-yr PFS rates of 46%, 24%, and 29% (median, 9.6, 3.2, and 3.9 months), and in those with 10 or greater mut/Mb and less than 10 mut/Mb, they were 42% and 17% (median, 8.3 and 2.8 months), respectively.

The single-arm, nonrandomized CheckMate 817 study evaluated the programmed death-ligand 1 (PD-L1) inhibitor nivolumab at a flat dose of 240 mg given intravenously every 2 weeks plus the CTLA-4 inhibitor ipilimumab at 1 mg/kg IV every 6 weeks, with treatment until disease progression or unacceptable toxicity for up to 2 years. Participants had stage IV non–small cell lung cancer (NSCLC), had received no prior systemic therapy, and had no known sensitizing EGFR or ALK alterations.

“Nivolumab and ipilimumab are immune checkpoint inhibitors with distinct ... but complementary mechanisms of action,” Dr. Barlesi said, adding that in combination they have demonstrated clinical benefit vs. chemotherapy in the first-line treatment of NSCLC.

However, data are limited on safety and efficacy of immunotherapy in patients with advanced NSCLC with other comorbidities such as brain metastases, kidney and renal disease, and HIV, as such patients – despite comprising the majority of NSCLC patients at presentation – are typically ineligible for trial registration, he explained, adding that CheckMate 817 is a multicohort, nonrandomized, phase 3b study evaluating the safety and efficacy of nivolumab plus ipilimumab in such patients.

The findings show a safety profile “clearly comparable” to that observed in prior studies using weight-based nivolumab, he noted.

“Nivolumab plus ipilimumab showed clearly encouraging clinical activity in this special population, with an overall response rate of 24%,” he said. “As expected, unfortunately, the outcomes in these special populations were affected by poor performance status, however, despite the poor performance status or comorbidities, those patients were shown to achieve durable responses ... with [an overall] duration of response at 1 year, of 57%.”

CheckMate 817 was sponsored by Bristol-Myers Squibb. Dr. Barlesi disclosed financial relationships with Abbvie, ACEA, Amgen, Astra-Zeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, Medimmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, and Takeda.

SOURCE: Barlesi F et al. WCLC 2019: Abstract OA04.02.