M. Alexander Otto

SAN ANTONIO — Women 65-70 years old are often offered the option of skipping radiation after lumpectomy for hormone receptor–positive early-stage breast cancer and moving straight to endocrine therapy.

The recurrence rate with and without radiation is well known so women can be counseled accurately about their options. For some, the 10% risk of recurrence at 10 years without radiation seems reasonable, for others it does not.

Omitting radiation for older postmenopausal women is “very reasonable to offer so long as they are willing to accept the risk,” said Reshma Jagsi, MD, chief of radiation oncology at Emory University, Atlanta.

The option, however, isn’t generally offered to postmenopausal women younger than 65 years old because their risk from skipping adjuvant radiation isn’t known, but that’s about to change.

Several teams are investigating the issue, including one led by Dr. Jagsi, who presented her and her colleagues’ latest results at the San Antonio Breast Cancer Symposium.

In the single-arm IDEA [Individualized Decisions for Endocrine therapy Alone] study, 200 women 50-69 years old with pT1N0 unifocal hormone receptor–positive, HER2-negative invasive breast cancer agreed to the approach when it was offered to them following lumpectomy with sentinel lymph node biopsy. The mean tumor size was 10 mm with margins of at least 2 mm.

The women were at low risk for recurrence, with recurrence risk scores no higher than 18 points on the Oncotype DX 21-gene assay; the mean score was 11 points.

Radiation would have been the usual next step after lumpectomy, but instead the patients went directly to endocrine therapy for 5 years, with adherence above 80%.

At 5 years, the results are “promising,” Dr. Jagsi said at the meeting. Overall and breast cancer–specific survival were both 100%, and the recurrence rate was just 1%, with two recurrences before the 5-year point. The women were a mean of 62 years old.

A similar single-arm trial, LUMINA, recently reported comparable results.

Dr. Jagsi called the findings of the studies “reassuring,” but cautioned that it will be a while before younger postmenopausal women can be offered radiation-free treatment like their older peers.

Even though the results suggest “that this might well be a really good idea,” longer follow-up and randomized data are needed “before we change the standard of care,” she said.

Of concern, for instance, is that there were six additional recurrences in the IDEA study past the 5-year mark, for a total of three recurrences among the 60 women 50-59 years old (5%) and five among the 140 women 60-69 years old (3.6%). Five of the recurrent cases were adherent to endocrine therapy.

Also, so few women in IDEA have passed the 5-year mark that “we can’t [conclude] anything” about long-term relapse risks, Dr. Jagsi said. Besides that, skipping radiation for such women at this point is “not reasonable,” Dr. Jagsi added.

Carlos Arteaga, MD, director of the UT Southwestern Simmons Cancer Center, Dallas, agreed.

“I think we have to wait. We have randomized studies that will test this in a formal way. Be that as it may, this provides the basis for a conversation physicians can have with patients because this could be an option” at some point, said Dr. Arteaga, who moderated Dr. Jagsi’s presentation.

“This is a big step in trying not to do too much for patients who don’t need it,” Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio, said in an interview.

IDEA was published in the Journal of Clinical Oncology to coincide with Dr. Jagsi’s presentation.

The study was funded by the Susan G. Komen Breast Cancer Foundation and the University of Michigan Rogel Cancer Center. Dr. Jagsi has stock in Equity Quotient and research support form Genentech. Disclosure information for Arteaga was not available. Dr. Kaklamani has extensive industry ties, including being a speaker for Pfizer, Genentech, Novartis, and AstraZeneca.

SAN ANTONIO — Women 65-70 years old are often offered the option of skipping radiation after lumpectomy for hormone receptor–positive early-stage breast cancer and moving straight to endocrine therapy.

The recurrence rate with and without radiation is well known so women can be counseled accurately about their options. For some, the 10% risk of recurrence at 10 years without radiation seems reasonable, for others it does not.

Omitting radiation for older postmenopausal women is “very reasonable to offer so long as they are willing to accept the risk,” said Reshma Jagsi, MD, chief of radiation oncology at Emory University, Atlanta.

The option, however, isn’t generally offered to postmenopausal women younger than 65 years old because their risk from skipping adjuvant radiation isn’t known, but that’s about to change.

Several teams are investigating the issue, including one led by Dr. Jagsi, who presented her and her colleagues’ latest results at the San Antonio Breast Cancer Symposium.

In the single-arm IDEA [Individualized Decisions for Endocrine therapy Alone] study, 200 women 50-69 years old with pT1N0 unifocal hormone receptor–positive, HER2-negative invasive breast cancer agreed to the approach when it was offered to them following lumpectomy with sentinel lymph node biopsy. The mean tumor size was 10 mm with margins of at least 2 mm.

The women were at low risk for recurrence, with recurrence risk scores no higher than 18 points on the Oncotype DX 21-gene assay; the mean score was 11 points.

Radiation would have been the usual next step after lumpectomy, but instead the patients went directly to endocrine therapy for 5 years, with adherence above 80%.

At 5 years, the results are “promising,” Dr. Jagsi said at the meeting. Overall and breast cancer–specific survival were both 100%, and the recurrence rate was just 1%, with two recurrences before the 5-year point. The women were a mean of 62 years old.

A similar single-arm trial, LUMINA, recently reported comparable results.

Dr. Jagsi called the findings of the studies “reassuring,” but cautioned that it will be a while before younger postmenopausal women can be offered radiation-free treatment like their older peers.

Even though the results suggest “that this might well be a really good idea,” longer follow-up and randomized data are needed “before we change the standard of care,” she said.

Of concern, for instance, is that there were six additional recurrences in the IDEA study past the 5-year mark, for a total of three recurrences among the 60 women 50-59 years old (5%) and five among the 140 women 60-69 years old (3.6%). Five of the recurrent cases were adherent to endocrine therapy.

Also, so few women in IDEA have passed the 5-year mark that “we can’t [conclude] anything” about long-term relapse risks, Dr. Jagsi said. Besides that, skipping radiation for such women at this point is “not reasonable,” Dr. Jagsi added.

Carlos Arteaga, MD, director of the UT Southwestern Simmons Cancer Center, Dallas, agreed.

“I think we have to wait. We have randomized studies that will test this in a formal way. Be that as it may, this provides the basis for a conversation physicians can have with patients because this could be an option” at some point, said Dr. Arteaga, who moderated Dr. Jagsi’s presentation.

“This is a big step in trying not to do too much for patients who don’t need it,” Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio, said in an interview.

IDEA was published in the Journal of Clinical Oncology to coincide with Dr. Jagsi’s presentation.

The study was funded by the Susan G. Komen Breast Cancer Foundation and the University of Michigan Rogel Cancer Center. Dr. Jagsi has stock in Equity Quotient and research support form Genentech. Disclosure information for Arteaga was not available. Dr. Kaklamani has extensive industry ties, including being a speaker for Pfizer, Genentech, Novartis, and AstraZeneca.

SAN ANTONIO — Women 65-70 years old are often offered the option of skipping radiation after lumpectomy for hormone receptor–positive early-stage breast cancer and moving straight to endocrine therapy.

The recurrence rate with and without radiation is well known so women can be counseled accurately about their options. For some, the 10% risk of recurrence at 10 years without radiation seems reasonable, for others it does not.

Omitting radiation for older postmenopausal women is “very reasonable to offer so long as they are willing to accept the risk,” said Reshma Jagsi, MD, chief of radiation oncology at Emory University, Atlanta.

The option, however, isn’t generally offered to postmenopausal women younger than 65 years old because their risk from skipping adjuvant radiation isn’t known, but that’s about to change.

Several teams are investigating the issue, including one led by Dr. Jagsi, who presented her and her colleagues’ latest results at the San Antonio Breast Cancer Symposium.

In the single-arm IDEA [Individualized Decisions for Endocrine therapy Alone] study, 200 women 50-69 years old with pT1N0 unifocal hormone receptor–positive, HER2-negative invasive breast cancer agreed to the approach when it was offered to them following lumpectomy with sentinel lymph node biopsy. The mean tumor size was 10 mm with margins of at least 2 mm.

The women were at low risk for recurrence, with recurrence risk scores no higher than 18 points on the Oncotype DX 21-gene assay; the mean score was 11 points.

Radiation would have been the usual next step after lumpectomy, but instead the patients went directly to endocrine therapy for 5 years, with adherence above 80%.

At 5 years, the results are “promising,” Dr. Jagsi said at the meeting. Overall and breast cancer–specific survival were both 100%, and the recurrence rate was just 1%, with two recurrences before the 5-year point. The women were a mean of 62 years old.

A similar single-arm trial, LUMINA, recently reported comparable results.

Dr. Jagsi called the findings of the studies “reassuring,” but cautioned that it will be a while before younger postmenopausal women can be offered radiation-free treatment like their older peers.

Even though the results suggest “that this might well be a really good idea,” longer follow-up and randomized data are needed “before we change the standard of care,” she said.

Of concern, for instance, is that there were six additional recurrences in the IDEA study past the 5-year mark, for a total of three recurrences among the 60 women 50-59 years old (5%) and five among the 140 women 60-69 years old (3.6%). Five of the recurrent cases were adherent to endocrine therapy.

Also, so few women in IDEA have passed the 5-year mark that “we can’t [conclude] anything” about long-term relapse risks, Dr. Jagsi said. Besides that, skipping radiation for such women at this point is “not reasonable,” Dr. Jagsi added.

Carlos Arteaga, MD, director of the UT Southwestern Simmons Cancer Center, Dallas, agreed.

“I think we have to wait. We have randomized studies that will test this in a formal way. Be that as it may, this provides the basis for a conversation physicians can have with patients because this could be an option” at some point, said Dr. Arteaga, who moderated Dr. Jagsi’s presentation.

“This is a big step in trying not to do too much for patients who don’t need it,” Virginia Kaklamani, MD, leader of the breast cancer program at UT Health San Antonio, said in an interview.

IDEA was published in the Journal of Clinical Oncology to coincide with Dr. Jagsi’s presentation.

The study was funded by the Susan G. Komen Breast Cancer Foundation and the University of Michigan Rogel Cancer Center. Dr. Jagsi has stock in Equity Quotient and research support form Genentech. Disclosure information for Arteaga was not available. Dr. Kaklamani has extensive industry ties, including being a speaker for Pfizer, Genentech, Novartis, and AstraZeneca.

TOPLINE:

Commercial health insurance does not necessarily protect cancer patients from potentially devastating out-of-pocket costs.

METHODOLOGY:

• Out-of-pocket costs contribute to financial toxicity in cancer, but little is known about how they vary across various tumor types and stages over time.
• To find out, investigators reviewed claims data for 7494 US patients diagnosed with stage I-IV breast, cervical, colorectal, lung, ovarian, or prostate cancer from 2016 to 2020.
• They assessed cumulative out-of-pocket (OOP) costs — defined as copayments, deductibles, and coinsurance — in the first 3 years following diagnosis.
• Subjects had private, commercial health insurance through United Healthcare.

TAKEAWAY:

• By the end of 3 years, average cumulative OOP costs ranged from $16,673 for stage I prostate cancer to $35,253 for stage IV lung cancer.
• Across all cancer types, average OOP costs in the first year ranged from $2,754 for stage I anal cancer to $25,876 for stage IV vaginal cancer.
• However, the upper limits of OOP costs exceeded $100,000 across many tumors and stages in the first year, reaching a high of $450,374 for stage I breast cancer and far exceeding $200,000 for stage II-IV colorectal and lung cancer.
• OOP costs were generally highest during the first year of treatment and for cancers diagnosed at later stages.

IN PRACTICE:

“OOP costs may present an extreme economic stressor on patients diagnosed with cancer,” leading to emotional distress, reduced treatment adherence, and poor outcomes. “Even cancer patients with insurance coverage [are] not protected.” Future research is “needed to help clarify the type of patient most burdened by OOP costs” as well as ways to reduce them, including promoting “diagnosis at an earlier stage and increas[ing] access to health plans that minimize patient cost sharing.”

SOURCE:

The work was led by November McGarvey of BluePath Solutions, Los Angeles, and published in the Journal of Medical Economics.

LIMITATIONS:

The study did not include additional OOP costs, such as transportation. It also did not assess the long-term impacts of cancer-related out-of-pocket spending. Details on health plan types and features were limited, and the results are limited to patients with commercial health insurance.

DISCLOSURES:

The work was funded by Grail. The investigators are employees of Grail or BluePath Solutions.

TOPLINE:

Commercial health insurance does not necessarily protect cancer patients from potentially devastating out-of-pocket costs.

METHODOLOGY:

• Out-of-pocket costs contribute to financial toxicity in cancer, but little is known about how they vary across various tumor types and stages over time.
• To find out, investigators reviewed claims data for 7494 US patients diagnosed with stage I-IV breast, cervical, colorectal, lung, ovarian, or prostate cancer from 2016 to 2020.
• They assessed cumulative out-of-pocket (OOP) costs — defined as copayments, deductibles, and coinsurance — in the first 3 years following diagnosis.
• Subjects had private, commercial health insurance through United Healthcare.

TAKEAWAY:

• By the end of 3 years, average cumulative OOP costs ranged from $16,673 for stage I prostate cancer to $35,253 for stage IV lung cancer.
• Across all cancer types, average OOP costs in the first year ranged from $2,754 for stage I anal cancer to $25,876 for stage IV vaginal cancer.
• However, the upper limits of OOP costs exceeded $100,000 across many tumors and stages in the first year, reaching a high of $450,374 for stage I breast cancer and far exceeding $200,000 for stage II-IV colorectal and lung cancer.
• OOP costs were generally highest during the first year of treatment and for cancers diagnosed at later stages.

IN PRACTICE:

“OOP costs may present an extreme economic stressor on patients diagnosed with cancer,” leading to emotional distress, reduced treatment adherence, and poor outcomes. “Even cancer patients with insurance coverage [are] not protected.” Future research is “needed to help clarify the type of patient most burdened by OOP costs” as well as ways to reduce them, including promoting “diagnosis at an earlier stage and increas[ing] access to health plans that minimize patient cost sharing.”

SOURCE:

The work was led by November McGarvey of BluePath Solutions, Los Angeles, and published in the Journal of Medical Economics.

LIMITATIONS:

The study did not include additional OOP costs, such as transportation. It also did not assess the long-term impacts of cancer-related out-of-pocket spending. Details on health plan types and features were limited, and the results are limited to patients with commercial health insurance.

DISCLOSURES:

The work was funded by Grail. The investigators are employees of Grail or BluePath Solutions.

TOPLINE:

Commercial health insurance does not necessarily protect cancer patients from potentially devastating out-of-pocket costs.

METHODOLOGY:

• Out-of-pocket costs contribute to financial toxicity in cancer, but little is known about how they vary across various tumor types and stages over time.
• To find out, investigators reviewed claims data for 7494 US patients diagnosed with stage I-IV breast, cervical, colorectal, lung, ovarian, or prostate cancer from 2016 to 2020.
• They assessed cumulative out-of-pocket (OOP) costs — defined as copayments, deductibles, and coinsurance — in the first 3 years following diagnosis.
• Subjects had private, commercial health insurance through United Healthcare.

TAKEAWAY:

• By the end of 3 years, average cumulative OOP costs ranged from $16,673 for stage I prostate cancer to $35,253 for stage IV lung cancer.
• Across all cancer types, average OOP costs in the first year ranged from $2,754 for stage I anal cancer to $25,876 for stage IV vaginal cancer.
• However, the upper limits of OOP costs exceeded $100,000 across many tumors and stages in the first year, reaching a high of $450,374 for stage I breast cancer and far exceeding $200,000 for stage II-IV colorectal and lung cancer.
• OOP costs were generally highest during the first year of treatment and for cancers diagnosed at later stages.

IN PRACTICE:

“OOP costs may present an extreme economic stressor on patients diagnosed with cancer,” leading to emotional distress, reduced treatment adherence, and poor outcomes. “Even cancer patients with insurance coverage [are] not protected.” Future research is “needed to help clarify the type of patient most burdened by OOP costs” as well as ways to reduce them, including promoting “diagnosis at an earlier stage and increas[ing] access to health plans that minimize patient cost sharing.”

SOURCE:

The work was led by November McGarvey of BluePath Solutions, Los Angeles, and published in the Journal of Medical Economics.

LIMITATIONS:

The study did not include additional OOP costs, such as transportation. It also did not assess the long-term impacts of cancer-related out-of-pocket spending. Details on health plan types and features were limited, and the results are limited to patients with commercial health insurance.

DISCLOSURES:

The work was funded by Grail. The investigators are employees of Grail or BluePath Solutions.

A small trial headed by MD Anderson Cancer Center, Houston, has helped to further identify women who can safely skip surgery after neoadjuvant therapy for early breast cancer.

Among 50 women in the study with cT1-2N0-1M0 triple negative or HER2-positive disease, 31 (62%) had a complete pathologic response (pCR) to neoadjuvant therapy on image-guided vacuum-assisted core biopsy (VACB).

They went onto whole breast radiation with a boost, but given their response to neoadjuvant treatment and the accuracy of VACB, the women did not have surgery.

So far, it seems to have been the right call: At 3 years, there’s been no tumor recurrences and disease-free and overall survival are both 100%.

Eliminating “breast surgery in highly-selected patients with image-guided VACB-determined pCR following” neoadjuvant systemic therapy has “very promising 3-year results,” lead investigator Henry M. Kuerer, MD, PhD, a breast cancer surgeon at MD Anderson, who presented the findings at the European Society for Medical Oncology (ESMO) 2023 annual meeting.

The study speaks to a trend in breast cancer toward deescalation of treatment – particularly surgery – to save women from the side effects of treatments they don’t need.

With the success of modern systemic therapy, “it’s only natural that we think this way,” said Ava Kwong, PhD, chief of breast surgery at the University of Hong Kong, who discussed Dr. Kuerer’s presentation at the meeting.

“This study is really important,” she said. “It’s addressing a very important question whether we can omit surgery in certain groups of patients ... We do want to deescalate surgery,” and the study results are “very good,” she said.

However, larger trials with longer follow-up are needed to draw any firm conclusions, she said.

Dr. Kuerer agreed. He and his team will continue to follow the study subjects, and they have opened up a new trial with 100 patients. A similar study is ongoing in Korea, as well, he noted.
 

Study details

Women in the trial were a median of 60.4 years old; 58% had HER2-positive and the rest triple-negative unicentric breast cancer. Mean baseline tumor size was 2.8 cm. Just 12% of the participants had lymph node involvement. Neoadjuvant systemic therapy was clinician’s choice.

Breast lesions had to shrink to less than 2 cm on imaging after systemic therapy to be eligible for the study, and a minimum of 12 cores had to be obtained on VACB.

The 38% of women in the study with residual disease after systemic treatment went on to surgery.

Two patients were circulating tumor cell (CTC)-positive at baseline, two were positive at 6 months, and one at 12 months. No patients had CTCs detected at more than one timepoint.

The work was funded by the National Cancer Institute. Dr. Kuerer is an adviser for Merck. Dr. Kwong is an adviser/speaker/reviewer/author for Stryker, AstraZeneca, Merck, and Roche. She also disclosed research funding from Merck, Roche, and Gilead and funding for genetic testing from AstraZeneca.

A small trial headed by MD Anderson Cancer Center, Houston, has helped to further identify women who can safely skip surgery after neoadjuvant therapy for early breast cancer.

Among 50 women in the study with cT1-2N0-1M0 triple negative or HER2-positive disease, 31 (62%) had a complete pathologic response (pCR) to neoadjuvant therapy on image-guided vacuum-assisted core biopsy (VACB).

They went onto whole breast radiation with a boost, but given their response to neoadjuvant treatment and the accuracy of VACB, the women did not have surgery.

So far, it seems to have been the right call: At 3 years, there’s been no tumor recurrences and disease-free and overall survival are both 100%.

Eliminating “breast surgery in highly-selected patients with image-guided VACB-determined pCR following” neoadjuvant systemic therapy has “very promising 3-year results,” lead investigator Henry M. Kuerer, MD, PhD, a breast cancer surgeon at MD Anderson, who presented the findings at the European Society for Medical Oncology (ESMO) 2023 annual meeting.

The study speaks to a trend in breast cancer toward deescalation of treatment – particularly surgery – to save women from the side effects of treatments they don’t need.

With the success of modern systemic therapy, “it’s only natural that we think this way,” said Ava Kwong, PhD, chief of breast surgery at the University of Hong Kong, who discussed Dr. Kuerer’s presentation at the meeting.

“This study is really important,” she said. “It’s addressing a very important question whether we can omit surgery in certain groups of patients ... We do want to deescalate surgery,” and the study results are “very good,” she said.

However, larger trials with longer follow-up are needed to draw any firm conclusions, she said.

Dr. Kuerer agreed. He and his team will continue to follow the study subjects, and they have opened up a new trial with 100 patients. A similar study is ongoing in Korea, as well, he noted.
 

Study details

Women in the trial were a median of 60.4 years old; 58% had HER2-positive and the rest triple-negative unicentric breast cancer. Mean baseline tumor size was 2.8 cm. Just 12% of the participants had lymph node involvement. Neoadjuvant systemic therapy was clinician’s choice.

Breast lesions had to shrink to less than 2 cm on imaging after systemic therapy to be eligible for the study, and a minimum of 12 cores had to be obtained on VACB.

The 38% of women in the study with residual disease after systemic treatment went on to surgery.

Two patients were circulating tumor cell (CTC)-positive at baseline, two were positive at 6 months, and one at 12 months. No patients had CTCs detected at more than one timepoint.

The work was funded by the National Cancer Institute. Dr. Kuerer is an adviser for Merck. Dr. Kwong is an adviser/speaker/reviewer/author for Stryker, AstraZeneca, Merck, and Roche. She also disclosed research funding from Merck, Roche, and Gilead and funding for genetic testing from AstraZeneca.

A small trial headed by MD Anderson Cancer Center, Houston, has helped to further identify women who can safely skip surgery after neoadjuvant therapy for early breast cancer.

Among 50 women in the study with cT1-2N0-1M0 triple negative or HER2-positive disease, 31 (62%) had a complete pathologic response (pCR) to neoadjuvant therapy on image-guided vacuum-assisted core biopsy (VACB).

They went onto whole breast radiation with a boost, but given their response to neoadjuvant treatment and the accuracy of VACB, the women did not have surgery.

So far, it seems to have been the right call: At 3 years, there’s been no tumor recurrences and disease-free and overall survival are both 100%.

Eliminating “breast surgery in highly-selected patients with image-guided VACB-determined pCR following” neoadjuvant systemic therapy has “very promising 3-year results,” lead investigator Henry M. Kuerer, MD, PhD, a breast cancer surgeon at MD Anderson, who presented the findings at the European Society for Medical Oncology (ESMO) 2023 annual meeting.

The study speaks to a trend in breast cancer toward deescalation of treatment – particularly surgery – to save women from the side effects of treatments they don’t need.

With the success of modern systemic therapy, “it’s only natural that we think this way,” said Ava Kwong, PhD, chief of breast surgery at the University of Hong Kong, who discussed Dr. Kuerer’s presentation at the meeting.

“This study is really important,” she said. “It’s addressing a very important question whether we can omit surgery in certain groups of patients ... We do want to deescalate surgery,” and the study results are “very good,” she said.

However, larger trials with longer follow-up are needed to draw any firm conclusions, she said.

Dr. Kuerer agreed. He and his team will continue to follow the study subjects, and they have opened up a new trial with 100 patients. A similar study is ongoing in Korea, as well, he noted.
 

Study details

Women in the trial were a median of 60.4 years old; 58% had HER2-positive and the rest triple-negative unicentric breast cancer. Mean baseline tumor size was 2.8 cm. Just 12% of the participants had lymph node involvement. Neoadjuvant systemic therapy was clinician’s choice.

Breast lesions had to shrink to less than 2 cm on imaging after systemic therapy to be eligible for the study, and a minimum of 12 cores had to be obtained on VACB.

The 38% of women in the study with residual disease after systemic treatment went on to surgery.

Two patients were circulating tumor cell (CTC)-positive at baseline, two were positive at 6 months, and one at 12 months. No patients had CTCs detected at more than one timepoint.

The work was funded by the National Cancer Institute. Dr. Kuerer is an adviser for Merck. Dr. Kwong is an adviser/speaker/reviewer/author for Stryker, AstraZeneca, Merck, and Roche. She also disclosed research funding from Merck, Roche, and Gilead and funding for genetic testing from AstraZeneca.

The antibody-drug conjugate tisotumab vedotin bested chemotherapy for the second- or third-line treatment of recurrent/metastatic cervical cancer in the InnovaTV 301 trial, which was presented at the European Society of Medical Oncology (ESMO) Congress 2023.

Median overall survival (OS) was 11.5 months among 253 women randomized to tisotumab vedotin (TV) monotherapy versus 9.5 months among 249 randomized to investigators’ choice of chemotherapy, a 30% reduction in the risk of death (P = .0038).

Median progression-free survival (PFS) was 4.2 months with TV versus 2.9 months with chemotherapy (P < .0001), but survival benefits were not statistically significant in a number of subgroups.

Nonetheless, “tisotumab vedotin should be considered as a potential new standard of care for patients who have progressed after first-line systemic therapy,” said lead investigator Ignace Vergote, MD, PhD, a gynecologic oncologist and researcher at the Catholic University of Leuven, Belgium, who presented the findings.
 

New and emerging options

The trial serves as the confirmation the Food and Drug Administration required when it gave TV accelerated approval in 2021 for recurrent or metastatic cervical cancer (r/m CC) that’s progressed during or after first-line treatment, an approval based on response rates in an earlier phase 2 trial, the InnovaTV 204 study.

TV is the only antibody-drug conjugate approved for the indication, but another agent is also under investigation, the anti-PD-1 cemiplimab. It’s not yet approved for r/m CC, but it is approved in the United States for locally advanced/metastatic basal cell carcinoma, cutaneous squamous cell carcinoma, and non–small cell lung cancer.

Cemiplimab outcomes were similar to TV’s in a phase 3 trial following progression on first-line treatment without anti-PD-1 therapy, with a median OS of 12 months with cemiplimab versus 8.5 months with investigators’ choice of chemotherapy.

Pembrolizumab is also approved as monotherapy for r/m CC for PD-L1 positive women after progression on or during first-line treatment based on response outcomes, not survival.

The question now is how to pick among the various options, said Krishnansu Tewari, MD, a gynecologic oncologist and researcher at the University of California, Irvine, who discussed InnovaTV 301 at the meeting.

In the second line for r/m CC, “we can hypothetically consider” TV monotherapy; pembrolizumab in PD-L1-positive women not previously exposed to a checkpoint inhibitor (CPI); cemiplimab in women not previously exposed to a CPI, and perhaps TV plus pembrolizumab, also in women new to CPIs.

It remains particularly unclear at the moment how to select between TV and cemiplimab monotherapy, if cemiplimab is approved for the indication.

One difference is that unlike in the cemiplimab trial, 28.1% of women treated with TV in the phase 3 trial had been on an anti-PD-(L)1 in the first line. However, although PFS benefits were statistically significant for TV after checkpoint inhibitor exposure, OS benefit was not.

Regarding cost, TV was administered at 2 mg/kg every 3 weeks in Innova; 40 mg costs around $7,000.

Cemiplimab was dosed at 350 mg every 3 weeks in its trial; a single dose costs over $10,000.
 

Subgroups fall short of statistical significance

In InnovaTV 301, 12-month OS was about 48.7% with TV versus 35% with chemotherapy; 6-month PFS was 30.4% with TV versus 18.9%.

The PFS benefit with TV did not reach statistical significance among the 35.2% of women who had not been treated with bevacizumab in the first-line, and there was no OS benefit or trend to benefit (HR 1.0) for them.

In addition to women previously treated with an anti-PD-1, OS benefits with TV were not statistically significant among the 54.2% of women with baseline performance scores of 0; the 36.8% with adeno or adenosquamous carcinoma, and the 62.8% who had been on one prior systemic regimen instead two.

Women in the trial were a median of 50 years old, and fewer than 7% were from the United States. Investigator choice of chemotherapy included topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed.

The rate of grade 3 or higher adverse events was 29.2% with TV and 45.2% with chemotherapy.

The known side effects of TV were all higher than in the chemotherapy arm, including grade 3 or worse peripheral neuropathy (5.2%), ocular events (3.2%), and bleeding (0.8%).

The study was funded in part by Genmab and SeaGen, the companies co-developing TV. Dr. Vergote is an adviser to both companies and many others. Dr. Tewari is an adviser/consultant, researcher, and speaker for SeaGen and Genmab as well as for Merck, AstraZeneca, and other companies.

The antibody-drug conjugate tisotumab vedotin bested chemotherapy for the second- or third-line treatment of recurrent/metastatic cervical cancer in the InnovaTV 301 trial, which was presented at the European Society of Medical Oncology (ESMO) Congress 2023.

Median overall survival (OS) was 11.5 months among 253 women randomized to tisotumab vedotin (TV) monotherapy versus 9.5 months among 249 randomized to investigators’ choice of chemotherapy, a 30% reduction in the risk of death (P = .0038).

Median progression-free survival (PFS) was 4.2 months with TV versus 2.9 months with chemotherapy (P < .0001), but survival benefits were not statistically significant in a number of subgroups.

Nonetheless, “tisotumab vedotin should be considered as a potential new standard of care for patients who have progressed after first-line systemic therapy,” said lead investigator Ignace Vergote, MD, PhD, a gynecologic oncologist and researcher at the Catholic University of Leuven, Belgium, who presented the findings.
 

New and emerging options

The trial serves as the confirmation the Food and Drug Administration required when it gave TV accelerated approval in 2021 for recurrent or metastatic cervical cancer (r/m CC) that’s progressed during or after first-line treatment, an approval based on response rates in an earlier phase 2 trial, the InnovaTV 204 study.

TV is the only antibody-drug conjugate approved for the indication, but another agent is also under investigation, the anti-PD-1 cemiplimab. It’s not yet approved for r/m CC, but it is approved in the United States for locally advanced/metastatic basal cell carcinoma, cutaneous squamous cell carcinoma, and non–small cell lung cancer.

Cemiplimab outcomes were similar to TV’s in a phase 3 trial following progression on first-line treatment without anti-PD-1 therapy, with a median OS of 12 months with cemiplimab versus 8.5 months with investigators’ choice of chemotherapy.

Pembrolizumab is also approved as monotherapy for r/m CC for PD-L1 positive women after progression on or during first-line treatment based on response outcomes, not survival.

The question now is how to pick among the various options, said Krishnansu Tewari, MD, a gynecologic oncologist and researcher at the University of California, Irvine, who discussed InnovaTV 301 at the meeting.

In the second line for r/m CC, “we can hypothetically consider” TV monotherapy; pembrolizumab in PD-L1-positive women not previously exposed to a checkpoint inhibitor (CPI); cemiplimab in women not previously exposed to a CPI, and perhaps TV plus pembrolizumab, also in women new to CPIs.

It remains particularly unclear at the moment how to select between TV and cemiplimab monotherapy, if cemiplimab is approved for the indication.

One difference is that unlike in the cemiplimab trial, 28.1% of women treated with TV in the phase 3 trial had been on an anti-PD-(L)1 in the first line. However, although PFS benefits were statistically significant for TV after checkpoint inhibitor exposure, OS benefit was not.

Regarding cost, TV was administered at 2 mg/kg every 3 weeks in Innova; 40 mg costs around $7,000.

Cemiplimab was dosed at 350 mg every 3 weeks in its trial; a single dose costs over $10,000.
 

Subgroups fall short of statistical significance

In InnovaTV 301, 12-month OS was about 48.7% with TV versus 35% with chemotherapy; 6-month PFS was 30.4% with TV versus 18.9%.

The PFS benefit with TV did not reach statistical significance among the 35.2% of women who had not been treated with bevacizumab in the first-line, and there was no OS benefit or trend to benefit (HR 1.0) for them.

In addition to women previously treated with an anti-PD-1, OS benefits with TV were not statistically significant among the 54.2% of women with baseline performance scores of 0; the 36.8% with adeno or adenosquamous carcinoma, and the 62.8% who had been on one prior systemic regimen instead two.

Women in the trial were a median of 50 years old, and fewer than 7% were from the United States. Investigator choice of chemotherapy included topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed.

The rate of grade 3 or higher adverse events was 29.2% with TV and 45.2% with chemotherapy.

The known side effects of TV were all higher than in the chemotherapy arm, including grade 3 or worse peripheral neuropathy (5.2%), ocular events (3.2%), and bleeding (0.8%).

The study was funded in part by Genmab and SeaGen, the companies co-developing TV. Dr. Vergote is an adviser to both companies and many others. Dr. Tewari is an adviser/consultant, researcher, and speaker for SeaGen and Genmab as well as for Merck, AstraZeneca, and other companies.

The antibody-drug conjugate tisotumab vedotin bested chemotherapy for the second- or third-line treatment of recurrent/metastatic cervical cancer in the InnovaTV 301 trial, which was presented at the European Society of Medical Oncology (ESMO) Congress 2023.

Median overall survival (OS) was 11.5 months among 253 women randomized to tisotumab vedotin (TV) monotherapy versus 9.5 months among 249 randomized to investigators’ choice of chemotherapy, a 30% reduction in the risk of death (P = .0038).

Median progression-free survival (PFS) was 4.2 months with TV versus 2.9 months with chemotherapy (P < .0001), but survival benefits were not statistically significant in a number of subgroups.

Nonetheless, “tisotumab vedotin should be considered as a potential new standard of care for patients who have progressed after first-line systemic therapy,” said lead investigator Ignace Vergote, MD, PhD, a gynecologic oncologist and researcher at the Catholic University of Leuven, Belgium, who presented the findings.
 

New and emerging options

The trial serves as the confirmation the Food and Drug Administration required when it gave TV accelerated approval in 2021 for recurrent or metastatic cervical cancer (r/m CC) that’s progressed during or after first-line treatment, an approval based on response rates in an earlier phase 2 trial, the InnovaTV 204 study.

TV is the only antibody-drug conjugate approved for the indication, but another agent is also under investigation, the anti-PD-1 cemiplimab. It’s not yet approved for r/m CC, but it is approved in the United States for locally advanced/metastatic basal cell carcinoma, cutaneous squamous cell carcinoma, and non–small cell lung cancer.

Cemiplimab outcomes were similar to TV’s in a phase 3 trial following progression on first-line treatment without anti-PD-1 therapy, with a median OS of 12 months with cemiplimab versus 8.5 months with investigators’ choice of chemotherapy.

Pembrolizumab is also approved as monotherapy for r/m CC for PD-L1 positive women after progression on or during first-line treatment based on response outcomes, not survival.

The question now is how to pick among the various options, said Krishnansu Tewari, MD, a gynecologic oncologist and researcher at the University of California, Irvine, who discussed InnovaTV 301 at the meeting.

In the second line for r/m CC, “we can hypothetically consider” TV monotherapy; pembrolizumab in PD-L1-positive women not previously exposed to a checkpoint inhibitor (CPI); cemiplimab in women not previously exposed to a CPI, and perhaps TV plus pembrolizumab, also in women new to CPIs.

It remains particularly unclear at the moment how to select between TV and cemiplimab monotherapy, if cemiplimab is approved for the indication.

One difference is that unlike in the cemiplimab trial, 28.1% of women treated with TV in the phase 3 trial had been on an anti-PD-(L)1 in the first line. However, although PFS benefits were statistically significant for TV after checkpoint inhibitor exposure, OS benefit was not.

Regarding cost, TV was administered at 2 mg/kg every 3 weeks in Innova; 40 mg costs around $7,000.

Cemiplimab was dosed at 350 mg every 3 weeks in its trial; a single dose costs over $10,000.
 

Subgroups fall short of statistical significance

In InnovaTV 301, 12-month OS was about 48.7% with TV versus 35% with chemotherapy; 6-month PFS was 30.4% with TV versus 18.9%.

The PFS benefit with TV did not reach statistical significance among the 35.2% of women who had not been treated with bevacizumab in the first-line, and there was no OS benefit or trend to benefit (HR 1.0) for them.

In addition to women previously treated with an anti-PD-1, OS benefits with TV were not statistically significant among the 54.2% of women with baseline performance scores of 0; the 36.8% with adeno or adenosquamous carcinoma, and the 62.8% who had been on one prior systemic regimen instead two.

Women in the trial were a median of 50 years old, and fewer than 7% were from the United States. Investigator choice of chemotherapy included topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed.

The rate of grade 3 or higher adverse events was 29.2% with TV and 45.2% with chemotherapy.

The known side effects of TV were all higher than in the chemotherapy arm, including grade 3 or worse peripheral neuropathy (5.2%), ocular events (3.2%), and bleeding (0.8%).

The study was funded in part by Genmab and SeaGen, the companies co-developing TV. Dr. Vergote is an adviser to both companies and many others. Dr. Tewari is an adviser/consultant, researcher, and speaker for SeaGen and Genmab as well as for Merck, AstraZeneca, and other companies.

Six weeks of induction chemotherapy before definitive chemoradiation for locally advanced cervical cancer substantially improves progression-free and overall survival and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.

Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.

She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.

The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.

Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m² followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m² plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.

Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.

“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.

Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.

KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.

Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.

He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.

Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.

It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.

The median age in the study was 46 years, and 82% of the women had squamous cell tumors.

Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.

One woman died of adverse events in the induction arm and two died in the CRT-alone arm.

Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.

The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.

Six weeks of induction chemotherapy before definitive chemoradiation for locally advanced cervical cancer substantially improves progression-free and overall survival and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.

Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.

She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.

The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.

Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m² followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m² plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.

Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.

“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.

Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.

KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.

Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.

He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.

Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.

It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.

The median age in the study was 46 years, and 82% of the women had squamous cell tumors.

Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.

One woman died of adverse events in the induction arm and two died in the CRT-alone arm.

Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.

The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.

Six weeks of induction chemotherapy before definitive chemoradiation for locally advanced cervical cancer substantially improves progression-free and overall survival and should be considered the new standard of care, according to Mary McCormack, MBBS, PhD, a gynecologic and breast oncologist at the University College Hospital, London.

Dr. McCormack was the lead investigator on a phase 3 trial called INTERLACE that tested the approach against stand-alone chemoradiation – the current standard of care – in 500 women, majority in the United Kingdom and Mexico.

She made her comments after presenting the results at the annual meeting of the European Society for Medical Oncology.

The 250 women randomized to induction chemotherapy before chemoradiation (CRT) had a 35% improvement in progression-free survival (PFS), with a 5-year PFS of 73% versus 64% among 250 randomized to CRT alone. Likewise, overall survival (OS) improved 39% in the induction group, with a 5-year OS of 80% versus 72% among women who went straight to CRT.

Induction chemotherapy consisted of 6 weekly doses of carboplatin AUC2 and paclitaxel 80 mg/m² followed by CRT within 7 days. CRT consisted of 5 weekly doses of cisplatin 40 mg/m² plus external beam radiotherapy and brachytherapy. Compliance in both arms was high.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiotherapy should be considered the new standard in locally advanced cervical cancer, and [it] is feasible across diverse healthcare settings,” Dr. McCormack said.

Study discussant Krishnansu Tewari, MD, a gynecologic oncologist at the University of California, Irvine, was impressed by the results.

“This is the first phase 3 randomized trial in locally advanced cervical cancer that has shown [an overall] survival benefit in over 2 decades. Physicians taking care of these patients could consider induction chemotherapy ... tomorrow morning,” he said.

Dr. Tewari brought up how to incorporate the findings with another trial presented earlier at the meeting, KEYNOTE-A18.

KEYNOTE-A18 added pembrolizumab to CRT, which resulted in substantially better PFS and a strong trend towards better OS that could reach statistical significance with additional follow-up.

Both trials are “practice changing” for locally advanced cervical cancer. “I think we are ready for a paradigm shift,” Dr. Tewari said.

He noted a limit in the INTERLACE presentation was that outcomes were not broken down by tumor stage.

Over three-quarters of the women had stage 2 disease; 9% had stage 1 disease, and only 14% had stage 3B or 4A tumors. Almost 60% of the women were node negative.

It’s unclear at this point if women who have node-negative stage 1B3 or stage 2A-B disease “really need induction chemotherapy. I would think that those patients are probably curable by standard chemoradiation plus brachytherapy, and that the real [benefit would be] for stage 3B and 4A patients,” he said.

The median age in the study was 46 years, and 82% of the women had squamous cell tumors.

Grade 3/4 adverse events were higher in the induction arm, 59% versus 48%, driven mostly by a higher incidence of neutropenia and other hematologic adverse events with induction.

One woman died of adverse events in the induction arm and two died in the CRT-alone arm.

Local and pelvic relapse rates were equal in both groups at 16%, but total distant relapses were lower with induction chemotherapy, 12% versus 20%, over a median follow-up of 64 months.

The work was funded by Cancer Research UK. Dr. McCormack is a consultant for AstraZeneca, Eisai, and GSK, and disclosed honoraria/meeting expenses from Daiicho Sankyo, Roche, and Medscape, the publisher of this article. Among other industry ties, Dr. Tewari is an advisor/consultant, researcher, and speaker for Merck, SeaGen, and AstraZeneca.

Enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) is being called the new standard of care for the upfront treatment of locally advanced/metastatic urothelial carcinoma following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.

The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).

The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.

“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.

“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.

The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.

Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).

It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.

After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.

However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
 

Major disruptions in the treatment paradigm

The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.

Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?

Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.

Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?

Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
 

EV-302/KEYNOTE-059 details

Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.

They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.

Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.

Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.

Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.

Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).

The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.

Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.

Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.

The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
 

CheckMate 901 details

In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.

PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).

Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.

Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).

The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.

EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.

Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.

Enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) is being called the new standard of care for the upfront treatment of locally advanced/metastatic urothelial carcinoma following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.

The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).

The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.

“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.

“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.

The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.

Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).

It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.

After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.

However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
 

Major disruptions in the treatment paradigm

The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.

Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?

Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.

Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?

Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
 

EV-302/KEYNOTE-059 details

Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.

They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.

Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.

Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.

Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.

Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).

The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.

Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.

Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.

The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
 

CheckMate 901 details

In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.

PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).

Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.

Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).

The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.

EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.

Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.

Enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) is being called the new standard of care for the upfront treatment of locally advanced/metastatic urothelial carcinoma following a phase 3 trial presented at the 2023 European Society for Medical Oncology annual meeting.

The combination soundly beat the current standard of care – platinum-based chemotherapy – with a median overall survival of 31.5 months among 442 subjects versus 16.1 months among 444 randomized to gemcitabine with cisplatin or carboplatin, an unprecedented 53% drop in the risk of mortality (P < .00001).

The elimination of chemotherapy also meant that there were substantially fewer grade 3 or higher adverse events with the new combination.

“This is the first time we’ve managed to beat chemotherapy in the first-line setting for overall survival despite multiple previous attempts.” The 30% remission rate with enfortumab vedotin plus pembrolizumab “is not something we’ve seen before,” said lead investigator Thomas Powles, MBBS, MD, a urologic oncologist and researcher at the University of London, who presented the findings.

“We welcome a new standard of care in the management of advanced, metastatic urothelial carcinoma, enfortumab vedotin plus pembrolizumab,” said Andrea Apolo, MD, a urologic oncology researcher at the National Cancer Institute in Bethesda, Md., and discussant on the trial, dubbed EV-302/KEYNOTE-A39.

The news overshadowed a second trial presented immediately after Dr. Powles’ that also showed improvement in overall survival versus standard platinum-based chemotherapy, CheckMate 901.

Instead of replacing chemotherapy, CheckMate 901 added nivolumab. With 304 patients randomized to each arm, nivolumab add-on led to a median overall survival of 21.7 months versus 18.9 months with stand-alone gemcitabine/cisplatin, a 22% drop in the risk of mortality (P = .0171).

It’s the first time that adding immunotherapy to first-line chemotherapy improved survival in metastatic urothelial carcinoma, said lead investigator Michiel van der Heijden, MD, PhD, a urologic oncologist and researcher at the Netherlands Cancer Institute, Amsterdam.

After decades of stagnation, Dr. Apolo said, it’s “monumental for our field” to have two trials that beat chemotherapy in the first-line setting.

However, she said that the much better survival with enfortumab vedotin/pembrolizumab means that the combination now “takes first place as the best first-line regimen in urothelial carcinoma.”
 

Major disruptions in the treatment paradigm

The crowning of a new first-line standard for locally advanced/metastatic urothelial carcinoma means that everything else in the treatment paradigm has to shift, Dr. Apolo said, and there are many new questions that need to be answered.

Among the most pressing, should the previous first-line standard – platinum-based chemotherapy – now move to the second line and be considered the treatment of choice after progression? Also, is there still a role for the previous second-line standards, pembrolizumab and other immunotherapies, if pembrolizumab fails in the first line?

Dr. Apolo said investigators also need to figure out if there is a role for enfortumab vedotin/pembrolizumab in earlier-stage disease, such as muscle-invasive bladder cancer, and if the dose and duration of enfortumab vedotin can be reduced to limit its peculiar ocular and other toxicities.

Finally, “we must discuss cost,” she said. Enfortumab vedotin plus pembrolizumab (EV+P) is expensive. “Will payers be able to afford” it?

Dr. Powles, the lead investigator on EV-302/KEYNOTE-A39, said he doesn’t know how negotiations are going with payers, but that he hopes they move quickly. “We’ve seen transformative results” with the combination for even aggressive cancers in very sick people. “I think it’s going to be a challenge with patients not to talk about these data.”
 

EV-302/KEYNOTE-059 details

Merck, the maker of pembrolizumab, and the makers/marketers of enfortumab vedotin, Astellas and Seagen, said they will use EV-302/KEYNOTE-059 to seek a first-line indication for locally advanced/metastatic urothelial carcinoma from the U.S. Food and Drug Administration and other regulators.

They also said the results serve as the confirmation FDA required when it gave accelerated approval to the combination in April 2023 for cisplatin-ineligible patients based on tumor response rates and response durability, according to press releases from the companies.

Pembrolizumab (P) in the trial was dosed at 200 mg on the first day of 3-week treatment cycles to a maximum of 35 cycles; enfortumab vedotin (EV) was given on the first and eighth day of the cycle with no limit in the number of cycles until progression or unacceptable toxicity.

Cisplatin or carboplatin (C) in the control arm was delivered on the first day and gemcitabine (G) on the first and eighth days for up to six 3-week cycles.

Patients in both arms were split about equally between performance statuses of 0 or 1; less than 4% in each group had statuses of 2.

Echoing the overall survival (OS) results, progression-free survival (PFS) was a median of 12.5 months with EV-P versus 6.3 months with GC, a 55% drop in the risk of progression or death (P < .00001).

The results held regardless of PD-L1 expression, cisplatin eligibility, and the presence or absence of visceral metastases.

Follow-up treatments in the trial begin to address Dr. Apolo’s questions: Almost 60% of GC patients went on to a PD-1/L1 for subsequent maintenance or progression, and almost a quarter of EV+P patients went on to subsequent platinum-based chemotherapy.

Grade 3 or higher adverse events occurred in 55.9% of subjects in the EV+P group versus 69.5% in the GC arm.

The most common in the chemotherapy arm were anemia, neutropenia, thrombocytopenia, fatigue, and nausea. The most common with EV+P were skin reactions, hyperglycemia, neutropenia, peripheral neuropathy, diarrhea, and anemia,
 

CheckMate 901 details

In CheckMate 901, gemcitabine and cisplatin were administered on the first day of 3-week treatment cycles for up to 6 cycles; subjects randomized to nivolumab add-on received 360 mg on day 1 of each cycle, followed by 480 mg every 4 weeks until disease progression or unacceptable toxicity for up to 2 years.

PFS results again mirrored OS, with a median PFS of 7.9 months in the nivolumab arm versus 7.6 months with stand-alone chemotherapy, a 28% drop in the risk of progression or death (P = .0012).

Although OS and PFS benefits were statistically significant overall, they were not significant in subgroup analyses of patients 65 years and older, women, or in patients with liver metastases.

Trends in OS and PFS actually favored chemotherapy in the 40 U.S. subjects (HR OS, 1.92; 95% confidence interval, 0.95-3.88).

The rate of grade 3 or higher adverse events was 61.8% with nivolumab add-on versus 51.7% with chemotherapy alone. Anemia and neutropenia were the most common in both arms, and higher in the nivolumab group.

EV-302/KEYNOTE-A39 was funded by Seagen, Astellas, and Merck. CheckMate 901 was funded by Bristol-Myers Squibb, the maker of nivolumab.

Dr. Powles reported extensive financial ties to pharmaceutical companies, including being an advisor to and receiving research funding from Bristol-Myers Squibb, Merck, SeaGen, and Astellas, as well as travel expenses from Merck. Among other disclosures, Dr. Heijden is an advisor to Seagen and an advisor and researcher for Bristol-Myers Squibb. Dr. Apolo is an unpaid consultant to Merck, Astellas, Seagen, Bristol-Myers Squibb, and other companies.

Pembrolizumab (Keytruda) improved progression-free survival when added to standard concurrent chemoradiotherapy in the first-line for newly diagnosed, locally advanced cervical cancer in the KEYNOTE-A18 trial, according to a study presented at the annual meeting of the European Society for Medical Oncology.

Overall survival (OS) trends also favored pembrolizumab add-on, but OS data in the interim analysis was not mature and did not reach statistical significance.

The study “supports pembrolizumab plus chemoradiotherapy as a new potential standard of care” in the first-line setting for high-risk, locally advanced cervical cancer, said lead investigator Domenica Lorusso, MD, PhD, a gynecologic oncologist at the Catholic University of Rome, who reported the findings at the meeting.

The results of the trial “are compelling, especially considering newly diagnosed patients with high-risk locally advanced cervical cancer have not seen an advance in treatment options in 20 years,” she said in a press release from pembrolizumab maker Merck.

Trial data are under review at the Food and Drug Administration as part of Merck’s application for a first-line indication for pembrolizumab added to concurrent chemoradiotherapy in newly diagnosed patients with high-risk, locally advanced cervical cancer; the agency’s decision is expected in Jan. 2024.

Pembrolizumab already carries indications for persistent, recurrent, or metastatic cervical cancer.

Women in the trial were new to treatment and had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease; almost 85% had squamous cell cancer. About half the women were White; 28% were Asian, and about 2% were Black. About 5% of subjects were PD-L1 negative.

Overall, 529 women were randomized to 200 mg pembrolizumab every 3 weeks for five cycles with concurrent chemoradiotherapy (CCRT); they then received pembrolizumab 400 mg every 6 weeks for 15 cycles; 531 were randomized to placebo with CCRT, followed by 15 6-week placebo cycles.

CCRT included five cycles of cisplatin 40 mg/m² every week for 5-6 weeks plus external beam radiotherapy followed by brachytherapy.

Two-year progression-free survival was 57.3% with placebo but 67.8% with pembrolizumab add-on, a 30% reduction in the risk of progression (P = .002).

On subgroup analysis, pembrolizumab’s PFS benefit was not statistically significant for White women (hazard ratio, 0.83; 95% confidence interval, 0.59-1.15) and women with stage 1B2 to 2B disease (HR, 0.91; 95% CI, 0.63-1.31), among others.

Although OS is not yet mature, 80.8% of placebo subjects but 87.2% of pembrolizumab women were alive at 2 years, a 27% drop in the risk of death (95% CI, 0.49-1.07).

At the meeting, Bradley Monk, MD, a gynecologic oncologist at the University of Arizona, Phoenix, who was also the study discussant, noted that “the magnitude of the benefit here is difficult to interpret because 55% of the patients [were] still on treatment” in the interim analysis, but the difference “is substantial enough for us to have confidence.”

Rates of grade 3/4 treatment-related adverse events were 60.6% in the placebo group and 67% with pembrolizumab, with anemia, nausea, and diarrhea the most common.

Grade 3/4 immune-mediated adverse events occurred in 1.1% of placebo and 4.2% of pembrolizumab subjects; hypothyroidism was the most common with pembrolizumab.

Protocol amendments in the trial included a change from PFS assessment by blinded, independent, central review to investigator assessment.

In the press release, Dr. Monk, said the results “demonstrate that, by moving an immunotherapy regimen to earlier stages of cervical cancer, we have the potential to improve outcomes for these patients compared to the current standard of care.”

The study was funded by Merck, maker of pembrolizumab. Investigators reported wide-ranging ties to the company, including Dr. Lorusso, who reported honoraria from Merck as well as ties to other companies. Dr. Monk also had deep industry ties, including being a speaker and consultant for Merck and reporting honoraria from the company.

Pembrolizumab (Keytruda) improved progression-free survival when added to standard concurrent chemoradiotherapy in the first-line for newly diagnosed, locally advanced cervical cancer in the KEYNOTE-A18 trial, according to a study presented at the annual meeting of the European Society for Medical Oncology.

Overall survival (OS) trends also favored pembrolizumab add-on, but OS data in the interim analysis was not mature and did not reach statistical significance.

The study “supports pembrolizumab plus chemoradiotherapy as a new potential standard of care” in the first-line setting for high-risk, locally advanced cervical cancer, said lead investigator Domenica Lorusso, MD, PhD, a gynecologic oncologist at the Catholic University of Rome, who reported the findings at the meeting.

The results of the trial “are compelling, especially considering newly diagnosed patients with high-risk locally advanced cervical cancer have not seen an advance in treatment options in 20 years,” she said in a press release from pembrolizumab maker Merck.

Trial data are under review at the Food and Drug Administration as part of Merck’s application for a first-line indication for pembrolizumab added to concurrent chemoradiotherapy in newly diagnosed patients with high-risk, locally advanced cervical cancer; the agency’s decision is expected in Jan. 2024.

Pembrolizumab already carries indications for persistent, recurrent, or metastatic cervical cancer.

Women in the trial were new to treatment and had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease; almost 85% had squamous cell cancer. About half the women were White; 28% were Asian, and about 2% were Black. About 5% of subjects were PD-L1 negative.

Overall, 529 women were randomized to 200 mg pembrolizumab every 3 weeks for five cycles with concurrent chemoradiotherapy (CCRT); they then received pembrolizumab 400 mg every 6 weeks for 15 cycles; 531 were randomized to placebo with CCRT, followed by 15 6-week placebo cycles.

CCRT included five cycles of cisplatin 40 mg/m² every week for 5-6 weeks plus external beam radiotherapy followed by brachytherapy.

Two-year progression-free survival was 57.3% with placebo but 67.8% with pembrolizumab add-on, a 30% reduction in the risk of progression (P = .002).

On subgroup analysis, pembrolizumab’s PFS benefit was not statistically significant for White women (hazard ratio, 0.83; 95% confidence interval, 0.59-1.15) and women with stage 1B2 to 2B disease (HR, 0.91; 95% CI, 0.63-1.31), among others.

Although OS is not yet mature, 80.8% of placebo subjects but 87.2% of pembrolizumab women were alive at 2 years, a 27% drop in the risk of death (95% CI, 0.49-1.07).

At the meeting, Bradley Monk, MD, a gynecologic oncologist at the University of Arizona, Phoenix, who was also the study discussant, noted that “the magnitude of the benefit here is difficult to interpret because 55% of the patients [were] still on treatment” in the interim analysis, but the difference “is substantial enough for us to have confidence.”

Rates of grade 3/4 treatment-related adverse events were 60.6% in the placebo group and 67% with pembrolizumab, with anemia, nausea, and diarrhea the most common.

Grade 3/4 immune-mediated adverse events occurred in 1.1% of placebo and 4.2% of pembrolizumab subjects; hypothyroidism was the most common with pembrolizumab.

Protocol amendments in the trial included a change from PFS assessment by blinded, independent, central review to investigator assessment.

In the press release, Dr. Monk, said the results “demonstrate that, by moving an immunotherapy regimen to earlier stages of cervical cancer, we have the potential to improve outcomes for these patients compared to the current standard of care.”

The study was funded by Merck, maker of pembrolizumab. Investigators reported wide-ranging ties to the company, including Dr. Lorusso, who reported honoraria from Merck as well as ties to other companies. Dr. Monk also had deep industry ties, including being a speaker and consultant for Merck and reporting honoraria from the company.

Pembrolizumab (Keytruda) improved progression-free survival when added to standard concurrent chemoradiotherapy in the first-line for newly diagnosed, locally advanced cervical cancer in the KEYNOTE-A18 trial, according to a study presented at the annual meeting of the European Society for Medical Oncology.

Overall survival (OS) trends also favored pembrolizumab add-on, but OS data in the interim analysis was not mature and did not reach statistical significance.

The study “supports pembrolizumab plus chemoradiotherapy as a new potential standard of care” in the first-line setting for high-risk, locally advanced cervical cancer, said lead investigator Domenica Lorusso, MD, PhD, a gynecologic oncologist at the Catholic University of Rome, who reported the findings at the meeting.

The results of the trial “are compelling, especially considering newly diagnosed patients with high-risk locally advanced cervical cancer have not seen an advance in treatment options in 20 years,” she said in a press release from pembrolizumab maker Merck.

Trial data are under review at the Food and Drug Administration as part of Merck’s application for a first-line indication for pembrolizumab added to concurrent chemoradiotherapy in newly diagnosed patients with high-risk, locally advanced cervical cancer; the agency’s decision is expected in Jan. 2024.

Pembrolizumab already carries indications for persistent, recurrent, or metastatic cervical cancer.

Women in the trial were new to treatment and had either stage 1B2-2B disease with lymph node involvement or stage 3-4A disease; almost 85% had squamous cell cancer. About half the women were White; 28% were Asian, and about 2% were Black. About 5% of subjects were PD-L1 negative.

Overall, 529 women were randomized to 200 mg pembrolizumab every 3 weeks for five cycles with concurrent chemoradiotherapy (CCRT); they then received pembrolizumab 400 mg every 6 weeks for 15 cycles; 531 were randomized to placebo with CCRT, followed by 15 6-week placebo cycles.

CCRT included five cycles of cisplatin 40 mg/m² every week for 5-6 weeks plus external beam radiotherapy followed by brachytherapy.

Two-year progression-free survival was 57.3% with placebo but 67.8% with pembrolizumab add-on, a 30% reduction in the risk of progression (P = .002).

On subgroup analysis, pembrolizumab’s PFS benefit was not statistically significant for White women (hazard ratio, 0.83; 95% confidence interval, 0.59-1.15) and women with stage 1B2 to 2B disease (HR, 0.91; 95% CI, 0.63-1.31), among others.

Although OS is not yet mature, 80.8% of placebo subjects but 87.2% of pembrolizumab women were alive at 2 years, a 27% drop in the risk of death (95% CI, 0.49-1.07).

At the meeting, Bradley Monk, MD, a gynecologic oncologist at the University of Arizona, Phoenix, who was also the study discussant, noted that “the magnitude of the benefit here is difficult to interpret because 55% of the patients [were] still on treatment” in the interim analysis, but the difference “is substantial enough for us to have confidence.”

Rates of grade 3/4 treatment-related adverse events were 60.6% in the placebo group and 67% with pembrolizumab, with anemia, nausea, and diarrhea the most common.

Grade 3/4 immune-mediated adverse events occurred in 1.1% of placebo and 4.2% of pembrolizumab subjects; hypothyroidism was the most common with pembrolizumab.

Protocol amendments in the trial included a change from PFS assessment by blinded, independent, central review to investigator assessment.

In the press release, Dr. Monk, said the results “demonstrate that, by moving an immunotherapy regimen to earlier stages of cervical cancer, we have the potential to improve outcomes for these patients compared to the current standard of care.”

The study was funded by Merck, maker of pembrolizumab. Investigators reported wide-ranging ties to the company, including Dr. Lorusso, who reported honoraria from Merck as well as ties to other companies. Dr. Monk also had deep industry ties, including being a speaker and consultant for Merck and reporting honoraria from the company.

Sentinel lymph node biopsy (SLNB) is the standard of care for axillary node staging in early breast cancer, but previous studies have shown that removal of axillary lymph nodes has no therapeutic effect.

The finding raises a question: Is SLNB even necessary when preoperative axillary imaging is negative?

A new randomized trial addresses the question and brings much “welcome clarity” to the issue, Seema Khan, MD, a surgical oncologist and breast cancer researcher at Northwestern University, Chicago, said in an editorial to the trial, both of which were published in JAMA Oncology.

In short, European investigators found that it’s safe to skip SLNBs in women with breast cancers no larger than 2 cm if preoperative ultrasounds of the axilla show no evidence of nodal disease.

At a median of follow-up of 5.7 years, distant disease-free survival and other outcomes were essentially equivalent between 708 women randomized to SLNB followed by full axillary dissection if nodes are positive and 697 other women randomized to observation without SLNB.

Adjuvant therapies were not significantly different between the two groups largely because adjuvant decisions were driven by tumor characteristics, not axillary studies.

The results support “the argument that sentinel node positivity is not, in and of itself, a critical parameter that determines therapeutic plans and outcomes in patients with stage I breast cancer. This is a major accomplishment of the SOUND [Sentinel Node vs. Observation After Axillary Ultra-Sound] trial, which will be strengthened when longer-term data become available” at 10-year follow up, Dr. Khan said.

Investigators led by Oreste Davide Gentilini, MD, a breast cancer surgeon at San Raffaele Scientific and Research Hospital, Milan, estimated that, of the 2.3 million breast cancers diagnosed globally each year, the study suggests “that approximately 500,000 patients might be able to take advantage of the total omission of axillary surgery,” sparing women lymphedema and other serious side effects and saving health care systems substantial dollars.
 

A case-by-case decision

The study included women of all ages, with a median age of 60 years.

Subjects had a single tumor 0.8-1.5 cm across with negative preoperative axillary ultrasonography. Almost 90% had estrogen receptor ERBB2 (formerly HER2) positive tumors. Almost all of the subjects had radiotherapy, and about 20% of women in each arm also had chemotherapy.

The trial was conducted in 18 sites, most in Italy with other sites in Switzerland, Spain, and Chile.

Overall, 13.7% of women in the SLNB group turned out to have positive axillary nodes, with 0.6% having four or more positive nodes.

However, it didn’t seem to make a difference in the overall study results.

Five-year distant disease-free survival was 97.7% in the SLNB group and 98% in the observation arm (P for noninferiority = .02).

Secondary outcomes were also essentially identical, including local/regional relapse (1.7% with SLNB versus 1.6% without); distant metastases (1.8% vs. 2%), and death from breast cancer (1% vs. 0.6%). The cumulative incidence of axillary lymph node recurrences in the observation arm was just 0.4%.

“These findings suggest that patients with BC of a diameter equal to or smaller than 2 cm and a negative result on preoperative axillary lymph node ultrasonography can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan,” Dr. Gentilini and associates concluded.

The team cautioned that decision to forgo SLNB must be made on a case-by-case basis in a multidisciplinary setting because there are still situations where nodal pathology is relevant, for instance when deciding to add chemotherapy to endocrine treatments in premenopausal women with endocrine-responsive disease.

Only about 20% of the subjects were under 50 years old and the team didn’t break down their results by age, which makes it difficult to apply their results to the situation.

The work was funded by the European Institute of Oncology. Dr. Khan didn’t have any disclosures. Dr. Gentilini reported personal fees from AstraZeneca, Bayer, BD, Eli Lilly, and MSD. Two other investigators also reported personal fees from those and/or other companies.

Sentinel lymph node biopsy (SLNB) is the standard of care for axillary node staging in early breast cancer, but previous studies have shown that removal of axillary lymph nodes has no therapeutic effect.

The finding raises a question: Is SLNB even necessary when preoperative axillary imaging is negative?

A new randomized trial addresses the question and brings much “welcome clarity” to the issue, Seema Khan, MD, a surgical oncologist and breast cancer researcher at Northwestern University, Chicago, said in an editorial to the trial, both of which were published in JAMA Oncology.

In short, European investigators found that it’s safe to skip SLNBs in women with breast cancers no larger than 2 cm if preoperative ultrasounds of the axilla show no evidence of nodal disease.

At a median of follow-up of 5.7 years, distant disease-free survival and other outcomes were essentially equivalent between 708 women randomized to SLNB followed by full axillary dissection if nodes are positive and 697 other women randomized to observation without SLNB.

Adjuvant therapies were not significantly different between the two groups largely because adjuvant decisions were driven by tumor characteristics, not axillary studies.

The results support “the argument that sentinel node positivity is not, in and of itself, a critical parameter that determines therapeutic plans and outcomes in patients with stage I breast cancer. This is a major accomplishment of the SOUND [Sentinel Node vs. Observation After Axillary Ultra-Sound] trial, which will be strengthened when longer-term data become available” at 10-year follow up, Dr. Khan said.

Investigators led by Oreste Davide Gentilini, MD, a breast cancer surgeon at San Raffaele Scientific and Research Hospital, Milan, estimated that, of the 2.3 million breast cancers diagnosed globally each year, the study suggests “that approximately 500,000 patients might be able to take advantage of the total omission of axillary surgery,” sparing women lymphedema and other serious side effects and saving health care systems substantial dollars.
 

A case-by-case decision

The study included women of all ages, with a median age of 60 years.

Subjects had a single tumor 0.8-1.5 cm across with negative preoperative axillary ultrasonography. Almost 90% had estrogen receptor ERBB2 (formerly HER2) positive tumors. Almost all of the subjects had radiotherapy, and about 20% of women in each arm also had chemotherapy.

The trial was conducted in 18 sites, most in Italy with other sites in Switzerland, Spain, and Chile.

Overall, 13.7% of women in the SLNB group turned out to have positive axillary nodes, with 0.6% having four or more positive nodes.

However, it didn’t seem to make a difference in the overall study results.

Five-year distant disease-free survival was 97.7% in the SLNB group and 98% in the observation arm (P for noninferiority = .02).

Secondary outcomes were also essentially identical, including local/regional relapse (1.7% with SLNB versus 1.6% without); distant metastases (1.8% vs. 2%), and death from breast cancer (1% vs. 0.6%). The cumulative incidence of axillary lymph node recurrences in the observation arm was just 0.4%.

“These findings suggest that patients with BC of a diameter equal to or smaller than 2 cm and a negative result on preoperative axillary lymph node ultrasonography can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan,” Dr. Gentilini and associates concluded.

The team cautioned that decision to forgo SLNB must be made on a case-by-case basis in a multidisciplinary setting because there are still situations where nodal pathology is relevant, for instance when deciding to add chemotherapy to endocrine treatments in premenopausal women with endocrine-responsive disease.

Only about 20% of the subjects were under 50 years old and the team didn’t break down their results by age, which makes it difficult to apply their results to the situation.

The work was funded by the European Institute of Oncology. Dr. Khan didn’t have any disclosures. Dr. Gentilini reported personal fees from AstraZeneca, Bayer, BD, Eli Lilly, and MSD. Two other investigators also reported personal fees from those and/or other companies.

Sentinel lymph node biopsy (SLNB) is the standard of care for axillary node staging in early breast cancer, but previous studies have shown that removal of axillary lymph nodes has no therapeutic effect.

The finding raises a question: Is SLNB even necessary when preoperative axillary imaging is negative?

A new randomized trial addresses the question and brings much “welcome clarity” to the issue, Seema Khan, MD, a surgical oncologist and breast cancer researcher at Northwestern University, Chicago, said in an editorial to the trial, both of which were published in JAMA Oncology.

In short, European investigators found that it’s safe to skip SLNBs in women with breast cancers no larger than 2 cm if preoperative ultrasounds of the axilla show no evidence of nodal disease.

At a median of follow-up of 5.7 years, distant disease-free survival and other outcomes were essentially equivalent between 708 women randomized to SLNB followed by full axillary dissection if nodes are positive and 697 other women randomized to observation without SLNB.

Adjuvant therapies were not significantly different between the two groups largely because adjuvant decisions were driven by tumor characteristics, not axillary studies.

The results support “the argument that sentinel node positivity is not, in and of itself, a critical parameter that determines therapeutic plans and outcomes in patients with stage I breast cancer. This is a major accomplishment of the SOUND [Sentinel Node vs. Observation After Axillary Ultra-Sound] trial, which will be strengthened when longer-term data become available” at 10-year follow up, Dr. Khan said.

Investigators led by Oreste Davide Gentilini, MD, a breast cancer surgeon at San Raffaele Scientific and Research Hospital, Milan, estimated that, of the 2.3 million breast cancers diagnosed globally each year, the study suggests “that approximately 500,000 patients might be able to take advantage of the total omission of axillary surgery,” sparing women lymphedema and other serious side effects and saving health care systems substantial dollars.
 

A case-by-case decision

The study included women of all ages, with a median age of 60 years.

Subjects had a single tumor 0.8-1.5 cm across with negative preoperative axillary ultrasonography. Almost 90% had estrogen receptor ERBB2 (formerly HER2) positive tumors. Almost all of the subjects had radiotherapy, and about 20% of women in each arm also had chemotherapy.

The trial was conducted in 18 sites, most in Italy with other sites in Switzerland, Spain, and Chile.

Overall, 13.7% of women in the SLNB group turned out to have positive axillary nodes, with 0.6% having four or more positive nodes.

However, it didn’t seem to make a difference in the overall study results.

Five-year distant disease-free survival was 97.7% in the SLNB group and 98% in the observation arm (P for noninferiority = .02).

Secondary outcomes were also essentially identical, including local/regional relapse (1.7% with SLNB versus 1.6% without); distant metastases (1.8% vs. 2%), and death from breast cancer (1% vs. 0.6%). The cumulative incidence of axillary lymph node recurrences in the observation arm was just 0.4%.

“These findings suggest that patients with BC of a diameter equal to or smaller than 2 cm and a negative result on preoperative axillary lymph node ultrasonography can be safely spared any axillary surgery whenever the lack of pathological information does not affect the postoperative treatment plan,” Dr. Gentilini and associates concluded.

The team cautioned that decision to forgo SLNB must be made on a case-by-case basis in a multidisciplinary setting because there are still situations where nodal pathology is relevant, for instance when deciding to add chemotherapy to endocrine treatments in premenopausal women with endocrine-responsive disease.

Only about 20% of the subjects were under 50 years old and the team didn’t break down their results by age, which makes it difficult to apply their results to the situation.

The work was funded by the European Institute of Oncology. Dr. Khan didn’t have any disclosures. Dr. Gentilini reported personal fees from AstraZeneca, Bayer, BD, Eli Lilly, and MSD. Two other investigators also reported personal fees from those and/or other companies.

A debate in Houston at the annual meeting of the Society of Hematologic Oncology tackled a vexing issue in hematology: Should smoldering myeloma be treated?

Hematologist Sagar Lonial, MD, a multiple myeloma specialist and researcher at Emory University, Atlanta, argued for treatment. Hematologist Angela Dispenzieri, MD, also a myeloma researcher and specialist at the Mayo Clinic in Rochester, Minn., took the opposing side, arguing for watchful waiting.

The two experts based their arguments largely on the same two studies, the only randomized trials to tackle the issue to date. While Dr. Dispenzieri focused on their shortcomings, Dr. Lonial focused on their strengths.

In a poll after the debate, about a third of audience members agreed that watchful waiting is the way to go, but about two-thirds favored a personalized approach to smoldering myeloma treatment based on patient risk.

“I’m taking this as a win,” Dr. Lonial said.

Different interpretations of two trials

The first of the two trials recruited from 2007 to 2010 and was conducted in Spain and Portugal. Fifty-seven high-risk patients were randomized to lenalidomide plus dexamethasone (Len-Dex) for up to 2 years; 62 others were randomized to observation.

At 3 years, 70% of observed patients had progressed to multiple myeloma versus only 20% in the Len-Dex group; 82% of Len-Dex patients were alive at data cut-off in 2015 versus 64% of observation patients.

The second, more recent trial, which was led by Dr. Lonial, randomized 92 intermediate or high-risk smoldering myeloma patients to lenalidomide alone for a median of 2 years and 90 others to observation. Three-year progression-free survival (PFS) was 91% in the treatment arm versus 66% with observation. Overall survival data have not yet been reported.

Dr. Dispenzieri acknowledged that the results from Spain and Portugal are impressive. “Treating with Len-Dex gives you a far superior freedom from progression. ... Overall survival was better too.” Results for Len-Dex were “fantastic,” she said.

However, the trial was done before myeloma-defining event criteria existed, so it’s very likely that the treatment arm in the Spanish study included actual myeloma cases, she said.

About 46% of treated patients in Dr. Lonial’s study met the current definition for high risk for progression based on the 2-20-20 rule, which Dr. Dispenzieri helped develop. Although there was an improvement in PFS in the high-risk group, there was no significant improvement for intermediate- and low-risk subjects. Also, more than 80% of observed patients hadn’t progressed by 2 years, and overall survival data are missing.

Meanwhile, treated patients in both trials had more adverse events, including secondary malignancies, and there’s the possibility that early treatment may make patients resistant to treatment later on when they progress to multiple myeloma, although that didn’t seem to happen in the Spanish trial.

“Of course, we want to prevent morbidity, of course we would love to cure the disease,” but “should we treat high-risk smoldering myeloma patients based on overall survival data from a trial of” just 119 “patients that may have been contaminated with actual myeloma” cases? Is it ethical to treat low- and intermediate-risk patients who have only a 50% chance of developing myeloma after 10 years?”

Her answer to both questions was “no and no. ... There’s just a lot of work to be done” to better understand the condition and when and how to intervene. In the meantime, “don’t treat smoldering melanoma patients” outside of a trial, she said.

“First, do no harm,” Dr. Dispenzieri cautioned in her final slide.

Dr. Lonial said he agreed with many of Dr. Dispenzieri’s points, but disagreed with her conclusion not to treat.

“Everybody can always be critical of randomized trials, but at the end of the day, we now have two randomized phase 3 trials comparing early intervention with no intervention demonstrating a significant delay in developing myeloma. I think it’s time to end the ‘we need more data; we need more trials.’ It’s time for us to take a stand.”

He argued for 2 years of lenalidomide for patients who meet the 2-20-20 high-risk definition, based on the median time people were treated in his trial.

He said he discusses the option “with every smoldering patient [who] walks in to see me” if they aren’t eligible for a trial.

Dr. Lonial mentioned his team is currently pulling together longer-term survival data for their trial.

A debate in Houston at the annual meeting of the Society of Hematologic Oncology tackled a vexing issue in hematology: Should smoldering myeloma be treated?

Hematologist Sagar Lonial, MD, a multiple myeloma specialist and researcher at Emory University, Atlanta, argued for treatment. Hematologist Angela Dispenzieri, MD, also a myeloma researcher and specialist at the Mayo Clinic in Rochester, Minn., took the opposing side, arguing for watchful waiting.

The two experts based their arguments largely on the same two studies, the only randomized trials to tackle the issue to date. While Dr. Dispenzieri focused on their shortcomings, Dr. Lonial focused on their strengths.

In a poll after the debate, about a third of audience members agreed that watchful waiting is the way to go, but about two-thirds favored a personalized approach to smoldering myeloma treatment based on patient risk.

“I’m taking this as a win,” Dr. Lonial said.

Different interpretations of two trials

The first of the two trials recruited from 2007 to 2010 and was conducted in Spain and Portugal. Fifty-seven high-risk patients were randomized to lenalidomide plus dexamethasone (Len-Dex) for up to 2 years; 62 others were randomized to observation.

At 3 years, 70% of observed patients had progressed to multiple myeloma versus only 20% in the Len-Dex group; 82% of Len-Dex patients were alive at data cut-off in 2015 versus 64% of observation patients.

The second, more recent trial, which was led by Dr. Lonial, randomized 92 intermediate or high-risk smoldering myeloma patients to lenalidomide alone for a median of 2 years and 90 others to observation. Three-year progression-free survival (PFS) was 91% in the treatment arm versus 66% with observation. Overall survival data have not yet been reported.

Dr. Dispenzieri acknowledged that the results from Spain and Portugal are impressive. “Treating with Len-Dex gives you a far superior freedom from progression. ... Overall survival was better too.” Results for Len-Dex were “fantastic,” she said.

However, the trial was done before myeloma-defining event criteria existed, so it’s very likely that the treatment arm in the Spanish study included actual myeloma cases, she said.

About 46% of treated patients in Dr. Lonial’s study met the current definition for high risk for progression based on the 2-20-20 rule, which Dr. Dispenzieri helped develop. Although there was an improvement in PFS in the high-risk group, there was no significant improvement for intermediate- and low-risk subjects. Also, more than 80% of observed patients hadn’t progressed by 2 years, and overall survival data are missing.

Meanwhile, treated patients in both trials had more adverse events, including secondary malignancies, and there’s the possibility that early treatment may make patients resistant to treatment later on when they progress to multiple myeloma, although that didn’t seem to happen in the Spanish trial.

“Of course, we want to prevent morbidity, of course we would love to cure the disease,” but “should we treat high-risk smoldering myeloma patients based on overall survival data from a trial of” just 119 “patients that may have been contaminated with actual myeloma” cases? Is it ethical to treat low- and intermediate-risk patients who have only a 50% chance of developing myeloma after 10 years?”

Her answer to both questions was “no and no. ... There’s just a lot of work to be done” to better understand the condition and when and how to intervene. In the meantime, “don’t treat smoldering melanoma patients” outside of a trial, she said.

“First, do no harm,” Dr. Dispenzieri cautioned in her final slide.

Dr. Lonial said he agreed with many of Dr. Dispenzieri’s points, but disagreed with her conclusion not to treat.

“Everybody can always be critical of randomized trials, but at the end of the day, we now have two randomized phase 3 trials comparing early intervention with no intervention demonstrating a significant delay in developing myeloma. I think it’s time to end the ‘we need more data; we need more trials.’ It’s time for us to take a stand.”

He argued for 2 years of lenalidomide for patients who meet the 2-20-20 high-risk definition, based on the median time people were treated in his trial.

He said he discusses the option “with every smoldering patient [who] walks in to see me” if they aren’t eligible for a trial.

Dr. Lonial mentioned his team is currently pulling together longer-term survival data for their trial.

A debate in Houston at the annual meeting of the Society of Hematologic Oncology tackled a vexing issue in hematology: Should smoldering myeloma be treated?

Hematologist Sagar Lonial, MD, a multiple myeloma specialist and researcher at Emory University, Atlanta, argued for treatment. Hematologist Angela Dispenzieri, MD, also a myeloma researcher and specialist at the Mayo Clinic in Rochester, Minn., took the opposing side, arguing for watchful waiting.

The two experts based their arguments largely on the same two studies, the only randomized trials to tackle the issue to date. While Dr. Dispenzieri focused on their shortcomings, Dr. Lonial focused on their strengths.

In a poll after the debate, about a third of audience members agreed that watchful waiting is the way to go, but about two-thirds favored a personalized approach to smoldering myeloma treatment based on patient risk.

“I’m taking this as a win,” Dr. Lonial said.

Different interpretations of two trials

The first of the two trials recruited from 2007 to 2010 and was conducted in Spain and Portugal. Fifty-seven high-risk patients were randomized to lenalidomide plus dexamethasone (Len-Dex) for up to 2 years; 62 others were randomized to observation.

At 3 years, 70% of observed patients had progressed to multiple myeloma versus only 20% in the Len-Dex group; 82% of Len-Dex patients were alive at data cut-off in 2015 versus 64% of observation patients.

The second, more recent trial, which was led by Dr. Lonial, randomized 92 intermediate or high-risk smoldering myeloma patients to lenalidomide alone for a median of 2 years and 90 others to observation. Three-year progression-free survival (PFS) was 91% in the treatment arm versus 66% with observation. Overall survival data have not yet been reported.

Dr. Dispenzieri acknowledged that the results from Spain and Portugal are impressive. “Treating with Len-Dex gives you a far superior freedom from progression. ... Overall survival was better too.” Results for Len-Dex were “fantastic,” she said.

However, the trial was done before myeloma-defining event criteria existed, so it’s very likely that the treatment arm in the Spanish study included actual myeloma cases, she said.

About 46% of treated patients in Dr. Lonial’s study met the current definition for high risk for progression based on the 2-20-20 rule, which Dr. Dispenzieri helped develop. Although there was an improvement in PFS in the high-risk group, there was no significant improvement for intermediate- and low-risk subjects. Also, more than 80% of observed patients hadn’t progressed by 2 years, and overall survival data are missing.

Meanwhile, treated patients in both trials had more adverse events, including secondary malignancies, and there’s the possibility that early treatment may make patients resistant to treatment later on when they progress to multiple myeloma, although that didn’t seem to happen in the Spanish trial.

“Of course, we want to prevent morbidity, of course we would love to cure the disease,” but “should we treat high-risk smoldering myeloma patients based on overall survival data from a trial of” just 119 “patients that may have been contaminated with actual myeloma” cases? Is it ethical to treat low- and intermediate-risk patients who have only a 50% chance of developing myeloma after 10 years?”

Her answer to both questions was “no and no. ... There’s just a lot of work to be done” to better understand the condition and when and how to intervene. In the meantime, “don’t treat smoldering melanoma patients” outside of a trial, she said.

“First, do no harm,” Dr. Dispenzieri cautioned in her final slide.

Dr. Lonial said he agreed with many of Dr. Dispenzieri’s points, but disagreed with her conclusion not to treat.

“Everybody can always be critical of randomized trials, but at the end of the day, we now have two randomized phase 3 trials comparing early intervention with no intervention demonstrating a significant delay in developing myeloma. I think it’s time to end the ‘we need more data; we need more trials.’ It’s time for us to take a stand.”

He argued for 2 years of lenalidomide for patients who meet the 2-20-20 high-risk definition, based on the median time people were treated in his trial.

He said he discusses the option “with every smoldering patient [who] walks in to see me” if they aren’t eligible for a trial.

Dr. Lonial mentioned his team is currently pulling together longer-term survival data for their trial.

Despite a growing list of Janus kinase (JAK) inhibitors, ruxolitinib remains the go-to for patients with symptomatic, higher risk myelofibrosis, according to Anthony M. Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta.

“We are thankfully starting to be blessed with more options than we’ve ever had,” he said, but “in the front-line proliferative setting, ruxolitinib has remained the standard of care.” It’s “well established in higher-risk patients and very much an option for very symptomatic lower-risk patients.”

Dr. Hunter helped his colleagues navigate the evolving field of JAK inhibition for myelofibrosis in a presentation titled “Choosing and Properly Using a JAK Inhibitor in Myelofibrosis,”at the Society of Hematologic Oncology annual meeting.

Ruxolitinib was the first JAK inhibitor for myelofibrosis on the U.S. market, approved in 2011. Two more have followed, fedratinib in 2019 and pacritinib in 2022.

A fourth JAK inhibitor for myelofibrosis, momelotinib, is under Food and Drug Administration review with a decision expected shortly.

JAK inhibitors disrupt a key pathogenic pathway in myelofibrosis and are a mainstay of treatment, but Dr. Hunter noted that they should not replace allogeneic transplants in patients who are candidates because transplants remain “the best way to achieve long term survival, especially in higher risk patients.”

He noted that not every patient needs a JAK inhibitor, especially “lower-risk, more asymptomatic patients who are predominantly manifesting with cytopenias. [They] are less likely to benefit.”

Dr. Hunter said that although ruxolitinib remains a treatment of choice, fedratinib “is certainly an option” with comparable rates of symptom control and splenomegaly reduction. Also, while ruxolitinib is dosed according to platelet levels, fedratinib allows for full dosing down to a platelet count of 50 x 10⁹/L.

“But there’s more GI toxicity than with ruxolitinib, especially in the first couple of months,” he said, as well as a black box warning of Wernicke’s encephalopathy. “I generally put all my [fedratinib] patients on thiamine repletion as a precaution.”

One of the most challenging aspects of using JAK inhibitors for myelofibrosis is their tendency to cause cytopenia, particularly anemia and thrombocytopenia, which, ironically, are also hallmarks of myelofibrosis itself.

Although there’s an alternative low-dose ruxolitinib regimen that can be effective in anemic settings, the approval of pacritinib and most likely momelotinib is particularly helpful for cytopenic patients, “a population which historically has been very hard to treat with our prior agents,” Dr. Hunter said.

Pacritinib is approved specifically for patients with platelet counts below 50 x 10⁹/L; momelotinib also included lower platelet counts in several studies. Both agents indirectly boost erythropoiesis with subsequent amelioration of anemia.

“Momelotinib is an important emerging agent for these more anemic patients,” with a spleen response comparable to ruxolitinib and significantly higher rates of transfusion independence, but with lower rates of symptom control, Dr. Hunter said.

Pacritinib “really helps extend the benefit of JAK inhibitors to a group of thrombocytopenic patients who have been hard to treat with ruxolitinib,” with the added potential of improving anemia, although, like fedratinib, it has more GI toxicity, he said.

There are multiple add-on options for JAK inhibitor patients with anemia, including luspatercept, an erythropoiesis-stimulating agent approved for anemia in patients with myelodysplastic syndromes; promising results were reported recently for myelofibrosis.

Fedratinib, pacritinib, and momelotinib all have activity in the second line after ruxolitinib failure, Dr. Hunter noted, but he cautioned that ruxolitinib must be tapered over a few weeks, not stopped abruptly, to avoid withdrawal symptoms. Some clinicians overlap JAK inhibitors a day or two to avoid issues.

“Clinical trials should still be considered in many of these settings,” he said, adding that emerging agents are under development, including multiple combination therapies, often with JAK inhibitors as the background.

No disclosure information was reported.

Despite a growing list of Janus kinase (JAK) inhibitors, ruxolitinib remains the go-to for patients with symptomatic, higher risk myelofibrosis, according to Anthony M. Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta.

“We are thankfully starting to be blessed with more options than we’ve ever had,” he said, but “in the front-line proliferative setting, ruxolitinib has remained the standard of care.” It’s “well established in higher-risk patients and very much an option for very symptomatic lower-risk patients.”

Dr. Hunter helped his colleagues navigate the evolving field of JAK inhibition for myelofibrosis in a presentation titled “Choosing and Properly Using a JAK Inhibitor in Myelofibrosis,”at the Society of Hematologic Oncology annual meeting.

Ruxolitinib was the first JAK inhibitor for myelofibrosis on the U.S. market, approved in 2011. Two more have followed, fedratinib in 2019 and pacritinib in 2022.

A fourth JAK inhibitor for myelofibrosis, momelotinib, is under Food and Drug Administration review with a decision expected shortly.

JAK inhibitors disrupt a key pathogenic pathway in myelofibrosis and are a mainstay of treatment, but Dr. Hunter noted that they should not replace allogeneic transplants in patients who are candidates because transplants remain “the best way to achieve long term survival, especially in higher risk patients.”

He noted that not every patient needs a JAK inhibitor, especially “lower-risk, more asymptomatic patients who are predominantly manifesting with cytopenias. [They] are less likely to benefit.”

Dr. Hunter said that although ruxolitinib remains a treatment of choice, fedratinib “is certainly an option” with comparable rates of symptom control and splenomegaly reduction. Also, while ruxolitinib is dosed according to platelet levels, fedratinib allows for full dosing down to a platelet count of 50 x 10⁹/L.

“But there’s more GI toxicity than with ruxolitinib, especially in the first couple of months,” he said, as well as a black box warning of Wernicke’s encephalopathy. “I generally put all my [fedratinib] patients on thiamine repletion as a precaution.”

One of the most challenging aspects of using JAK inhibitors for myelofibrosis is their tendency to cause cytopenia, particularly anemia and thrombocytopenia, which, ironically, are also hallmarks of myelofibrosis itself.

Although there’s an alternative low-dose ruxolitinib regimen that can be effective in anemic settings, the approval of pacritinib and most likely momelotinib is particularly helpful for cytopenic patients, “a population which historically has been very hard to treat with our prior agents,” Dr. Hunter said.

Pacritinib is approved specifically for patients with platelet counts below 50 x 10⁹/L; momelotinib also included lower platelet counts in several studies. Both agents indirectly boost erythropoiesis with subsequent amelioration of anemia.

“Momelotinib is an important emerging agent for these more anemic patients,” with a spleen response comparable to ruxolitinib and significantly higher rates of transfusion independence, but with lower rates of symptom control, Dr. Hunter said.

Pacritinib “really helps extend the benefit of JAK inhibitors to a group of thrombocytopenic patients who have been hard to treat with ruxolitinib,” with the added potential of improving anemia, although, like fedratinib, it has more GI toxicity, he said.

There are multiple add-on options for JAK inhibitor patients with anemia, including luspatercept, an erythropoiesis-stimulating agent approved for anemia in patients with myelodysplastic syndromes; promising results were reported recently for myelofibrosis.

Fedratinib, pacritinib, and momelotinib all have activity in the second line after ruxolitinib failure, Dr. Hunter noted, but he cautioned that ruxolitinib must be tapered over a few weeks, not stopped abruptly, to avoid withdrawal symptoms. Some clinicians overlap JAK inhibitors a day or two to avoid issues.

“Clinical trials should still be considered in many of these settings,” he said, adding that emerging agents are under development, including multiple combination therapies, often with JAK inhibitors as the background.

No disclosure information was reported.

Despite a growing list of Janus kinase (JAK) inhibitors, ruxolitinib remains the go-to for patients with symptomatic, higher risk myelofibrosis, according to Anthony M. Hunter, MD, a myeloid malignancies specialist at Emory University, Atlanta.

“We are thankfully starting to be blessed with more options than we’ve ever had,” he said, but “in the front-line proliferative setting, ruxolitinib has remained the standard of care.” It’s “well established in higher-risk patients and very much an option for very symptomatic lower-risk patients.”

Dr. Hunter helped his colleagues navigate the evolving field of JAK inhibition for myelofibrosis in a presentation titled “Choosing and Properly Using a JAK Inhibitor in Myelofibrosis,”at the Society of Hematologic Oncology annual meeting.

Ruxolitinib was the first JAK inhibitor for myelofibrosis on the U.S. market, approved in 2011. Two more have followed, fedratinib in 2019 and pacritinib in 2022.

A fourth JAK inhibitor for myelofibrosis, momelotinib, is under Food and Drug Administration review with a decision expected shortly.

JAK inhibitors disrupt a key pathogenic pathway in myelofibrosis and are a mainstay of treatment, but Dr. Hunter noted that they should not replace allogeneic transplants in patients who are candidates because transplants remain “the best way to achieve long term survival, especially in higher risk patients.”

He noted that not every patient needs a JAK inhibitor, especially “lower-risk, more asymptomatic patients who are predominantly manifesting with cytopenias. [They] are less likely to benefit.”

Dr. Hunter said that although ruxolitinib remains a treatment of choice, fedratinib “is certainly an option” with comparable rates of symptom control and splenomegaly reduction. Also, while ruxolitinib is dosed according to platelet levels, fedratinib allows for full dosing down to a platelet count of 50 x 10⁹/L.

“But there’s more GI toxicity than with ruxolitinib, especially in the first couple of months,” he said, as well as a black box warning of Wernicke’s encephalopathy. “I generally put all my [fedratinib] patients on thiamine repletion as a precaution.”

One of the most challenging aspects of using JAK inhibitors for myelofibrosis is their tendency to cause cytopenia, particularly anemia and thrombocytopenia, which, ironically, are also hallmarks of myelofibrosis itself.

Although there’s an alternative low-dose ruxolitinib regimen that can be effective in anemic settings, the approval of pacritinib and most likely momelotinib is particularly helpful for cytopenic patients, “a population which historically has been very hard to treat with our prior agents,” Dr. Hunter said.

Pacritinib is approved specifically for patients with platelet counts below 50 x 10⁹/L; momelotinib also included lower platelet counts in several studies. Both agents indirectly boost erythropoiesis with subsequent amelioration of anemia.

“Momelotinib is an important emerging agent for these more anemic patients,” with a spleen response comparable to ruxolitinib and significantly higher rates of transfusion independence, but with lower rates of symptom control, Dr. Hunter said.

Pacritinib “really helps extend the benefit of JAK inhibitors to a group of thrombocytopenic patients who have been hard to treat with ruxolitinib,” with the added potential of improving anemia, although, like fedratinib, it has more GI toxicity, he said.

There are multiple add-on options for JAK inhibitor patients with anemia, including luspatercept, an erythropoiesis-stimulating agent approved for anemia in patients with myelodysplastic syndromes; promising results were reported recently for myelofibrosis.

Fedratinib, pacritinib, and momelotinib all have activity in the second line after ruxolitinib failure, Dr. Hunter noted, but he cautioned that ruxolitinib must be tapered over a few weeks, not stopped abruptly, to avoid withdrawal symptoms. Some clinicians overlap JAK inhibitors a day or two to avoid issues.

“Clinical trials should still be considered in many of these settings,” he said, adding that emerging agents are under development, including multiple combination therapies, often with JAK inhibitors as the background.

No disclosure information was reported.