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M. Alexander Otto began his reporting career early in 1999 covering the pharmaceutical industry for a national pharmacists' magazine and freelancing for the Washington Post and other newspapers. He then joined BNA, now part of Bloomberg News, covering health law and the protection of people and animals in medical research. Alex next worked for the McClatchy Company. Based on his work, Alex won a year-long Knight Science Journalism Fellowship to MIT in 2008-2009. He joined the company shortly thereafter. Alex has a newspaper journalism degree from Syracuse (N.Y.) University and a master's degree in medical science -- a physician assistant degree -- from George Washington University. Alex is based in Seattle.
Novel hedgehog inhibitor strategies improve BCC outcomes
MD, a Mohs surgeon and chair of the department of dermatology at the Cleveland Clinic.
She and her colleagues have noticed an accelerated and durable response to hedgehog inhibitors after debulking and are studying cell signaling before and after debulking to better understand the issue.
Dr. Vidimos shared a remarkable case to illustrate the point during a clinical pearls talk at the annual meeting of the American College of Mohs Surgery.
An 82-year-old woman presented with a crusted, hemorrhagic, nodular basal cell carcinoma (BCC) that had overgrown over nearly her entire nose and left lower eyelid. A recurrence of a previous BCC, the tumor had been growing for a decade and had invaded her nasal bones but not the periorbital tissue.
An outside surgeon suggested a full rhinectomy and removal of the lower eyelid, but the woman refused.
Dr. Vidimos decided to treat her with vismodegib, but prior to doing so, she debulked the tumor to help with the pain and bleeding. She did not curette the portion of tumor extending through the ala into the nasal vestibule. “I let the vismodegib take care of that,” she said.
After 9 months, the tumor was virtually gone, with no recurrence after 3 years. Surgical debulking prior to hedgehog inhibition “reduces the tumor burden and may increase the efficacy and shorten the course of therapy,” Dr. Vidimos said.
The hedgehog inhibitors vismodegib (Erivedge) and sonidegib Odomzo are both approved for treating locally advanced BCC, with a complete response of 31% of locally advanced disease with vismodegib, according to one report.
But monotherapy is limited by intolerable side effects, most commonly muscle spasms, alopecia, and dysgeusia. To minimize the impact, Dr. Vidimos generally puts patients on treatment with Monday through Friday dosing and gives them the weekends off, a schedule she and her colleagues have reported works as well as daily dosing.
Still, many patients discontinue the drugs because of the side effects. Hedgehog inhibitors are also expensive and responses aren’t always durable. To increase efficacy and shorten the course of therapy, “we need alternative treatment strategies,” Dr. Vidimos said.
Up-front tumor debulking is one such strategy. Altered cell signaling pathways associated with tissue remodeling might improve response, and debulking may reduce the genetic heterogeneity of tumor cells, rendering remaining cells less resistant to hedgehog inhibition, she explained.
“It is exciting to see how tumor debulking may reduce tumor burden and heterogeneity, and thus lead to a durable response in extensive tumors,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who heard the presentation. “More investigation is needed to reproduce these results, but this approach may lead to improved outcomes with targeted therapies,” he said in an interview.
Combination therapy with other agents is another option, and there also seems to be a synergistic effect with radiation, with hedgehog inhibitors increasing cellular response to radiation therapy, Dr. Vidimos said.
Hedgehog inhibitors can also be used to shrink tumors before surgery. One small series found a 27% decrease in the area of the tumor after 3 to 6 months of preoperative vismodegib.
Dr. Vidimos shared another case to illustrate the point.
A 64-year-old woman fainted and presented to the ED with a hemoglobin of 3.2 mg/dL because of chronic blood loss from an ulcerated BCC on her upper back. The lesion measured 25 cm by 9 cm, and was 3.5 cm deep with no bone involvement. The woman was addicted to opioids by the time she presented.
She was started on vismodegib; the ulcer shrunk considerably after 6 months, and the woman underwent a resection. Only one small focus of BCC was found across 78 specimens submitted to Dr. Vidimos for Mohs reading.
Resection was followed by a muscle flap repair and radiation. At 5 and a half years, there is no evidence of disease; the only sign that the lesion had been there was a scar running along the woman’s upper spine.
The approach “was very successful for a very aggressive and worrisome tumor,” Dr. Vidimos said.
Dr. Vidimos did not have any relevant disclosures. Dr. Patel had no relevant disclosures.
MD, a Mohs surgeon and chair of the department of dermatology at the Cleveland Clinic.
She and her colleagues have noticed an accelerated and durable response to hedgehog inhibitors after debulking and are studying cell signaling before and after debulking to better understand the issue.
Dr. Vidimos shared a remarkable case to illustrate the point during a clinical pearls talk at the annual meeting of the American College of Mohs Surgery.
An 82-year-old woman presented with a crusted, hemorrhagic, nodular basal cell carcinoma (BCC) that had overgrown over nearly her entire nose and left lower eyelid. A recurrence of a previous BCC, the tumor had been growing for a decade and had invaded her nasal bones but not the periorbital tissue.
An outside surgeon suggested a full rhinectomy and removal of the lower eyelid, but the woman refused.
Dr. Vidimos decided to treat her with vismodegib, but prior to doing so, she debulked the tumor to help with the pain and bleeding. She did not curette the portion of tumor extending through the ala into the nasal vestibule. “I let the vismodegib take care of that,” she said.
After 9 months, the tumor was virtually gone, with no recurrence after 3 years. Surgical debulking prior to hedgehog inhibition “reduces the tumor burden and may increase the efficacy and shorten the course of therapy,” Dr. Vidimos said.
The hedgehog inhibitors vismodegib (Erivedge) and sonidegib Odomzo are both approved for treating locally advanced BCC, with a complete response of 31% of locally advanced disease with vismodegib, according to one report.
But monotherapy is limited by intolerable side effects, most commonly muscle spasms, alopecia, and dysgeusia. To minimize the impact, Dr. Vidimos generally puts patients on treatment with Monday through Friday dosing and gives them the weekends off, a schedule she and her colleagues have reported works as well as daily dosing.
Still, many patients discontinue the drugs because of the side effects. Hedgehog inhibitors are also expensive and responses aren’t always durable. To increase efficacy and shorten the course of therapy, “we need alternative treatment strategies,” Dr. Vidimos said.
Up-front tumor debulking is one such strategy. Altered cell signaling pathways associated with tissue remodeling might improve response, and debulking may reduce the genetic heterogeneity of tumor cells, rendering remaining cells less resistant to hedgehog inhibition, she explained.
“It is exciting to see how tumor debulking may reduce tumor burden and heterogeneity, and thus lead to a durable response in extensive tumors,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who heard the presentation. “More investigation is needed to reproduce these results, but this approach may lead to improved outcomes with targeted therapies,” he said in an interview.
Combination therapy with other agents is another option, and there also seems to be a synergistic effect with radiation, with hedgehog inhibitors increasing cellular response to radiation therapy, Dr. Vidimos said.
Hedgehog inhibitors can also be used to shrink tumors before surgery. One small series found a 27% decrease in the area of the tumor after 3 to 6 months of preoperative vismodegib.
Dr. Vidimos shared another case to illustrate the point.
A 64-year-old woman fainted and presented to the ED with a hemoglobin of 3.2 mg/dL because of chronic blood loss from an ulcerated BCC on her upper back. The lesion measured 25 cm by 9 cm, and was 3.5 cm deep with no bone involvement. The woman was addicted to opioids by the time she presented.
She was started on vismodegib; the ulcer shrunk considerably after 6 months, and the woman underwent a resection. Only one small focus of BCC was found across 78 specimens submitted to Dr. Vidimos for Mohs reading.
Resection was followed by a muscle flap repair and radiation. At 5 and a half years, there is no evidence of disease; the only sign that the lesion had been there was a scar running along the woman’s upper spine.
The approach “was very successful for a very aggressive and worrisome tumor,” Dr. Vidimos said.
Dr. Vidimos did not have any relevant disclosures. Dr. Patel had no relevant disclosures.
MD, a Mohs surgeon and chair of the department of dermatology at the Cleveland Clinic.
She and her colleagues have noticed an accelerated and durable response to hedgehog inhibitors after debulking and are studying cell signaling before and after debulking to better understand the issue.
Dr. Vidimos shared a remarkable case to illustrate the point during a clinical pearls talk at the annual meeting of the American College of Mohs Surgery.
An 82-year-old woman presented with a crusted, hemorrhagic, nodular basal cell carcinoma (BCC) that had overgrown over nearly her entire nose and left lower eyelid. A recurrence of a previous BCC, the tumor had been growing for a decade and had invaded her nasal bones but not the periorbital tissue.
An outside surgeon suggested a full rhinectomy and removal of the lower eyelid, but the woman refused.
Dr. Vidimos decided to treat her with vismodegib, but prior to doing so, she debulked the tumor to help with the pain and bleeding. She did not curette the portion of tumor extending through the ala into the nasal vestibule. “I let the vismodegib take care of that,” she said.
After 9 months, the tumor was virtually gone, with no recurrence after 3 years. Surgical debulking prior to hedgehog inhibition “reduces the tumor burden and may increase the efficacy and shorten the course of therapy,” Dr. Vidimos said.
The hedgehog inhibitors vismodegib (Erivedge) and sonidegib Odomzo are both approved for treating locally advanced BCC, with a complete response of 31% of locally advanced disease with vismodegib, according to one report.
But monotherapy is limited by intolerable side effects, most commonly muscle spasms, alopecia, and dysgeusia. To minimize the impact, Dr. Vidimos generally puts patients on treatment with Monday through Friday dosing and gives them the weekends off, a schedule she and her colleagues have reported works as well as daily dosing.
Still, many patients discontinue the drugs because of the side effects. Hedgehog inhibitors are also expensive and responses aren’t always durable. To increase efficacy and shorten the course of therapy, “we need alternative treatment strategies,” Dr. Vidimos said.
Up-front tumor debulking is one such strategy. Altered cell signaling pathways associated with tissue remodeling might improve response, and debulking may reduce the genetic heterogeneity of tumor cells, rendering remaining cells less resistant to hedgehog inhibition, she explained.
“It is exciting to see how tumor debulking may reduce tumor burden and heterogeneity, and thus lead to a durable response in extensive tumors,” said Vishal Patel, MD, assistant professor of dermatology and director of the cutaneous oncology program at George Washington University, Washington, who heard the presentation. “More investigation is needed to reproduce these results, but this approach may lead to improved outcomes with targeted therapies,” he said in an interview.
Combination therapy with other agents is another option, and there also seems to be a synergistic effect with radiation, with hedgehog inhibitors increasing cellular response to radiation therapy, Dr. Vidimos said.
Hedgehog inhibitors can also be used to shrink tumors before surgery. One small series found a 27% decrease in the area of the tumor after 3 to 6 months of preoperative vismodegib.
Dr. Vidimos shared another case to illustrate the point.
A 64-year-old woman fainted and presented to the ED with a hemoglobin of 3.2 mg/dL because of chronic blood loss from an ulcerated BCC on her upper back. The lesion measured 25 cm by 9 cm, and was 3.5 cm deep with no bone involvement. The woman was addicted to opioids by the time she presented.
She was started on vismodegib; the ulcer shrunk considerably after 6 months, and the woman underwent a resection. Only one small focus of BCC was found across 78 specimens submitted to Dr. Vidimos for Mohs reading.
Resection was followed by a muscle flap repair and radiation. At 5 and a half years, there is no evidence of disease; the only sign that the lesion had been there was a scar running along the woman’s upper spine.
The approach “was very successful for a very aggressive and worrisome tumor,” Dr. Vidimos said.
Dr. Vidimos did not have any relevant disclosures. Dr. Patel had no relevant disclosures.
FROM THE ACMS ANNUAL MEETING
Checkpoint inhibitor skin side effects more common in women
of 235 patients at Dana Farber Cancer Center, Boston.
Overall, 62.4% of the 93 women in the review and 48.6% of the 142 men experienced confirmed skin reactions, for an odds ratio (OR) of 2.11 for women compared with men (P = .01).
“Clinicians should consider these results in counseling female patients regarding an elevated risk of dermatologic adverse events” when taking checkpoint inhibitors, said investigators led by Harvard University medical student Jordan Said, who presented the results at the American Academy of Dermatology Virtual Meeting Experience.
Autoimmune-like adverse events are common with checkpoint inhibitors. Dermatologic side effects occur in about half of people receiving monotherapy and more than that among patients receiving combination therapy.
Skin reactions can include psoriasiform dermatitis, lichenoid reactions, vitiligo, and bullous pemphigoid and may require hospitalization and prolonged steroid treatment.
Not much is known about risk factors for these reactions. A higher incidence among women has been previously reported. A 2019 study found a higher risk for pneumonitis and endocrinopathy, including hypophysitis, among women who underwent treatment for non–small cell lung cancer or metastatic melanoma.
The 2019 study found that the risk was higher among premenopausal women than postmenopausal women, which led some to suggest that estrogen may play a role.
The results of the Dana Farber review argue against that notion. In their review, the investigators found that the risk was similarly elevated among the 27 premenopausal women (OR, 1.97; P = .40) and the 66 postmenopausal women (OR, 2.17, P = .05). In the study, women who were aged 52 years or older at the start of treatment were considered to be postmenopausal.
“This suggests that factors beyond sex hormones are likely contributory” to the difference in risk between men and women. It’s known that women are at higher risk for autoimmune disease overall, which might be related to the increased odds of autoimmune-like reactions, and it may be that sex-related differences in innate and adoptive immunity are at work, Mr. Said noted.
When asked for comment, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn., said that although some studies have reported a greater risk for side effects among women, others have not. “Additional research is needed to determine the interactions between sex and effects of immune checkpoint inhibitors, as well as many other possible triggers of immune-related adverse events,” he said.
“Continued work in this area will be so important to help determine how to best counsel women and to ensure early recognition and intervention for dermatologic side effects,” said Bernice Kwong, MD, director of the Supportive Dermato-Oncology Program at Stanford (Calif.) University.
The patients in the review were treated from 2011 to 2016 and underwent at least monthly evaluations by their medical teams. They were taking either nivolumab, pembrolizumab, or ipilimumab or a nivolumab/ipilimumab combination.
The median age of the men in the study was 65 years; the median age of women was 60 years. Almost 98% of the participants were White. The majority received one to three infusions, most commonly with pembrolizumab monotherapy.
No funding for the study was reported. Mr. Said has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
of 235 patients at Dana Farber Cancer Center, Boston.
Overall, 62.4% of the 93 women in the review and 48.6% of the 142 men experienced confirmed skin reactions, for an odds ratio (OR) of 2.11 for women compared with men (P = .01).
“Clinicians should consider these results in counseling female patients regarding an elevated risk of dermatologic adverse events” when taking checkpoint inhibitors, said investigators led by Harvard University medical student Jordan Said, who presented the results at the American Academy of Dermatology Virtual Meeting Experience.
Autoimmune-like adverse events are common with checkpoint inhibitors. Dermatologic side effects occur in about half of people receiving monotherapy and more than that among patients receiving combination therapy.
Skin reactions can include psoriasiform dermatitis, lichenoid reactions, vitiligo, and bullous pemphigoid and may require hospitalization and prolonged steroid treatment.
Not much is known about risk factors for these reactions. A higher incidence among women has been previously reported. A 2019 study found a higher risk for pneumonitis and endocrinopathy, including hypophysitis, among women who underwent treatment for non–small cell lung cancer or metastatic melanoma.
The 2019 study found that the risk was higher among premenopausal women than postmenopausal women, which led some to suggest that estrogen may play a role.
The results of the Dana Farber review argue against that notion. In their review, the investigators found that the risk was similarly elevated among the 27 premenopausal women (OR, 1.97; P = .40) and the 66 postmenopausal women (OR, 2.17, P = .05). In the study, women who were aged 52 years or older at the start of treatment were considered to be postmenopausal.
“This suggests that factors beyond sex hormones are likely contributory” to the difference in risk between men and women. It’s known that women are at higher risk for autoimmune disease overall, which might be related to the increased odds of autoimmune-like reactions, and it may be that sex-related differences in innate and adoptive immunity are at work, Mr. Said noted.
When asked for comment, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn., said that although some studies have reported a greater risk for side effects among women, others have not. “Additional research is needed to determine the interactions between sex and effects of immune checkpoint inhibitors, as well as many other possible triggers of immune-related adverse events,” he said.
“Continued work in this area will be so important to help determine how to best counsel women and to ensure early recognition and intervention for dermatologic side effects,” said Bernice Kwong, MD, director of the Supportive Dermato-Oncology Program at Stanford (Calif.) University.
The patients in the review were treated from 2011 to 2016 and underwent at least monthly evaluations by their medical teams. They were taking either nivolumab, pembrolizumab, or ipilimumab or a nivolumab/ipilimumab combination.
The median age of the men in the study was 65 years; the median age of women was 60 years. Almost 98% of the participants were White. The majority received one to three infusions, most commonly with pembrolizumab monotherapy.
No funding for the study was reported. Mr. Said has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
of 235 patients at Dana Farber Cancer Center, Boston.
Overall, 62.4% of the 93 women in the review and 48.6% of the 142 men experienced confirmed skin reactions, for an odds ratio (OR) of 2.11 for women compared with men (P = .01).
“Clinicians should consider these results in counseling female patients regarding an elevated risk of dermatologic adverse events” when taking checkpoint inhibitors, said investigators led by Harvard University medical student Jordan Said, who presented the results at the American Academy of Dermatology Virtual Meeting Experience.
Autoimmune-like adverse events are common with checkpoint inhibitors. Dermatologic side effects occur in about half of people receiving monotherapy and more than that among patients receiving combination therapy.
Skin reactions can include psoriasiform dermatitis, lichenoid reactions, vitiligo, and bullous pemphigoid and may require hospitalization and prolonged steroid treatment.
Not much is known about risk factors for these reactions. A higher incidence among women has been previously reported. A 2019 study found a higher risk for pneumonitis and endocrinopathy, including hypophysitis, among women who underwent treatment for non–small cell lung cancer or metastatic melanoma.
The 2019 study found that the risk was higher among premenopausal women than postmenopausal women, which led some to suggest that estrogen may play a role.
The results of the Dana Farber review argue against that notion. In their review, the investigators found that the risk was similarly elevated among the 27 premenopausal women (OR, 1.97; P = .40) and the 66 postmenopausal women (OR, 2.17, P = .05). In the study, women who were aged 52 years or older at the start of treatment were considered to be postmenopausal.
“This suggests that factors beyond sex hormones are likely contributory” to the difference in risk between men and women. It’s known that women are at higher risk for autoimmune disease overall, which might be related to the increased odds of autoimmune-like reactions, and it may be that sex-related differences in innate and adoptive immunity are at work, Mr. Said noted.
When asked for comment, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn., said that although some studies have reported a greater risk for side effects among women, others have not. “Additional research is needed to determine the interactions between sex and effects of immune checkpoint inhibitors, as well as many other possible triggers of immune-related adverse events,” he said.
“Continued work in this area will be so important to help determine how to best counsel women and to ensure early recognition and intervention for dermatologic side effects,” said Bernice Kwong, MD, director of the Supportive Dermato-Oncology Program at Stanford (Calif.) University.
The patients in the review were treated from 2011 to 2016 and underwent at least monthly evaluations by their medical teams. They were taking either nivolumab, pembrolizumab, or ipilimumab or a nivolumab/ipilimumab combination.
The median age of the men in the study was 65 years; the median age of women was 60 years. Almost 98% of the participants were White. The majority received one to three infusions, most commonly with pembrolizumab monotherapy.
No funding for the study was reported. Mr. Said has disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Lobaplatin deemed ‘promising alternative’ to cisplatin in nasopharyngeal carcinoma
Lobaplatin-based induction plus chemoradiation was as effective as, and safer than, a cisplatin-based regimen in a phase 3 trial of more than 500 patients with advanced nasopharyngeal carcinoma.
The lobaplatin regimen proved to be a “promising alternative regimen to cisplatin-based treatment,” Xing Lv, MD, of Sun Yat-sen University Cancer Centre in Guangzhou, China, and colleagues wrote in The Lancet Oncology.
A lobaplatin-based regimen might be particularly attractive when cisplatin is contraindicated, according to authors of a related editorial.
Given the encouraging results in this trial, lobaplatin might even “overtake carboplatin” in cisplatin-ineligible patients, wrote the editorialists, Stefano Cavalieri, MD, and Lisa Licitra, MD, both of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano in Italy.
“Furthermore, the optimal treatment compliance in patients receiving lobaplatin [in the trial] suggests that this agent might be a good candidate for research into escalation strategies,” the editorialists wrote.
Study rationale
Cisplatin-based induction followed by concurrent chemoradiotherapy is a standard treatment option in the United States, recommended by National Comprehensive Cancer Network guidelines for stage II-IVB nasopharyngeal carcinoma.
However, cisplatin is associated with poor treatment compliance due to significant hematologic and nonhematologic side effects. Cisplatin also requires increased hydration for renal protection, increasing the risk of fluid overload.
“Safer and more effective platinum drugs are needed for the treatment of nasopharyngeal carcinoma,” the investigators wrote.
Carboplatin is an alternative available in the United States, but “the evidence supporting equivalence between cisplatin with carboplatin is still controversial” for nasopharyngeal cancer, the editorialists wrote.
Study details
The phase 3 study enrolled 502 patients from five hospitals in China. The patients had previously untreated, non-keratinizing stage III–IVB nasopharyngeal carcinoma and a Karnofsky performance status score of at least 70. The study excluded patients older than 60 years of age, and adequate renal, hematologic, and hepatic function were required.
Half of patients (n = 252) were randomized to induction with lobaplatin and fluorouracil for two cycles followed by concurrent therapy with lobaplatin for two cycles plus intensity-modulated radiotherapy. The other half of patients (n = 250) were randomized to cisplatin-fluorouracil induction for two cycles, followed by intensity-modulated radiotherapy plus two cycles of cisplatin.
The investigators opted for two-cycle chemotherapy instead of three cycles after observing good activity and safety with two cycles in a phase 2 trial.
Treatment compliance was better in the lobaplatin arm, with 91% of those patients completing two cycles of concurrent chemotherapy, compared with 84% of patients in the cisplatin arm.
The 5-year progression-free survival rate was 75% in the lobaplatin arm and 75.5% in the cisplatin arm in the intention-to-treat population (P noninferiority = .007).
In the per-protocol population, the 5-year progression-free survival rates were 74.8% with lobaplatin and 76.4% with cisplatin (P noninferiority = .016).
The most common grade 3-4 adverse events were mucositis (41% in the lobaplatin arm and 40% in the cisplatin arm), leukopenia (16% and 23%, respectively), and neutropenia (10% and 24%, respectively).
Grade 1-2 nephrotoxicity, nausea, vomiting, and weight loss were significantly less common with lobaplatin (P < .0001 for all).
Questions about generalizability
The editorialists urged caution about generalizing the study results to a wider population.
Study subjects were younger and had no major comorbidities as well as good renal function, which is not always the case with nasopharyngeal carcinoma. In addition, although antiemesis prophylaxis was the standard of care for the study period (2013-2015), guidelines have since been updated to included more intense premedication, which likely would have reduced nausea, vomiting, weight loss, and possibly nephrotoxicity, especially in the cisplatin group.
Induction chemotherapy consisted of cisplatin and fluorouracil, whereas current standards for induction chemotherapy are cisplatin plus gemcitabine or docetaxel plus cisplatin and fluorouracil, the editorialists noted.
As for the two-cycle approach, it’s known that concomitant chemoradiotherapy with two cycles of cisplatin in head and neck cancer “provides similar outcomes to concomitant chemoradiotherapy with three cycles, but only in cases of accelerated intensity-modulated radiotherapy,” not with the standard fractionation used in the study (30-32 fractions, 5 days per week), the editorialists wrote.
The study was funded by the National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. The investigators and Dr. Cavalieri declared no competing interests. Dr. Licitra disclosed relationships AstraZeneca, Bristol Myers Squibb, and Hoffmann-La Roche.
Lobaplatin-based induction plus chemoradiation was as effective as, and safer than, a cisplatin-based regimen in a phase 3 trial of more than 500 patients with advanced nasopharyngeal carcinoma.
The lobaplatin regimen proved to be a “promising alternative regimen to cisplatin-based treatment,” Xing Lv, MD, of Sun Yat-sen University Cancer Centre in Guangzhou, China, and colleagues wrote in The Lancet Oncology.
A lobaplatin-based regimen might be particularly attractive when cisplatin is contraindicated, according to authors of a related editorial.
Given the encouraging results in this trial, lobaplatin might even “overtake carboplatin” in cisplatin-ineligible patients, wrote the editorialists, Stefano Cavalieri, MD, and Lisa Licitra, MD, both of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano in Italy.
“Furthermore, the optimal treatment compliance in patients receiving lobaplatin [in the trial] suggests that this agent might be a good candidate for research into escalation strategies,” the editorialists wrote.
Study rationale
Cisplatin-based induction followed by concurrent chemoradiotherapy is a standard treatment option in the United States, recommended by National Comprehensive Cancer Network guidelines for stage II-IVB nasopharyngeal carcinoma.
However, cisplatin is associated with poor treatment compliance due to significant hematologic and nonhematologic side effects. Cisplatin also requires increased hydration for renal protection, increasing the risk of fluid overload.
“Safer and more effective platinum drugs are needed for the treatment of nasopharyngeal carcinoma,” the investigators wrote.
Carboplatin is an alternative available in the United States, but “the evidence supporting equivalence between cisplatin with carboplatin is still controversial” for nasopharyngeal cancer, the editorialists wrote.
Study details
The phase 3 study enrolled 502 patients from five hospitals in China. The patients had previously untreated, non-keratinizing stage III–IVB nasopharyngeal carcinoma and a Karnofsky performance status score of at least 70. The study excluded patients older than 60 years of age, and adequate renal, hematologic, and hepatic function were required.
Half of patients (n = 252) were randomized to induction with lobaplatin and fluorouracil for two cycles followed by concurrent therapy with lobaplatin for two cycles plus intensity-modulated radiotherapy. The other half of patients (n = 250) were randomized to cisplatin-fluorouracil induction for two cycles, followed by intensity-modulated radiotherapy plus two cycles of cisplatin.
The investigators opted for two-cycle chemotherapy instead of three cycles after observing good activity and safety with two cycles in a phase 2 trial.
Treatment compliance was better in the lobaplatin arm, with 91% of those patients completing two cycles of concurrent chemotherapy, compared with 84% of patients in the cisplatin arm.
The 5-year progression-free survival rate was 75% in the lobaplatin arm and 75.5% in the cisplatin arm in the intention-to-treat population (P noninferiority = .007).
In the per-protocol population, the 5-year progression-free survival rates were 74.8% with lobaplatin and 76.4% with cisplatin (P noninferiority = .016).
The most common grade 3-4 adverse events were mucositis (41% in the lobaplatin arm and 40% in the cisplatin arm), leukopenia (16% and 23%, respectively), and neutropenia (10% and 24%, respectively).
Grade 1-2 nephrotoxicity, nausea, vomiting, and weight loss were significantly less common with lobaplatin (P < .0001 for all).
Questions about generalizability
The editorialists urged caution about generalizing the study results to a wider population.
Study subjects were younger and had no major comorbidities as well as good renal function, which is not always the case with nasopharyngeal carcinoma. In addition, although antiemesis prophylaxis was the standard of care for the study period (2013-2015), guidelines have since been updated to included more intense premedication, which likely would have reduced nausea, vomiting, weight loss, and possibly nephrotoxicity, especially in the cisplatin group.
Induction chemotherapy consisted of cisplatin and fluorouracil, whereas current standards for induction chemotherapy are cisplatin plus gemcitabine or docetaxel plus cisplatin and fluorouracil, the editorialists noted.
As for the two-cycle approach, it’s known that concomitant chemoradiotherapy with two cycles of cisplatin in head and neck cancer “provides similar outcomes to concomitant chemoradiotherapy with three cycles, but only in cases of accelerated intensity-modulated radiotherapy,” not with the standard fractionation used in the study (30-32 fractions, 5 days per week), the editorialists wrote.
The study was funded by the National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. The investigators and Dr. Cavalieri declared no competing interests. Dr. Licitra disclosed relationships AstraZeneca, Bristol Myers Squibb, and Hoffmann-La Roche.
Lobaplatin-based induction plus chemoradiation was as effective as, and safer than, a cisplatin-based regimen in a phase 3 trial of more than 500 patients with advanced nasopharyngeal carcinoma.
The lobaplatin regimen proved to be a “promising alternative regimen to cisplatin-based treatment,” Xing Lv, MD, of Sun Yat-sen University Cancer Centre in Guangzhou, China, and colleagues wrote in The Lancet Oncology.
A lobaplatin-based regimen might be particularly attractive when cisplatin is contraindicated, according to authors of a related editorial.
Given the encouraging results in this trial, lobaplatin might even “overtake carboplatin” in cisplatin-ineligible patients, wrote the editorialists, Stefano Cavalieri, MD, and Lisa Licitra, MD, both of Fondazione IRCCS Istituto Nazionale dei Tumori di Milano in Italy.
“Furthermore, the optimal treatment compliance in patients receiving lobaplatin [in the trial] suggests that this agent might be a good candidate for research into escalation strategies,” the editorialists wrote.
Study rationale
Cisplatin-based induction followed by concurrent chemoradiotherapy is a standard treatment option in the United States, recommended by National Comprehensive Cancer Network guidelines for stage II-IVB nasopharyngeal carcinoma.
However, cisplatin is associated with poor treatment compliance due to significant hematologic and nonhematologic side effects. Cisplatin also requires increased hydration for renal protection, increasing the risk of fluid overload.
“Safer and more effective platinum drugs are needed for the treatment of nasopharyngeal carcinoma,” the investigators wrote.
Carboplatin is an alternative available in the United States, but “the evidence supporting equivalence between cisplatin with carboplatin is still controversial” for nasopharyngeal cancer, the editorialists wrote.
Study details
The phase 3 study enrolled 502 patients from five hospitals in China. The patients had previously untreated, non-keratinizing stage III–IVB nasopharyngeal carcinoma and a Karnofsky performance status score of at least 70. The study excluded patients older than 60 years of age, and adequate renal, hematologic, and hepatic function were required.
Half of patients (n = 252) were randomized to induction with lobaplatin and fluorouracil for two cycles followed by concurrent therapy with lobaplatin for two cycles plus intensity-modulated radiotherapy. The other half of patients (n = 250) were randomized to cisplatin-fluorouracil induction for two cycles, followed by intensity-modulated radiotherapy plus two cycles of cisplatin.
The investigators opted for two-cycle chemotherapy instead of three cycles after observing good activity and safety with two cycles in a phase 2 trial.
Treatment compliance was better in the lobaplatin arm, with 91% of those patients completing two cycles of concurrent chemotherapy, compared with 84% of patients in the cisplatin arm.
The 5-year progression-free survival rate was 75% in the lobaplatin arm and 75.5% in the cisplatin arm in the intention-to-treat population (P noninferiority = .007).
In the per-protocol population, the 5-year progression-free survival rates were 74.8% with lobaplatin and 76.4% with cisplatin (P noninferiority = .016).
The most common grade 3-4 adverse events were mucositis (41% in the lobaplatin arm and 40% in the cisplatin arm), leukopenia (16% and 23%, respectively), and neutropenia (10% and 24%, respectively).
Grade 1-2 nephrotoxicity, nausea, vomiting, and weight loss were significantly less common with lobaplatin (P < .0001 for all).
Questions about generalizability
The editorialists urged caution about generalizing the study results to a wider population.
Study subjects were younger and had no major comorbidities as well as good renal function, which is not always the case with nasopharyngeal carcinoma. In addition, although antiemesis prophylaxis was the standard of care for the study period (2013-2015), guidelines have since been updated to included more intense premedication, which likely would have reduced nausea, vomiting, weight loss, and possibly nephrotoxicity, especially in the cisplatin group.
Induction chemotherapy consisted of cisplatin and fluorouracil, whereas current standards for induction chemotherapy are cisplatin plus gemcitabine or docetaxel plus cisplatin and fluorouracil, the editorialists noted.
As for the two-cycle approach, it’s known that concomitant chemoradiotherapy with two cycles of cisplatin in head and neck cancer “provides similar outcomes to concomitant chemoradiotherapy with three cycles, but only in cases of accelerated intensity-modulated radiotherapy,” not with the standard fractionation used in the study (30-32 fractions, 5 days per week), the editorialists wrote.
The study was funded by the National Science and Technology Pillar Program, International Cooperation Project of Science and Technology Program of Guangdong Province, Planned Science and Technology Project of Guangdong Province, and Cultivation Foundation for the Junior Teachers at Sun Yat-sen University. The investigators and Dr. Cavalieri declared no competing interests. Dr. Licitra disclosed relationships AstraZeneca, Bristol Myers Squibb, and Hoffmann-La Roche.
FROM THE LANCET ONCOLOGY
Survival benefit with nivolumab extends to 5 years in NSCLC
Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m2 once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.
At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.
The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.
There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.
According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”
“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.
Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”
No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.
The optimal duration of nivolumab treatment beyond 1 year is also uncertain.
The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.
The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.
They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.
Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.
This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.
Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m2 once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.
At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.
The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.
There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.
According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”
“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.
Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”
No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.
The optimal duration of nivolumab treatment beyond 1 year is also uncertain.
The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.
The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.
They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.
Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.
This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.
Across the two studies – CheckMate 017 and 057 – 854 patients were randomized 1:1 following progression on platinum therapy to either nivolumab at 3 mg/kg once every 2 weeks or docetaxel at 75 mg/m2 once every 3 weeks until further progression or unacceptable toxicity. Previously reported overall survival (OS) outcomes favored nivolumab.
At a minimum follow-up of 5.4 years, 50 nivolumab-treated patients and 9 docetaxel-treated patients were still alive.
The 5-year OS rates were 13.4% in the nivolumab arm and 2.6% in the docetaxel arm. The 5-year progression-free survival (PFS) rates were 8% and 0%, respectively.
There were no new safety signals with nivolumab, and there was no evidence of select late-onset grade 3-4 adverse events.
According to the study authors, this analysis is the longest phase 3 follow-up to date of a PD-1 inhibitor in previously treated, advanced NSCLC, and it suggests that “long-term survival beyond 5 years may ... be possible in NSCLC.”
“The results indicate that some patients with NSCLC can have long-lasting benefit from checkpoint inhibitors. We have seen similar results in terms of long-term OS with pembrolizumab,” said investigator Hossein Borghaei, DO, chief of thoracic medical oncology at the Fox Chase Cancer Center in Philadelphia.
Dr. Borghaei said the question now is “how to identify the population that really benefits from these treatments. We think PD-L1–high [patients] have a better chance, [as do patients with] tumors that have a higher percentage of tumor-infiltrating lymphocytes, but there’s nothing concrete beyond that.”
No baseline clinical or tumor factors emerged to distinguish between long-and short-term survivors, but the 5-year OS rate was 18.3% among nivolumab-treated patients with PD-L1 expression at or above 1% versus 8% among patients with expression below 1%.
The optimal duration of nivolumab treatment beyond 1 year is also uncertain.
The median duration of therapy was 36.9 months in the 5-year survivors treated with nivolumab, and 36% of patients (18/50) were still on nivolumab at the 5-year mark.
The median duration of time off treatment was 41.9 months among patients who discontinued nivolumab. Five patients (10%) were off treatment with no subsequent therapy and had not progressed at 5 years, “suggesting benefit even for patients who stopped nivolumab treatment,” the researchers wrote.
They also found that nivolumab-treated patients who remained alive at 3 years appeared to stabilize and plateau thereafter, with early response suggesting better long-term outcomes. The majority of patients without disease progression at 2, 3, and 4 years, for instance, remained progression free at 5 years. Nearly one-third of patients who achieved an objective response with nivolumab – but none of the patients who responded to docetaxel – had ongoing responses at 5 years.
Similarly, nivolumab-treated patients without disease progression at 2 years and 3 years had an 82% and 93% chance of survival, respectively, and a 59.6% and 78.3% chance of remaining progression free at 5 years.
This research was funded by Bristol-Myers Squibb. Dr. Borghaei and coauthors disclosed numerous ties to the company, including employment.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Cell-free DNA improves response prediction in breast cancer
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
When the two techniques were in agreement, the accuracy of response prediction was 92.6% in the study, with a predictive value for complete response of 87.5% and a predictive value for absence of complete response of 94.7%, which was substantially better than either method alone.
“Our work identifies a new parameter that is easily combinable with MRI for a more accurate prediction of response following neoadjuvant treatment, with possible implications for current protocols for the evaluation of nodal residual disease,” researcher Francesco Ravera, MD, PhD, of the University of Genoa (Italy), said in a press release.
Dr. Ravera and colleagues presented their research in a poster at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract LB063).
Accurate response prediction is important because it guides subsequent surgical management, Dr. Ravera and colleagues noted. Pathological complete responders – generally about 25% of patients after neoadjuvant therapy – typically undergo a sentinel lymph node biopsy to ensure cancer hasn’t spread, while incomplete responders often have a complete axillary lymph node dissection.
Response is currently assessed by MRI, but accuracy is suboptimal, the researchers noted. A more accurate method might “allow the omission of sentinel lymph node biopsy in complete responders, which could be replaced by longitudinal radiologic monitoring. This would represent substantial progress in the pursuit of an effective, minimally invasive treatment,” Dr. Ravera said.
He and his colleagues turned to plasma cfDNA because it has shown potential for providing useful diagnostic, recurrence, and treatment response information in neoplastic patients.
When healthy cells die, they release similarly sized DNA fragments into the blood, but cancer cells release fragments of varying sizes. The heart of the research was using electrophoresis to assess the degree of fragmentation – called cfDNA integrity – in plasma samples from 38 patients after anthracycline/taxane-based regimens.
The researchers compared how well cfDNA, preoperative MRI, and the combination of the two methods predicted response according to surgical histology.
A total of 11 patients had pathological complete responses to neoadjuvant therapy.
The ratio of large 321-1,000 base pair sized fragments to smaller 150-220 base pair sized fragments, which the team dubbed the “cfDNA integrity index,” best predicted response. At a cutoff above 2.71, the index was 81.6% accurate in predicting pathological complete response, with a sensitivity of 81.8% and specificity of 81.5%.
The predictive power wasn’t much better than MRI, which was 77.1% accurate, with a sensitivity of 72.7% and a specificity of 81.5%.
The two techniques were concordant in their prediction in over two-thirds of patients. When the techniques agreed, accuracy was over 90%.
Prospective studies are needed to evaluate the cfDNA integrity index in combination with MRI, the researchers concluded.
The study was sponsored by the University of Genoa and others. Dr. Ravera disclosed no conflicts of interest.
FROM AACR 2021
Adverse reactions to immunotherapy can appear after a year
Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.
They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.
In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”
Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.
The findings were published online in Annals of Oncology.
“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.
“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.
Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
Largest series to document delayed reactions
Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.
Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.
An expert not involved in the study agrees.
“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.
“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.
Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
Median onset was 16 months
The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.
The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.
In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.
Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.
Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
An early warning system
The most common reactions were colitis, pneumonitis, and rash.
The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.
“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.
Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.
On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.
Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
Question on treatment duration
No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.
The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.
The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.
However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.
“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.
Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.
No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.
They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.
In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”
Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.
The findings were published online in Annals of Oncology.
“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.
“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.
Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
Largest series to document delayed reactions
Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.
Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.
An expert not involved in the study agrees.
“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.
“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.
Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
Median onset was 16 months
The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.
The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.
In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.
Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.
Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
An early warning system
The most common reactions were colitis, pneumonitis, and rash.
The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.
“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.
Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.
On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.
Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
Question on treatment duration
No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.
The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.
The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.
However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.
“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.
Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.
No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Clinicians should be on the lookout for immune-related adverse events (irAEs) even after patients have been receiving anti-PD-1 immunotherapy for a year or longer, according to team of international investigators.
They reported that, among melanoma patients, the incidence of new-onset reactions that occurred 1 year or longer after anti-PD-1 treatment was 5.3%.
In a review of 118 patients, the investigators found that irAEs are often “high grade, difficult to manage, and can lead to death.”
Reactions are more likely to occur in those for whom treatment with an anti-PD-1 checkpoint inhibitor – primarily pembrolizumab and nivolumab – continued for longer than a year, and patients can present “long after stopping” the treatment, the investigators noted.
The findings were published online in Annals of Oncology.
“We do not yet understand why some patients have no side effects for months or years, then develop toxicities so late in their course,” said one of the coauthors, Douglas Johnson, MD, assistant professor of hematology/oncology at Vanderbilt University, Nashville, Tenn.
“Physicians should continue to monitor patients for side effects, even if they have been on anti-PD-1 therapy for some time, since delayed side effects may cause morbidity and even death,” Dr. Johnson said.
Patients and clinicians need “to be aware of these risks when making decisions regarding therapy continuation” and need “to consider irAE as a possible diagnosis in any presentation where there is a history of checkpoint inhibitor treatment, regardless of the time frame, to enable early recognition and appropriate treatment,” Dr. Johnson and colleagues concluded.
Largest series to document delayed reactions
Immunotherapies have revolutionized cancer treatment of many types of tumors, but they carry a well known risk for autoimmune toxicity, which typically occurs within the first 4-6 months, the authors wrote.
Delayed reactions have been reported but are not as well described. The new study is the largest to date on this question, and Dr. Johnson said the findings likely apply across indications, not simply in regard to melanoma patients.
An expert not involved in the study agrees.
“We are definitely seeing delayed reactions to immunotherapy in our practice” in several organ systems, including the skin, said Jennifer Choi, MD, chief of oncodermatology at Northwestern University’s Comprehensive Cancer Center, Chicago.
“Some of these side effects can take months to resolve and may require systemic treatment, such as steroids, nonsteroidal immunosuppressants, or biologics. Clinicians must be on high alert of any possible side effect for a patient on immunotherapy throughout their entire course, and even after they have completed treatment,” Dr. Choi said in an interview.
Anti-PD-1 therapy doesn’t “follow the typical drug hypersensitivity laws and rules with respect to timing,” said Adam Friedman, MD, professor and chair of dermatology at George Washington University, Washington.
Median onset was 16 months
The investigators reported in detail on 118 patients. A total of 140 delayed irAEs that occurred 1 year or longer after treatment were identified in 20 centers around the world.
The median onset of delayed irAE was 16 months after start of treatment. Most occurred in conjunction with stand-alone anti-PD-1 therapy, but in the case of 20 patients, a combination of an anti-PD-1 drug and the anti-CTLA-4 drug ipilimumab was used.
In 39% of patients (n = 55), the adverse reaction was of grade 3 or worse. These included two deaths: one case of fatal encephalitis with concurrent anti-PD-1 use, and a death from immune-related multiple organ failure 11 months after anti-PD-1 discontinuation.
Most of the patients (n = 87; 74%) were receiving anti-PD-1 therapy at the time of onset of the adverse reaction; 15 patients (12%) were within 3 months of their last dose, and 16 (14%) were 3 months past their last dose.
Among the subgroup who developed an irAE after discontinuation of treatment was a patient with grade 4 colitis that required colectomy 26 months afterward, although Dr. Johnson noted it’s difficult to be sure that the colitis was related to the immunotherapy, because it occurred so long after treatment had ended.
An early warning system
The most common reactions were colitis, pneumonitis, and rash.
The reactions were often tough to manage, the authors reported. Eighty patients (68%) required steroids, and 27 (23%) required steroids plus additional immunosuppressives, such as tumor necrosis factor blockers, particularly for colitis and renal, rheumatologic, and neurologic complications. Rheumatologic events required a median corticosteroid course of 15 months plus additional immunosuppression in half of cases and often left patients with ongoing morbidity.
“Often, the skin is one of the first and most easily visible immune-related adverse event that develops,” said Bernice Kwong, MD, director of the supportive dermato-oncology program at Stanford (Calif.) University, who was not involved in the study and was approached for comment.
Presentations can range from small itchy plaques to total body dermatitis. It is something to be aware of, because the skin can act as an early warning system to catch internal organ damage earlier, she said.
On a positive note, the investigators found no indication that the effect of immunotherapy was diminished by delayed reactions and their treatment.
Managing events “gets a little complicated” when anti-PD-1 drugs are still being administered, but “we have successfully utilized systemic steroid pulses for several weeks without impeding the efficacy of the therapy. For the lichenoid and psoriasiform dermatitis, topical steroids and oral retinoids have been useful and can be used concurrently with immunotherapy,” Dr. Friedman said.
Question on treatment duration
No obvious factors were predictive of delayed events, including previous autoimmune disease or earlier reactions, which usually affected different organs, the authors said.
The findings raise a question about the appropriate duration of anti-PD-1 therapy, at least for melanoma.
The standard duration of adjuvant therapy was empirically determined to be 1 year for melanoma, and trials support anti-PD-1 therapy for up to 2 years for metastatic disease.
However, the authors suggest that “shorter treatment duration may reduce the risk of delayed irAE” and may be sufficient for patients who have a complete response.
“This should be considered when making decisions regarding therapy continuation in responding patients,” they wrote.
Ongoing clinical trials are investigating the optimal duration of therapy, they wrote.
No outside funding was reported. Dr. Johnson has been an adviser for Array Biopharma, BMS, Iovance, Jansen, Merck, and Novartis and has received research funding from BMS and Incyte. Other investigators reported similar ties. Dr. Choi, Dr. Kwong, and Dr. Friedman have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Combo provides ‘broad benefit’ across NHL subtypes
The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.
Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.
Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.
Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
Patient and treatment details
The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).
All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.
The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.
Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
Progression-free survival benefit
At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).
The PFS advantage with copanlisib was seen across subtypes:
- Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
- Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
- Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
- Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)
The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.
He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.
The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
More than double the rate of serious AEs
The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.
There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.
Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.
More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.
Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.
In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.
Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.
The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.
The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.
Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.
Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.
Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
Patient and treatment details
The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).
All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.
The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.
Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
Progression-free survival benefit
At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).
The PFS advantage with copanlisib was seen across subtypes:
- Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
- Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
- Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
- Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)
The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.
He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.
The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
More than double the rate of serious AEs
The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.
There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.
Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.
More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.
Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.
In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.
Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.
The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.
The trial, dubbed CHRONOS-3, is the first to report “a broad benefit” across histologic subtypes of relapsed, indolent NHL, and the results are “essentially a long-awaited proof of concept” for combining a PI3K inhibitor with rituximab, according to investigator Matthew Matasar, MD, of Memorial Sloan Kettering Cancer Center in New York.
Dr. Matasar presented results from CHRONOS-3 at the American Association for Cancer Research Annual Meeting 2021: Week 1 (Abstract CT001). The findings were simultaneously published in The Lancet Oncology.
Charles Swanton, MBPhD, of the Francis Crick Institute and UCL Cancer Institute in London, called the results “strongly positive” and said the copanlisib-rituximab combination is “a potential new treatment option” for indolent NHL in patients with a long remission after first-line therapy or those who are unfit for chemotherapy.
Dr. Swanton noted, however, that “one should also bear in mind” the serious adverse events (AEs) seen with copanlisib, particularly hypertension and hyperglycemia. When asked about these AEs, Dr. Matasar said he thinks the combination would be appropriate for patients who meet the study criteria as long as they don’t have severe baseline diabetes or uncontrolled hypertension.
Patient and treatment details
The study included 458 patients with CD20-positive, relapsed, indolent, B-cell NHL. Subtypes included follicular lymphoma (n = 275), marginal zone lymphoma (n = 95), small lymphocytic lymphoma (n = 50), and lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia (n = 38).
All patients were progression free and treatment free before their relapse for at least 12 months after their last rituximab-containing regimen, or at least 6 months before relapse if they were unwilling or unable to undergo chemotherapy.
The patients’ median age was 63 years, and just over half of them were men (52%). About 37% of patients had a history of hypertension at baseline, and about 15% had a history of diabetes.
Patients were randomized to receive copanlisib plus rituximab (n = 307) or rituximab plus placebo (n = 151). Copanlisib was given at 60 mg IV on days 1, 8, and 15 of a 28-day cycle. In both arms, rituximab was given at 375 mg/m2 on days 1, 8, 15, and 22 during cycle 1 and on day 1 of cycles 3, 5, 7, and 9.
Progression-free survival benefit
At a median follow-up of 19.2 months, the median progression-free survival (PFS) was 21.5 months in the copanlisib-rituximab arm and 13.8 months in the placebo-rituximab arm (hazard ratio, 0.52; P < .0001).
The PFS advantage with copanlisib was seen across subtypes:
- Follicular lymphoma – 22.2 months vs. 18.7 months (P = .001)
- Small lymphocytic lymphoma – 14.2 months vs. 5.7 months (P < .0001)
- Marginal zone lymphoma – 22.1 months vs. 11.5 months (P = .012)
- Lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia – 33.4 months vs. 16.6 months (P = .054)
The PFS difference among patients with lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia was likely not statistically significant because of the small sample size, Dr. Matasar said.
He reported that the overall response rate was 81% with copanlisib-rituximab, including a 34% complete response rate. In the placebo arm, the overall response rate was 48%, and 15% of patients had a complete response.
The median overall survival was not estimable in either treatment arm. At a median follow-up of 30.1 months, 14% of patients in the copanlisib arm and 13.2% of patients in the placebo arm had died.
More than double the rate of serious AEs
The rate of serious treatment-emergent AEs was 47.2% in the combination arm and 18.5% in the placebo arm.
There were six grade 5 treatment-emergent AEs in the combination arm. One of these – pneumonitis – was deemed treatment related. There was one treatment-emergent death in the placebo arm.
Hyperglycemia and hypertension were the most common grade 3/4 treatment-emergent AEs with the combination. Diarrhea, nausea, neutropenia, and pyrexia were also more frequent with the combination than with rituximab-placebo.
More than half of patients in the combination arm (56.3%) developed grade 3/4 hyperglycemia. In the placebo arm, the incidence of grade 3 hyperglycemia was 8.2%, and there was no grade 4 hyperglycemia.
Rates of grade 3 hypertension were 39.7% in the combination arm and 8.9% in the placebo arm. There was no grade 4 hypertension.
In the combination arm, 2.6% of patients stopped treatment because of hyperglycemia and 0.7% stopped because of hypertension.
Any-grade pneumonitis occurred in 6.8% of patients in the combination arm and 1.4% of those in the placebo arm. The rate of grade 3/4 pneumonitis was 2.7% in the copanlisib arm, and the rate of grade 3 pneumonitis was 0.7% in the placebo arm.
The study was funded by Bayer, the company developing copanlisib. Dr. Matasar disclosed relationships with Bayer, its subsidiaries, and Roche/Genentech. Dr. Swanton disclosed relationships with numerous companies, including Pfizer, Novartis, and GlaxoSmithKline.
FROM AACR 2021
Endometrial thickness could predict cancer, guide lymph node assessment
In a retrospective study of 378 patients who had hysterectomies for EIN, those with a preoperative endometrial stripe of 20 mm or greater were two times more likely to have endometrial cancer on final pathology, and those with an endometrial thickness of 15 mm or greater were 1.8 times more likely to have cancer.
“This data suggests that increasing endometrial thickness may be a useful preoperative marker to identify who’s at higher risk of concurrent endometrial cancer. It could also be considered a criterion for selectively using a sentinel lymph node algorithm in patients with a preoperative diagnosis of EIN. However, prospective studies are warranted to further establish this association,” said Devon Abt, MD, of Beth Israel Deaconess Medical Center in Boston.
She presented the data at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11103).
Risk of overtreatment
There are no clear consensus guidelines on lymph node assessment for patients with EIN, Dr. Abt noted. She pointed out that roughly 40% of patients with EIN are diagnosed with endometrial cancer. However, it’s usually low-stage, low-grade disease, and only about 10% of patients will have high-risk features that warrant lymph node evaluation.
“Typically, we identify patients with concurrent endometrial cancer based on intraoperative pathology, or frozen section,” Dr. Abt explained. “We then apply the Mayo criteria, which stratifies patients as high or low risk for lymph node metastasis based on pathologic criteria. ... This information helps guide our intraoperative decisions to perform, or not perform, pelvic and para-aortic lymphadenectomy.”
Dr. Abt noted, however, that “lymphadenectomy is not benign” and increases surgical time as well as the risk of complications.
Taking these factors into account, some centers have implemented routine sentinel lymph node algorithms for staging endometrial cancers, Dr. Abt said.
What she and her colleagues wanted to determine is if there is value in this practice. Should sentinel lymph node mapping and biopsy be offered routinely to all patients with a preoperative diagnosis of EIN?
Study details
Dr. Abt and colleagues conducted a retrospective, single-center study of 378 patients with EIN. Ultimately, 27% (n = 103) of the patients were diagnosed with endometrial cancer – 95% with stage 1a disease and 5% with stage 1b.
Increasing age, White race, and hypertension were significantly associated with the presence of endometrial cancer. Body mass index, parity, hormone therapy exposure, and baseline CA 125 were not.
The median preoperative endometrial thickness was 14 mm among patients with endometrial cancer and 11 mm in patients without cancer (P = .002).
Overall, 31% of the cancer cases were considered high risk for nodal metastases by Mayo criteria, but an endometrial stripe of 15 mm or higher increased the chance of being considered high risk.
The risk of cancer was 47% among patients with an endometrial stripe of at least 20 mm versus 21% among patients with a measurement below 15 mm.
Only 10 patients underwent lymph node evaluation, 5 with sentinel lymph node dissection and 5 with lymphadenectomy. Six of the 10 patients had endometrial cancer on final pathology, but none had positive lymph nodes.
“Given the low-grade and early-stage disease in this cohort, adherence to a routine sentinel lymph node algorithm in all patients with EIN would result in overtreatment,” Dr. Abt said.
Discussant Nicole Fleming, MD, of the University of Texas MD Anderson Cancer Center, Houston, said she would advocate for more selective use of sentinel lymph node biopsies in EIN as well.
Dr. Fleming said, in general, lymph node biopsy may be reasonable in settings where frozen sections are unreliable and the patient seems to be at high risk of invasive cancer. However, at academic centers with dedicated gynecologic pathologists, given the low risk of invasive cancer and the fact that lymph nodes “are probably not going to provide you a lot of useful therapeutic decision-making tools,” potentially eliminating sentinel lymph node biopsy might make sense, Dr. Fleming said.
Dr. Fleming disclosed relationships with Tesaro, Bristol-Myers Squibb, Pfizer, and GlaxoSmithKline. Dr. Abt reported having no relevant disclosures and did not report any study funding.
In a retrospective study of 378 patients who had hysterectomies for EIN, those with a preoperative endometrial stripe of 20 mm or greater were two times more likely to have endometrial cancer on final pathology, and those with an endometrial thickness of 15 mm or greater were 1.8 times more likely to have cancer.
“This data suggests that increasing endometrial thickness may be a useful preoperative marker to identify who’s at higher risk of concurrent endometrial cancer. It could also be considered a criterion for selectively using a sentinel lymph node algorithm in patients with a preoperative diagnosis of EIN. However, prospective studies are warranted to further establish this association,” said Devon Abt, MD, of Beth Israel Deaconess Medical Center in Boston.
She presented the data at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11103).
Risk of overtreatment
There are no clear consensus guidelines on lymph node assessment for patients with EIN, Dr. Abt noted. She pointed out that roughly 40% of patients with EIN are diagnosed with endometrial cancer. However, it’s usually low-stage, low-grade disease, and only about 10% of patients will have high-risk features that warrant lymph node evaluation.
“Typically, we identify patients with concurrent endometrial cancer based on intraoperative pathology, or frozen section,” Dr. Abt explained. “We then apply the Mayo criteria, which stratifies patients as high or low risk for lymph node metastasis based on pathologic criteria. ... This information helps guide our intraoperative decisions to perform, or not perform, pelvic and para-aortic lymphadenectomy.”
Dr. Abt noted, however, that “lymphadenectomy is not benign” and increases surgical time as well as the risk of complications.
Taking these factors into account, some centers have implemented routine sentinel lymph node algorithms for staging endometrial cancers, Dr. Abt said.
What she and her colleagues wanted to determine is if there is value in this practice. Should sentinel lymph node mapping and biopsy be offered routinely to all patients with a preoperative diagnosis of EIN?
Study details
Dr. Abt and colleagues conducted a retrospective, single-center study of 378 patients with EIN. Ultimately, 27% (n = 103) of the patients were diagnosed with endometrial cancer – 95% with stage 1a disease and 5% with stage 1b.
Increasing age, White race, and hypertension were significantly associated with the presence of endometrial cancer. Body mass index, parity, hormone therapy exposure, and baseline CA 125 were not.
The median preoperative endometrial thickness was 14 mm among patients with endometrial cancer and 11 mm in patients without cancer (P = .002).
Overall, 31% of the cancer cases were considered high risk for nodal metastases by Mayo criteria, but an endometrial stripe of 15 mm or higher increased the chance of being considered high risk.
The risk of cancer was 47% among patients with an endometrial stripe of at least 20 mm versus 21% among patients with a measurement below 15 mm.
Only 10 patients underwent lymph node evaluation, 5 with sentinel lymph node dissection and 5 with lymphadenectomy. Six of the 10 patients had endometrial cancer on final pathology, but none had positive lymph nodes.
“Given the low-grade and early-stage disease in this cohort, adherence to a routine sentinel lymph node algorithm in all patients with EIN would result in overtreatment,” Dr. Abt said.
Discussant Nicole Fleming, MD, of the University of Texas MD Anderson Cancer Center, Houston, said she would advocate for more selective use of sentinel lymph node biopsies in EIN as well.
Dr. Fleming said, in general, lymph node biopsy may be reasonable in settings where frozen sections are unreliable and the patient seems to be at high risk of invasive cancer. However, at academic centers with dedicated gynecologic pathologists, given the low risk of invasive cancer and the fact that lymph nodes “are probably not going to provide you a lot of useful therapeutic decision-making tools,” potentially eliminating sentinel lymph node biopsy might make sense, Dr. Fleming said.
Dr. Fleming disclosed relationships with Tesaro, Bristol-Myers Squibb, Pfizer, and GlaxoSmithKline. Dr. Abt reported having no relevant disclosures and did not report any study funding.
In a retrospective study of 378 patients who had hysterectomies for EIN, those with a preoperative endometrial stripe of 20 mm or greater were two times more likely to have endometrial cancer on final pathology, and those with an endometrial thickness of 15 mm or greater were 1.8 times more likely to have cancer.
“This data suggests that increasing endometrial thickness may be a useful preoperative marker to identify who’s at higher risk of concurrent endometrial cancer. It could also be considered a criterion for selectively using a sentinel lymph node algorithm in patients with a preoperative diagnosis of EIN. However, prospective studies are warranted to further establish this association,” said Devon Abt, MD, of Beth Israel Deaconess Medical Center in Boston.
She presented the data at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 11103).
Risk of overtreatment
There are no clear consensus guidelines on lymph node assessment for patients with EIN, Dr. Abt noted. She pointed out that roughly 40% of patients with EIN are diagnosed with endometrial cancer. However, it’s usually low-stage, low-grade disease, and only about 10% of patients will have high-risk features that warrant lymph node evaluation.
“Typically, we identify patients with concurrent endometrial cancer based on intraoperative pathology, or frozen section,” Dr. Abt explained. “We then apply the Mayo criteria, which stratifies patients as high or low risk for lymph node metastasis based on pathologic criteria. ... This information helps guide our intraoperative decisions to perform, or not perform, pelvic and para-aortic lymphadenectomy.”
Dr. Abt noted, however, that “lymphadenectomy is not benign” and increases surgical time as well as the risk of complications.
Taking these factors into account, some centers have implemented routine sentinel lymph node algorithms for staging endometrial cancers, Dr. Abt said.
What she and her colleagues wanted to determine is if there is value in this practice. Should sentinel lymph node mapping and biopsy be offered routinely to all patients with a preoperative diagnosis of EIN?
Study details
Dr. Abt and colleagues conducted a retrospective, single-center study of 378 patients with EIN. Ultimately, 27% (n = 103) of the patients were diagnosed with endometrial cancer – 95% with stage 1a disease and 5% with stage 1b.
Increasing age, White race, and hypertension were significantly associated with the presence of endometrial cancer. Body mass index, parity, hormone therapy exposure, and baseline CA 125 were not.
The median preoperative endometrial thickness was 14 mm among patients with endometrial cancer and 11 mm in patients without cancer (P = .002).
Overall, 31% of the cancer cases were considered high risk for nodal metastases by Mayo criteria, but an endometrial stripe of 15 mm or higher increased the chance of being considered high risk.
The risk of cancer was 47% among patients with an endometrial stripe of at least 20 mm versus 21% among patients with a measurement below 15 mm.
Only 10 patients underwent lymph node evaluation, 5 with sentinel lymph node dissection and 5 with lymphadenectomy. Six of the 10 patients had endometrial cancer on final pathology, but none had positive lymph nodes.
“Given the low-grade and early-stage disease in this cohort, adherence to a routine sentinel lymph node algorithm in all patients with EIN would result in overtreatment,” Dr. Abt said.
Discussant Nicole Fleming, MD, of the University of Texas MD Anderson Cancer Center, Houston, said she would advocate for more selective use of sentinel lymph node biopsies in EIN as well.
Dr. Fleming said, in general, lymph node biopsy may be reasonable in settings where frozen sections are unreliable and the patient seems to be at high risk of invasive cancer. However, at academic centers with dedicated gynecologic pathologists, given the low risk of invasive cancer and the fact that lymph nodes “are probably not going to provide you a lot of useful therapeutic decision-making tools,” potentially eliminating sentinel lymph node biopsy might make sense, Dr. Fleming said.
Dr. Fleming disclosed relationships with Tesaro, Bristol-Myers Squibb, Pfizer, and GlaxoSmithKline. Dr. Abt reported having no relevant disclosures and did not report any study funding.
FROM SGO 2021
Negative results when immunotherapy was added to chemoradiotherapy
The JAVELIN Head and Neck 100 trial randomly assigned 697 patients who had already undergone chemoradiotherapy for locally advanced, untreated disease to receive either avelumab or placebo.
This was the first phase 3 trial in which an immune checkpoint inhibitor was given concurrently with radiotherapy in addition to chemotherapy for any indication, noted the researchers. Checkpoint inhibitors have proved effective for recurrent or metastatic disease after standard options have failed. The current trial was one of the few trials to combine a checkpoint inhibitor with standard-of-care treatment in the first-line setting.
Not only did avelumab fail to improve outcomes, but there was also a trend for better progression-free survival (PFS) in the placebo arm, suggesting that avelumab may have had an “antagonistic effect,” the team reports.
Although not statistically significant, survival curves separated in favor of placebo. There was no obvious explanation for what happened, said lead investigator Nancy Lee, MD, of Memorial Sloan Kettering Cancer Center, New York.
“Be very careful when you are thinking about immunotherapy with fractionated radiotherapy,” Dr. Lee said in an interview.
The trial was terminated early for futility. The results were published online in The Lancet Oncology.
Possible detrimental effect?
The trial was conducted in patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity. Overall, 66% of patients had human papillomavirus (HPV)–negative disease, which is associated with poorer prognosis. The rest had HPV-positive disease.
Participants received either avelumab at 10 mg/kg intravenously or placebo along with cisplatin every 3 weeks and 70 Gy of intensity-modulated radiotherapy delivered in 35 fractions during the 9-week concurrent chemoradiotherapy phase of the trial. This was followed by avelumab or placebo maintenance for up to 12 months.
At a median follow-up of almost 15 months, the median PFS was not reached in the avelumab arm (118 events; 95% confidence interval, 16.9 months – not estimable) or in the placebo arm (106 events; 95% CI, 23 months – not estimable).
There was a hint of PFS benefit in a subgroup of 36 patients with tumors showing high PD-LI expression who were taking avelumab.
However, the overall results show that PFS (hazard ratio [HR], 1.21; 95% CI, .93-1.57; P = .920) and overall survival (HR, 1.31; 95% CI, 0.93–1.85; P = .937) trended in favor of placebo.
The findings cannot be explained by increased toxicity in the avelumab arm because there were no substantial safety differences in comparison with placebo, the researchers said.
Concurrent chemotherapy was probably not a problem either. There are robust data on the use of avelumab and other checkpoint inhibitors in combination with chemotherapy for numerous oncology indications. Two such drugs – pembrolizumab and nivolumab – are approved for recurrent or metastatic squamous cell head and neck cancer in combination with chemotherapy.
Dr. Lee suspects the findings could be due to a previously unrecognized negative interaction between avelumab and the high-volume fractionated radiotherapy used for locally advanced head and neck cancer.
“With chemoradiotherapy, we are killing T cells, but we are curing patients. What’s weird is why, when we combine it with immunotherapy, it looks like there’s a detrimental effect. That’s the mystery. We are looking [at tissue samples] to find out mechanistically or biologically why we saw what we saw,” she said.
Results from similar study eagerly awaited
A nearly identical phase 3 trial is underway. The KEYNOTE-412 trial is investigating the addition of pembrolizumab to chemoradiotherapy in the first-line treatment of locally advanced squamous cell head and neck cancer.
If this study also suggests worse survival with the immune checkpoint inhibitor, it’s unlikely there was something specific about avelumab that accounts for the JAVELIN findings, and “we can say we shouldn’t consider using immunotherapy with radiation at all,” Dr. Lee said.
“It could be that there is a detrimental effect of the combination of checkpoint inhibitors with definitive radiotherapy,” said Sjoukje Oosting, MD, PhD, medical oncologist at University Medical Center Groningen, the Netherlands. She was commenting after the JAVELIN results with avelumab were presented at a conference last year and said she now “eagerly awaits” the results with pembrolizumab.
For the time being, Dr. Lee said, “We have to be cautious.” Checkpoint inhibitors might still prove useful in some relationship to first-line chemoradiotherapy.
Studies are underway. One trial is investigating the adjuvant use of immunotherapy after upfront chemoradiotherapy for head and neck cancer.
The JAVELIN trial of avelumab was funded by Pfizer and Merck. The KEYNOTE-412 trial of pembrolizumab is funded by Merck. Dr. Lee is an adviser for and has received research funding from both companies. Dr. Oosting has received research grants from Celldex and Novartis.
A version of this article first appeared on Medscape.com.
The JAVELIN Head and Neck 100 trial randomly assigned 697 patients who had already undergone chemoradiotherapy for locally advanced, untreated disease to receive either avelumab or placebo.
This was the first phase 3 trial in which an immune checkpoint inhibitor was given concurrently with radiotherapy in addition to chemotherapy for any indication, noted the researchers. Checkpoint inhibitors have proved effective for recurrent or metastatic disease after standard options have failed. The current trial was one of the few trials to combine a checkpoint inhibitor with standard-of-care treatment in the first-line setting.
Not only did avelumab fail to improve outcomes, but there was also a trend for better progression-free survival (PFS) in the placebo arm, suggesting that avelumab may have had an “antagonistic effect,” the team reports.
Although not statistically significant, survival curves separated in favor of placebo. There was no obvious explanation for what happened, said lead investigator Nancy Lee, MD, of Memorial Sloan Kettering Cancer Center, New York.
“Be very careful when you are thinking about immunotherapy with fractionated radiotherapy,” Dr. Lee said in an interview.
The trial was terminated early for futility. The results were published online in The Lancet Oncology.
Possible detrimental effect?
The trial was conducted in patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity. Overall, 66% of patients had human papillomavirus (HPV)–negative disease, which is associated with poorer prognosis. The rest had HPV-positive disease.
Participants received either avelumab at 10 mg/kg intravenously or placebo along with cisplatin every 3 weeks and 70 Gy of intensity-modulated radiotherapy delivered in 35 fractions during the 9-week concurrent chemoradiotherapy phase of the trial. This was followed by avelumab or placebo maintenance for up to 12 months.
At a median follow-up of almost 15 months, the median PFS was not reached in the avelumab arm (118 events; 95% confidence interval, 16.9 months – not estimable) or in the placebo arm (106 events; 95% CI, 23 months – not estimable).
There was a hint of PFS benefit in a subgroup of 36 patients with tumors showing high PD-LI expression who were taking avelumab.
However, the overall results show that PFS (hazard ratio [HR], 1.21; 95% CI, .93-1.57; P = .920) and overall survival (HR, 1.31; 95% CI, 0.93–1.85; P = .937) trended in favor of placebo.
The findings cannot be explained by increased toxicity in the avelumab arm because there were no substantial safety differences in comparison with placebo, the researchers said.
Concurrent chemotherapy was probably not a problem either. There are robust data on the use of avelumab and other checkpoint inhibitors in combination with chemotherapy for numerous oncology indications. Two such drugs – pembrolizumab and nivolumab – are approved for recurrent or metastatic squamous cell head and neck cancer in combination with chemotherapy.
Dr. Lee suspects the findings could be due to a previously unrecognized negative interaction between avelumab and the high-volume fractionated radiotherapy used for locally advanced head and neck cancer.
“With chemoradiotherapy, we are killing T cells, but we are curing patients. What’s weird is why, when we combine it with immunotherapy, it looks like there’s a detrimental effect. That’s the mystery. We are looking [at tissue samples] to find out mechanistically or biologically why we saw what we saw,” she said.
Results from similar study eagerly awaited
A nearly identical phase 3 trial is underway. The KEYNOTE-412 trial is investigating the addition of pembrolizumab to chemoradiotherapy in the first-line treatment of locally advanced squamous cell head and neck cancer.
If this study also suggests worse survival with the immune checkpoint inhibitor, it’s unlikely there was something specific about avelumab that accounts for the JAVELIN findings, and “we can say we shouldn’t consider using immunotherapy with radiation at all,” Dr. Lee said.
“It could be that there is a detrimental effect of the combination of checkpoint inhibitors with definitive radiotherapy,” said Sjoukje Oosting, MD, PhD, medical oncologist at University Medical Center Groningen, the Netherlands. She was commenting after the JAVELIN results with avelumab were presented at a conference last year and said she now “eagerly awaits” the results with pembrolizumab.
For the time being, Dr. Lee said, “We have to be cautious.” Checkpoint inhibitors might still prove useful in some relationship to first-line chemoradiotherapy.
Studies are underway. One trial is investigating the adjuvant use of immunotherapy after upfront chemoradiotherapy for head and neck cancer.
The JAVELIN trial of avelumab was funded by Pfizer and Merck. The KEYNOTE-412 trial of pembrolizumab is funded by Merck. Dr. Lee is an adviser for and has received research funding from both companies. Dr. Oosting has received research grants from Celldex and Novartis.
A version of this article first appeared on Medscape.com.
The JAVELIN Head and Neck 100 trial randomly assigned 697 patients who had already undergone chemoradiotherapy for locally advanced, untreated disease to receive either avelumab or placebo.
This was the first phase 3 trial in which an immune checkpoint inhibitor was given concurrently with radiotherapy in addition to chemotherapy for any indication, noted the researchers. Checkpoint inhibitors have proved effective for recurrent or metastatic disease after standard options have failed. The current trial was one of the few trials to combine a checkpoint inhibitor with standard-of-care treatment in the first-line setting.
Not only did avelumab fail to improve outcomes, but there was also a trend for better progression-free survival (PFS) in the placebo arm, suggesting that avelumab may have had an “antagonistic effect,” the team reports.
Although not statistically significant, survival curves separated in favor of placebo. There was no obvious explanation for what happened, said lead investigator Nancy Lee, MD, of Memorial Sloan Kettering Cancer Center, New York.
“Be very careful when you are thinking about immunotherapy with fractionated radiotherapy,” Dr. Lee said in an interview.
The trial was terminated early for futility. The results were published online in The Lancet Oncology.
Possible detrimental effect?
The trial was conducted in patients with locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity. Overall, 66% of patients had human papillomavirus (HPV)–negative disease, which is associated with poorer prognosis. The rest had HPV-positive disease.
Participants received either avelumab at 10 mg/kg intravenously or placebo along with cisplatin every 3 weeks and 70 Gy of intensity-modulated radiotherapy delivered in 35 fractions during the 9-week concurrent chemoradiotherapy phase of the trial. This was followed by avelumab or placebo maintenance for up to 12 months.
At a median follow-up of almost 15 months, the median PFS was not reached in the avelumab arm (118 events; 95% confidence interval, 16.9 months – not estimable) or in the placebo arm (106 events; 95% CI, 23 months – not estimable).
There was a hint of PFS benefit in a subgroup of 36 patients with tumors showing high PD-LI expression who were taking avelumab.
However, the overall results show that PFS (hazard ratio [HR], 1.21; 95% CI, .93-1.57; P = .920) and overall survival (HR, 1.31; 95% CI, 0.93–1.85; P = .937) trended in favor of placebo.
The findings cannot be explained by increased toxicity in the avelumab arm because there were no substantial safety differences in comparison with placebo, the researchers said.
Concurrent chemotherapy was probably not a problem either. There are robust data on the use of avelumab and other checkpoint inhibitors in combination with chemotherapy for numerous oncology indications. Two such drugs – pembrolizumab and nivolumab – are approved for recurrent or metastatic squamous cell head and neck cancer in combination with chemotherapy.
Dr. Lee suspects the findings could be due to a previously unrecognized negative interaction between avelumab and the high-volume fractionated radiotherapy used for locally advanced head and neck cancer.
“With chemoradiotherapy, we are killing T cells, but we are curing patients. What’s weird is why, when we combine it with immunotherapy, it looks like there’s a detrimental effect. That’s the mystery. We are looking [at tissue samples] to find out mechanistically or biologically why we saw what we saw,” she said.
Results from similar study eagerly awaited
A nearly identical phase 3 trial is underway. The KEYNOTE-412 trial is investigating the addition of pembrolizumab to chemoradiotherapy in the first-line treatment of locally advanced squamous cell head and neck cancer.
If this study also suggests worse survival with the immune checkpoint inhibitor, it’s unlikely there was something specific about avelumab that accounts for the JAVELIN findings, and “we can say we shouldn’t consider using immunotherapy with radiation at all,” Dr. Lee said.
“It could be that there is a detrimental effect of the combination of checkpoint inhibitors with definitive radiotherapy,” said Sjoukje Oosting, MD, PhD, medical oncologist at University Medical Center Groningen, the Netherlands. She was commenting after the JAVELIN results with avelumab were presented at a conference last year and said she now “eagerly awaits” the results with pembrolizumab.
For the time being, Dr. Lee said, “We have to be cautious.” Checkpoint inhibitors might still prove useful in some relationship to first-line chemoradiotherapy.
Studies are underway. One trial is investigating the adjuvant use of immunotherapy after upfront chemoradiotherapy for head and neck cancer.
The JAVELIN trial of avelumab was funded by Pfizer and Merck. The KEYNOTE-412 trial of pembrolizumab is funded by Merck. Dr. Lee is an adviser for and has received research funding from both companies. Dr. Oosting has received research grants from Celldex and Novartis.
A version of this article first appeared on Medscape.com.
Technique combines ‘best of both worlds’ to target lung nodules
The technique – bronchoscopic transbronchial microwave ablation – had a 100% technical success rate and produced low rates of complications in a single-center study.
“We combined the best of both worlds [for this] technique,” said investigator Joyce Chan, MBBS, of Prince of Wales Hospital in Hong Kong, when describing the method at the European Lung Cancer Virtual Congress 2021 (Abstract 64MO).
Dr. Chan explained that microwave ablation of lung nodules is faster and produces larger ablation zones, compared with radiofrequency ablation, and bronchoscopic ablation is thought to produce fewer pleural-based complications than percutaneous ablation.
Bronchoscopic transbronchial microwave ablation is performed in a hybrid operating room. First, the patient is intubated and anesthetized. Then, electromagnetic navigation bronchoscopy is used to zero in on the lung nodule, which is punctured by a microwave catheter. Cone-beam CT is used to confirm the location of the catheter.
“Next, we connect the system externally to a console, and then we just press the button to microwave it, just like what you do to food,” Dr. Chan explained.
Ablation takes about 10 minutes, and another CT is done to assess success. Ground-glass opacities are seen in the ablated area.
Study results
Dr. Chan and colleagues performed a retrospective analysis of 36 patients who underwent bronchoscopic transbronchial microwave ablation between March 2019 and December 2020.
The patients were unfit for or unwilling to undergo surgical resection. They had to have stage 1a lung cancers, isolated lung oligometastases, or radiologically suspicious lesions. The nodules had to be less than 3 cm in size, preferably with a bronchus leading directly to the lesion.
The patients had a mean age of 68 years. Their lesions had a mean maximal diameter of 15.2 mm, and 68% were in the peripheral one-third of the lung.
In all, 44 nodules were treated with bronchoscopic transbronchial microwave ablation. The technical success rate was 100%, although eight nodules required double ablation.
The majority of patients (95%) were discharged within 3 days, with 77% discharged on day 1. Complications included mild pain (15.9%), pneumothorax (9.1%), fever/ablation reaction (4.5%), self-limiting hemoptysis (2.3%), and bronchopleural fistula (2.3%).
The ablation zone volume decreased “rapidly” in the first 6-9 months, then leveled off, Dr. Chan noted.
In the 16 nodules with 1 year of follow-up, there were 2 complete responses, 13 partial responses, and no progressions.
It’s too soon to know if the recurrence rate will be lower than the up to 30% recurrence rate with percutaneous microwave ablation, and it’s too soon to know if, without transpleural puncture, the risk of tumor seeding is lower, Dr. Chan said.
“This presentation ... is extremely important,” said invited discussant John Edwards, MBChB, PhD, of Sheffield (England) Teaching Hospitals National Health Service Foundation Trust. “There is a great novelty value in the combination. The complications and the radiologic response rates were quite acceptable.”
The research was funded by the University Grants Committee in Hong Kong. Dr. Chan reported having no disclosures. Her colleagues disclosed relationships with Medtronic, Siemens Healthineers, and Johnson & Johnson. Dr. Edwards disclosed relationships with AstraZeneca, Zimmer Biomet, Stryker Leibinger, Pacific Biosciences, BioNano Genomics, Argenx, and Moderna.
The technique – bronchoscopic transbronchial microwave ablation – had a 100% technical success rate and produced low rates of complications in a single-center study.
“We combined the best of both worlds [for this] technique,” said investigator Joyce Chan, MBBS, of Prince of Wales Hospital in Hong Kong, when describing the method at the European Lung Cancer Virtual Congress 2021 (Abstract 64MO).
Dr. Chan explained that microwave ablation of lung nodules is faster and produces larger ablation zones, compared with radiofrequency ablation, and bronchoscopic ablation is thought to produce fewer pleural-based complications than percutaneous ablation.
Bronchoscopic transbronchial microwave ablation is performed in a hybrid operating room. First, the patient is intubated and anesthetized. Then, electromagnetic navigation bronchoscopy is used to zero in on the lung nodule, which is punctured by a microwave catheter. Cone-beam CT is used to confirm the location of the catheter.
“Next, we connect the system externally to a console, and then we just press the button to microwave it, just like what you do to food,” Dr. Chan explained.
Ablation takes about 10 minutes, and another CT is done to assess success. Ground-glass opacities are seen in the ablated area.
Study results
Dr. Chan and colleagues performed a retrospective analysis of 36 patients who underwent bronchoscopic transbronchial microwave ablation between March 2019 and December 2020.
The patients were unfit for or unwilling to undergo surgical resection. They had to have stage 1a lung cancers, isolated lung oligometastases, or radiologically suspicious lesions. The nodules had to be less than 3 cm in size, preferably with a bronchus leading directly to the lesion.
The patients had a mean age of 68 years. Their lesions had a mean maximal diameter of 15.2 mm, and 68% were in the peripheral one-third of the lung.
In all, 44 nodules were treated with bronchoscopic transbronchial microwave ablation. The technical success rate was 100%, although eight nodules required double ablation.
The majority of patients (95%) were discharged within 3 days, with 77% discharged on day 1. Complications included mild pain (15.9%), pneumothorax (9.1%), fever/ablation reaction (4.5%), self-limiting hemoptysis (2.3%), and bronchopleural fistula (2.3%).
The ablation zone volume decreased “rapidly” in the first 6-9 months, then leveled off, Dr. Chan noted.
In the 16 nodules with 1 year of follow-up, there were 2 complete responses, 13 partial responses, and no progressions.
It’s too soon to know if the recurrence rate will be lower than the up to 30% recurrence rate with percutaneous microwave ablation, and it’s too soon to know if, without transpleural puncture, the risk of tumor seeding is lower, Dr. Chan said.
“This presentation ... is extremely important,” said invited discussant John Edwards, MBChB, PhD, of Sheffield (England) Teaching Hospitals National Health Service Foundation Trust. “There is a great novelty value in the combination. The complications and the radiologic response rates were quite acceptable.”
The research was funded by the University Grants Committee in Hong Kong. Dr. Chan reported having no disclosures. Her colleagues disclosed relationships with Medtronic, Siemens Healthineers, and Johnson & Johnson. Dr. Edwards disclosed relationships with AstraZeneca, Zimmer Biomet, Stryker Leibinger, Pacific Biosciences, BioNano Genomics, Argenx, and Moderna.
The technique – bronchoscopic transbronchial microwave ablation – had a 100% technical success rate and produced low rates of complications in a single-center study.
“We combined the best of both worlds [for this] technique,” said investigator Joyce Chan, MBBS, of Prince of Wales Hospital in Hong Kong, when describing the method at the European Lung Cancer Virtual Congress 2021 (Abstract 64MO).
Dr. Chan explained that microwave ablation of lung nodules is faster and produces larger ablation zones, compared with radiofrequency ablation, and bronchoscopic ablation is thought to produce fewer pleural-based complications than percutaneous ablation.
Bronchoscopic transbronchial microwave ablation is performed in a hybrid operating room. First, the patient is intubated and anesthetized. Then, electromagnetic navigation bronchoscopy is used to zero in on the lung nodule, which is punctured by a microwave catheter. Cone-beam CT is used to confirm the location of the catheter.
“Next, we connect the system externally to a console, and then we just press the button to microwave it, just like what you do to food,” Dr. Chan explained.
Ablation takes about 10 minutes, and another CT is done to assess success. Ground-glass opacities are seen in the ablated area.
Study results
Dr. Chan and colleagues performed a retrospective analysis of 36 patients who underwent bronchoscopic transbronchial microwave ablation between March 2019 and December 2020.
The patients were unfit for or unwilling to undergo surgical resection. They had to have stage 1a lung cancers, isolated lung oligometastases, or radiologically suspicious lesions. The nodules had to be less than 3 cm in size, preferably with a bronchus leading directly to the lesion.
The patients had a mean age of 68 years. Their lesions had a mean maximal diameter of 15.2 mm, and 68% were in the peripheral one-third of the lung.
In all, 44 nodules were treated with bronchoscopic transbronchial microwave ablation. The technical success rate was 100%, although eight nodules required double ablation.
The majority of patients (95%) were discharged within 3 days, with 77% discharged on day 1. Complications included mild pain (15.9%), pneumothorax (9.1%), fever/ablation reaction (4.5%), self-limiting hemoptysis (2.3%), and bronchopleural fistula (2.3%).
The ablation zone volume decreased “rapidly” in the first 6-9 months, then leveled off, Dr. Chan noted.
In the 16 nodules with 1 year of follow-up, there were 2 complete responses, 13 partial responses, and no progressions.
It’s too soon to know if the recurrence rate will be lower than the up to 30% recurrence rate with percutaneous microwave ablation, and it’s too soon to know if, without transpleural puncture, the risk of tumor seeding is lower, Dr. Chan said.
“This presentation ... is extremely important,” said invited discussant John Edwards, MBChB, PhD, of Sheffield (England) Teaching Hospitals National Health Service Foundation Trust. “There is a great novelty value in the combination. The complications and the radiologic response rates were quite acceptable.”
The research was funded by the University Grants Committee in Hong Kong. Dr. Chan reported having no disclosures. Her colleagues disclosed relationships with Medtronic, Siemens Healthineers, and Johnson & Johnson. Dr. Edwards disclosed relationships with AstraZeneca, Zimmer Biomet, Stryker Leibinger, Pacific Biosciences, BioNano Genomics, Argenx, and Moderna.
FROM ELCC 2021