Hold the checkpoint inhibitors when pneumonitis symptoms occur

BOSTON – Treatment of pneumonitis associated with the PD-1 axis checkpoint inhibitors requires close monitoring of patients and rapid clinical response, an oncologist advised.

“We need to be vigilant when we treat our patients. If a patient has cough or shortness of breath, you take it seriously, even if [it is] a patient who has lung cancer and is a smoker,” said Dr. Scott Gettinger of Yale Cancer Center, New Haven, Conn.

He recommended that before starting patients on a programmed death-1 (PD-1) axis inhibitor such as pembrolizumab (Keytruda) or nivolumab (Opdivo), clinicians get baseline oxygen saturation levels to obtain an objective measure for following patients during therapy.

“When you suspect pneumonitis you have to start steroids right away, or patients can spiral down,” he said at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Pneumonitis – characterized by cough, dyspnea, and hypoxia – is a common adverse event associated with PD-1 and PD-ligand 1 (PD-L1) inhibitors, but is rarely seen in patients treated with CTLA-4 inhibitors such as ipilimumab (Yervoy). Current evidence suggests that pneumonitis is more prevalent in patients with non–small-cell lung cancer, occurring in approximately 4%-6% of patients cases, than in melanoma (1%). The difference is probably due to a history of smoking common to the majority of patients with NSCLC, Dr. Gettinger said.

“The other theme that we’re beginning to see is that maybe pneumonitis is a bit more common with anti-PD-1 vs. anti-PD-L1 antibodies,” he said.

It’s theorized that PD-1 inhibitors may block binding of PD-L2 to one of its binding partners, thereby interfering with respiratory tolerance, he said.

Evidence from the pivotal clinical trial of nivolumab in lung cancer (Checkmate 057) suggests that the time to onset of pneumonitis was a median of 31.1 weeks (range 11.7 to 56.9 weeks). The pneumonitis resolved in about 5-7 weeks.

Investigators at Memorial Sloan Kettering Cancer Center in New York City reported at the European Cancer Congress 2015 on pneumonitis in 36 of 653 patients treated with an anti PD-1/PD-L1 monoclonal antibody from 2009 through 2014, 33 of whom had received a PD-1 inhibitor, and 3 of whom received a PD-L1 inhibitor.

They found that pneumonitis in patients with lung cancer tended to resemble chronic obstructive pneumonia, whereas patients with melanoma were more likely to have ground-glass opacifications on radiography. There was a trend, falling just short of significance, toward association of COP-like pneumonitis with development of grade 3 or greater, and with a requirement for more than one type of immunosuppression, compared to other subtypes.

Algorithms for management

Dr. Gettinger briefly outlined an algorithm offered by Bristol-Myers Squibb for management of suspected pulmonary toxicity with nivolumab. For management of patients with grade 1 toxicities (asymptomatic, with radiographic changes only), it recommends that clinicians consider delay of immuno-oncologic (I-O) therapy, monitor for symptoms every 2-3 days, and consider consultations with pulmonary and infectious disease specialists.

For grade 2 pneumonitis, marked by mild to moderate new symptoms, the algorithm calls for clinicians to delay I-O therapy per protocol, consult with pulmonary and ID specialists, monitor symptoms daily and consider hospitalization, start the patient on steroids with 1.0 mg/kg per day methylprednisolone IV or the oral equivalent, and consider bronchoscopy and lung biopsy.

For patients with grade 3 or 4 toxicities, marked by severe new symptoms, new or worsening hypoxia, or other life-threatening symptoms, the algorithm states that clinicians should discontinue I-O therapy, hospitalize the patient, consult with pulmonary and ID, give 2-4 mg/kg per day methylprednisolone IV or the oral equivalent, add prophylactic antibiotics for opportunistic infections, and consider bronchoscopy and lung biopsy.

At Yale, Dr. Gettinger and colleagues, when presented with a symptomatic patient on a PD-axis inhibitor, will first rule out other etiologies such as infection, chronic obstructive pulmonary disease exacerbation, or cancer progression), typically with bronchoscopy.

For patients with moderate pneumonitis, they may treat with prednisone for 1 or 2 weeks, with a 4-6 week taper begun as symptoms start to resolve.

“In a patient who has profound hypoxia and shortness of breath, we may want to go higher: We might give them 2 mg/kg twice a day of [methylprednisolone] in the hospital, wait until they get better, and then slowly taper them, whether it be over 4 or 6 weeks or longer. Occasionally our patients need to get even higher doses of steroids and there’s really nothing to guide us. Who knows if 1 gram of [methylprednisolone] may be better than 60 g of prednisone? But we do it, and patients do get better with the higher doses,” he said.

In rare instances, patients may required other immunosuppressive agents, such as infliximab (Remicade), cyclophosphamide, or mycophenolate mofetil.

Patients who require additional immunosuppressive agents to resolve severe pneumonitis tend to have poor outcomes, Dr. Gettinger said.

Re-challenge of patients with a PD-1 or PD-L1 inhibitor following resolution of pneumonitis appears to be inadvisable for all patients except possibly those with grade 1 (asymptomatic) toxicity, due to the high risk of recurrence, he said.

BOSTON – Treatment of pneumonitis associated with the PD-1 axis checkpoint inhibitors requires close monitoring of patients and rapid clinical response, an oncologist advised.

“We need to be vigilant when we treat our patients. If a patient has cough or shortness of breath, you take it seriously, even if [it is] a patient who has lung cancer and is a smoker,” said Dr. Scott Gettinger of Yale Cancer Center, New Haven, Conn.

He recommended that before starting patients on a programmed death-1 (PD-1) axis inhibitor such as pembrolizumab (Keytruda) or nivolumab (Opdivo), clinicians get baseline oxygen saturation levels to obtain an objective measure for following patients during therapy.

“When you suspect pneumonitis you have to start steroids right away, or patients can spiral down,” he said at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Pneumonitis – characterized by cough, dyspnea, and hypoxia – is a common adverse event associated with PD-1 and PD-ligand 1 (PD-L1) inhibitors, but is rarely seen in patients treated with CTLA-4 inhibitors such as ipilimumab (Yervoy). Current evidence suggests that pneumonitis is more prevalent in patients with non–small-cell lung cancer, occurring in approximately 4%-6% of patients cases, than in melanoma (1%). The difference is probably due to a history of smoking common to the majority of patients with NSCLC, Dr. Gettinger said.

“The other theme that we’re beginning to see is that maybe pneumonitis is a bit more common with anti-PD-1 vs. anti-PD-L1 antibodies,” he said.

It’s theorized that PD-1 inhibitors may block binding of PD-L2 to one of its binding partners, thereby interfering with respiratory tolerance, he said.

Evidence from the pivotal clinical trial of nivolumab in lung cancer (Checkmate 057) suggests that the time to onset of pneumonitis was a median of 31.1 weeks (range 11.7 to 56.9 weeks). The pneumonitis resolved in about 5-7 weeks.

Investigators at Memorial Sloan Kettering Cancer Center in New York City reported at the European Cancer Congress 2015 on pneumonitis in 36 of 653 patients treated with an anti PD-1/PD-L1 monoclonal antibody from 2009 through 2014, 33 of whom had received a PD-1 inhibitor, and 3 of whom received a PD-L1 inhibitor.

They found that pneumonitis in patients with lung cancer tended to resemble chronic obstructive pneumonia, whereas patients with melanoma were more likely to have ground-glass opacifications on radiography. There was a trend, falling just short of significance, toward association of COP-like pneumonitis with development of grade 3 or greater, and with a requirement for more than one type of immunosuppression, compared to other subtypes.

Algorithms for management

Dr. Gettinger briefly outlined an algorithm offered by Bristol-Myers Squibb for management of suspected pulmonary toxicity with nivolumab. For management of patients with grade 1 toxicities (asymptomatic, with radiographic changes only), it recommends that clinicians consider delay of immuno-oncologic (I-O) therapy, monitor for symptoms every 2-3 days, and consider consultations with pulmonary and infectious disease specialists.

For grade 2 pneumonitis, marked by mild to moderate new symptoms, the algorithm calls for clinicians to delay I-O therapy per protocol, consult with pulmonary and ID specialists, monitor symptoms daily and consider hospitalization, start the patient on steroids with 1.0 mg/kg per day methylprednisolone IV or the oral equivalent, and consider bronchoscopy and lung biopsy.

For patients with grade 3 or 4 toxicities, marked by severe new symptoms, new or worsening hypoxia, or other life-threatening symptoms, the algorithm states that clinicians should discontinue I-O therapy, hospitalize the patient, consult with pulmonary and ID, give 2-4 mg/kg per day methylprednisolone IV or the oral equivalent, add prophylactic antibiotics for opportunistic infections, and consider bronchoscopy and lung biopsy.

At Yale, Dr. Gettinger and colleagues, when presented with a symptomatic patient on a PD-axis inhibitor, will first rule out other etiologies such as infection, chronic obstructive pulmonary disease exacerbation, or cancer progression), typically with bronchoscopy.

For patients with moderate pneumonitis, they may treat with prednisone for 1 or 2 weeks, with a 4-6 week taper begun as symptoms start to resolve.

“In a patient who has profound hypoxia and shortness of breath, we may want to go higher: We might give them 2 mg/kg twice a day of [methylprednisolone] in the hospital, wait until they get better, and then slowly taper them, whether it be over 4 or 6 weeks or longer. Occasionally our patients need to get even higher doses of steroids and there’s really nothing to guide us. Who knows if 1 gram of [methylprednisolone] may be better than 60 g of prednisone? But we do it, and patients do get better with the higher doses,” he said.

In rare instances, patients may required other immunosuppressive agents, such as infliximab (Remicade), cyclophosphamide, or mycophenolate mofetil.

Patients who require additional immunosuppressive agents to resolve severe pneumonitis tend to have poor outcomes, Dr. Gettinger said.

Re-challenge of patients with a PD-1 or PD-L1 inhibitor following resolution of pneumonitis appears to be inadvisable for all patients except possibly those with grade 1 (asymptomatic) toxicity, due to the high risk of recurrence, he said.

BOSTON – Treatment of pneumonitis associated with the PD-1 axis checkpoint inhibitors requires close monitoring of patients and rapid clinical response, an oncologist advised.

“We need to be vigilant when we treat our patients. If a patient has cough or shortness of breath, you take it seriously, even if [it is] a patient who has lung cancer and is a smoker,” said Dr. Scott Gettinger of Yale Cancer Center, New Haven, Conn.

He recommended that before starting patients on a programmed death-1 (PD-1) axis inhibitor such as pembrolizumab (Keytruda) or nivolumab (Opdivo), clinicians get baseline oxygen saturation levels to obtain an objective measure for following patients during therapy.

“When you suspect pneumonitis you have to start steroids right away, or patients can spiral down,” he said at the AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Pneumonitis – characterized by cough, dyspnea, and hypoxia – is a common adverse event associated with PD-1 and PD-ligand 1 (PD-L1) inhibitors, but is rarely seen in patients treated with CTLA-4 inhibitors such as ipilimumab (Yervoy). Current evidence suggests that pneumonitis is more prevalent in patients with non–small-cell lung cancer, occurring in approximately 4%-6% of patients cases, than in melanoma (1%). The difference is probably due to a history of smoking common to the majority of patients with NSCLC, Dr. Gettinger said.

“The other theme that we’re beginning to see is that maybe pneumonitis is a bit more common with anti-PD-1 vs. anti-PD-L1 antibodies,” he said.

It’s theorized that PD-1 inhibitors may block binding of PD-L2 to one of its binding partners, thereby interfering with respiratory tolerance, he said.

Evidence from the pivotal clinical trial of nivolumab in lung cancer (Checkmate 057) suggests that the time to onset of pneumonitis was a median of 31.1 weeks (range 11.7 to 56.9 weeks). The pneumonitis resolved in about 5-7 weeks.

Investigators at Memorial Sloan Kettering Cancer Center in New York City reported at the European Cancer Congress 2015 on pneumonitis in 36 of 653 patients treated with an anti PD-1/PD-L1 monoclonal antibody from 2009 through 2014, 33 of whom had received a PD-1 inhibitor, and 3 of whom received a PD-L1 inhibitor.

They found that pneumonitis in patients with lung cancer tended to resemble chronic obstructive pneumonia, whereas patients with melanoma were more likely to have ground-glass opacifications on radiography. There was a trend, falling just short of significance, toward association of COP-like pneumonitis with development of grade 3 or greater, and with a requirement for more than one type of immunosuppression, compared to other subtypes.

Algorithms for management

Dr. Gettinger briefly outlined an algorithm offered by Bristol-Myers Squibb for management of suspected pulmonary toxicity with nivolumab. For management of patients with grade 1 toxicities (asymptomatic, with radiographic changes only), it recommends that clinicians consider delay of immuno-oncologic (I-O) therapy, monitor for symptoms every 2-3 days, and consider consultations with pulmonary and infectious disease specialists.

For grade 2 pneumonitis, marked by mild to moderate new symptoms, the algorithm calls for clinicians to delay I-O therapy per protocol, consult with pulmonary and ID specialists, monitor symptoms daily and consider hospitalization, start the patient on steroids with 1.0 mg/kg per day methylprednisolone IV or the oral equivalent, and consider bronchoscopy and lung biopsy.

For patients with grade 3 or 4 toxicities, marked by severe new symptoms, new or worsening hypoxia, or other life-threatening symptoms, the algorithm states that clinicians should discontinue I-O therapy, hospitalize the patient, consult with pulmonary and ID, give 2-4 mg/kg per day methylprednisolone IV or the oral equivalent, add prophylactic antibiotics for opportunistic infections, and consider bronchoscopy and lung biopsy.

At Yale, Dr. Gettinger and colleagues, when presented with a symptomatic patient on a PD-axis inhibitor, will first rule out other etiologies such as infection, chronic obstructive pulmonary disease exacerbation, or cancer progression), typically with bronchoscopy.

For patients with moderate pneumonitis, they may treat with prednisone for 1 or 2 weeks, with a 4-6 week taper begun as symptoms start to resolve.

“In a patient who has profound hypoxia and shortness of breath, we may want to go higher: We might give them 2 mg/kg twice a day of [methylprednisolone] in the hospital, wait until they get better, and then slowly taper them, whether it be over 4 or 6 weeks or longer. Occasionally our patients need to get even higher doses of steroids and there’s really nothing to guide us. Who knows if 1 gram of [methylprednisolone] may be better than 60 g of prednisone? But we do it, and patients do get better with the higher doses,” he said.

In rare instances, patients may required other immunosuppressive agents, such as infliximab (Remicade), cyclophosphamide, or mycophenolate mofetil.

Patients who require additional immunosuppressive agents to resolve severe pneumonitis tend to have poor outcomes, Dr. Gettinger said.

Re-challenge of patients with a PD-1 or PD-L1 inhibitor following resolution of pneumonitis appears to be inadvisable for all patients except possibly those with grade 1 (asymptomatic) toxicity, due to the high risk of recurrence, he said.