Sharon Worcester

The first report from a Spanish registry of patients with acquired hemophilia A shows a strikingly high rate of infection-related deaths among older patients in the 2 months after they start immunosuppressive therapy.

The findings also indicate that an unusually large proportion of patients were on antithrombotic therapy, which may have led to misdiagnosis or delayed diagnosis of acquired hemophilia A (AHA) in some cases, Marıa-Eva Mingot-Castellano, MD, PhD, of Hospital Universitario Virgen del Rocıo, Seville, Spain, and Hospital Regional Universitario de Malaga (Spain) and colleagues reported on behalf of the Acquired Haemophilia-A Spanish Registry (AHASR).

The report was published online in Blood Advances.

These data provide useful clinical information about a rare disease, and they underscore the need for vigilance when prescribing immunosuppressive therapy for frail, elderly patients with AHA, hematologist Nigel Key, MD, said in an interview.

“The findings point to the fact that we still have a high death rate with this disorder, whether directly or indirectly related,” said Dr. Key, the Harold R. Roberts Distinguished Professor and vice chief for research in the division of hematology at the University of North Carolina at Chapel Hill. “[AHA] is still a high-morbidity, high-mortality condition, and these are very high-risk patients.”



The Spanish AHA registry data

The authors retrospectively collected data on 154 patients who were diagnosed with AHA at 36 Spanish hospitals from May 2014 through September 2020 and followed for a median of 12 months.

The patients were mostly men (56.3%) and had a median age of 74 years at diagnosis.

A third were on antithrombotic therapy at diagnosis, and hemostatic treatment was used in 70% of cases.

“Only one patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy,” the authors wrote, noting that “steroids alone were less efficient than the other strategies (68.2% vs. 87.2%), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%; vs. steroids/calcineurin inhibitors, 81.2%; vs. rituximab-based regimens, 87.5%).

Women and those with high inhibitor levels were less likely to achieve CR, they said.

Of the 154 registry participants, 36 died, and 15 (9.9%) of those died as a result of infection, the leading cause of death. Five (3.3%) died as a result of hemorrhage. All of the hemorrhage-related deaths and half of the infection-related deaths occurred within 2 months of diagnosis, they noted, adding that “prior antithrombotic therapy was inversely associated with survival, irrespective of age.”

The median age of nonsurvivors was significantly higher than that of survivors (79 vs. 73 years), and the median age of those who died from infection was significantly higher than that of patients who died from other causes (85 vs. 78 years).



Additional insights

“One remarkable finding, not described before in AHA, was the high proportion of patients on antithrombotic therapy in the days before AHA diagnosis, namely one-third of the whole series,” the authors wrote. “This proportion is comparable to that of the Spanish population of similar age groups.”

Further, the use of antithrombotic therapy prior to AHA diagnosis was associated with mortality during follow-up in patients aged 75 years and older, they noted.

The older age and comorbidity burden among affected patients underscores their vulnerability and the importance of prompt diagnosis, they added, explaining how misdiagnosis might occur: “Attributing the bleeding episode to a hemostatic imbalance caused by the antithrombotic therapy may entail a risk of misdiagnosis. Frail patients could be admitted to hospital shortly after having been administered anticoagulants. In these cases, misdiagnosis would prevent early [immunosuppressive therapy], and patients could be exposed to potentially life-threatening bleedings.”

Delayed diagnoses have also been described in other registries. For example, in the China Acquired Hemophilia Registry (CARE), nearly half of participants had a delayed diagnosis, and younger patients were more likely than older patients to be referred for consultation, the authors explained.

“Interestingly, antiplatelet therapy has been described to delay AHA diagnosis or lead to misdiagnosis of AHA patients. Furthermore, the underlying diseases that prompted antithrombotic therapy highlight the vulnerability of these patients and could contribute to a negative outcome,” they noted.

Given the high rate of fatal infection in the first months of immunosuppressive therapy in the series, and the association between antithrombotic therapy and mortality, particular care should be taken to avoid misdiagnosis, the authors stressed.

They noted, however, that the study has some important limitations inherent in retrospective analyses and studies with limited sample size and missing data.

Still, the findings add value, they said.

“AHA is not well-known among clinicians unfamiliar with hemostatic disorders. Lack of awareness may preclude early diagnosis, thus exposing patients to an unacceptably high bleeding risk,” they explained, adding that existing management guidelines for the use of immunosuppressive therapy “rely on registry findings and authors’ experience rather than on comparative studies.”

“Therefore, any valuable knowledge regarding clinical experience in managing this disorder should be helpful,” they wrote. “The rarity of the condition prompts the design of registries to compile as much information as possible concerning baseline status, diagnosis, treatment, and follow-up ... to continuously update guidelines on disease management procedures.”

Indeed, the AHASR is “a good-sized registry” and these data are valuable, Dr. Key said.

“I like the fact that they focused on a couple of things here to do with outcomes, particularly analyzing the causes of death,” he said, noting that the reported death is not remarkably different from what has been reported previously, but it does “raise the question of morbidity also related to the therapy – particularly infection.”

The data are especially useful with respect to use of immunosuppressive regimens, he said.

“These are, for the most part, old or frail patients. ... They can’t just be put on cyclophosphamide and sent away without monitoring blood counts and being given advice about what to look out for regarding infection and when to seek treatment,” he said, adding that immunosuppressive regimens are “given for very good and necessary reasons, but are not benign.”

“There ought to be consideration, if necessary, of advice from an infectious disease specialist,” he added, noting that “rheumatologists deal with this all the time, but hematologists often underestimate the infectious morbidity of [immunosuppressive therapy].”

The study authors reported having no conflicts of interest to disclose. Dr. Key has served at the chair of a grant committee for Novo Nordisk.

[email protected]

The first report from a Spanish registry of patients with acquired hemophilia A shows a strikingly high rate of infection-related deaths among older patients in the 2 months after they start immunosuppressive therapy.

The findings also indicate that an unusually large proportion of patients were on antithrombotic therapy, which may have led to misdiagnosis or delayed diagnosis of acquired hemophilia A (AHA) in some cases, Marıa-Eva Mingot-Castellano, MD, PhD, of Hospital Universitario Virgen del Rocıo, Seville, Spain, and Hospital Regional Universitario de Malaga (Spain) and colleagues reported on behalf of the Acquired Haemophilia-A Spanish Registry (AHASR).

The report was published online in Blood Advances.

These data provide useful clinical information about a rare disease, and they underscore the need for vigilance when prescribing immunosuppressive therapy for frail, elderly patients with AHA, hematologist Nigel Key, MD, said in an interview.

“The findings point to the fact that we still have a high death rate with this disorder, whether directly or indirectly related,” said Dr. Key, the Harold R. Roberts Distinguished Professor and vice chief for research in the division of hematology at the University of North Carolina at Chapel Hill. “[AHA] is still a high-morbidity, high-mortality condition, and these are very high-risk patients.”



The Spanish AHA registry data

The authors retrospectively collected data on 154 patients who were diagnosed with AHA at 36 Spanish hospitals from May 2014 through September 2020 and followed for a median of 12 months.

The patients were mostly men (56.3%) and had a median age of 74 years at diagnosis.

A third were on antithrombotic therapy at diagnosis, and hemostatic treatment was used in 70% of cases.

“Only one patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy,” the authors wrote, noting that “steroids alone were less efficient than the other strategies (68.2% vs. 87.2%), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%; vs. steroids/calcineurin inhibitors, 81.2%; vs. rituximab-based regimens, 87.5%).

Women and those with high inhibitor levels were less likely to achieve CR, they said.

Of the 154 registry participants, 36 died, and 15 (9.9%) of those died as a result of infection, the leading cause of death. Five (3.3%) died as a result of hemorrhage. All of the hemorrhage-related deaths and half of the infection-related deaths occurred within 2 months of diagnosis, they noted, adding that “prior antithrombotic therapy was inversely associated with survival, irrespective of age.”

The median age of nonsurvivors was significantly higher than that of survivors (79 vs. 73 years), and the median age of those who died from infection was significantly higher than that of patients who died from other causes (85 vs. 78 years).



Additional insights

“One remarkable finding, not described before in AHA, was the high proportion of patients on antithrombotic therapy in the days before AHA diagnosis, namely one-third of the whole series,” the authors wrote. “This proportion is comparable to that of the Spanish population of similar age groups.”

Further, the use of antithrombotic therapy prior to AHA diagnosis was associated with mortality during follow-up in patients aged 75 years and older, they noted.

The older age and comorbidity burden among affected patients underscores their vulnerability and the importance of prompt diagnosis, they added, explaining how misdiagnosis might occur: “Attributing the bleeding episode to a hemostatic imbalance caused by the antithrombotic therapy may entail a risk of misdiagnosis. Frail patients could be admitted to hospital shortly after having been administered anticoagulants. In these cases, misdiagnosis would prevent early [immunosuppressive therapy], and patients could be exposed to potentially life-threatening bleedings.”

Delayed diagnoses have also been described in other registries. For example, in the China Acquired Hemophilia Registry (CARE), nearly half of participants had a delayed diagnosis, and younger patients were more likely than older patients to be referred for consultation, the authors explained.

“Interestingly, antiplatelet therapy has been described to delay AHA diagnosis or lead to misdiagnosis of AHA patients. Furthermore, the underlying diseases that prompted antithrombotic therapy highlight the vulnerability of these patients and could contribute to a negative outcome,” they noted.

Given the high rate of fatal infection in the first months of immunosuppressive therapy in the series, and the association between antithrombotic therapy and mortality, particular care should be taken to avoid misdiagnosis, the authors stressed.

They noted, however, that the study has some important limitations inherent in retrospective analyses and studies with limited sample size and missing data.

Still, the findings add value, they said.

“AHA is not well-known among clinicians unfamiliar with hemostatic disorders. Lack of awareness may preclude early diagnosis, thus exposing patients to an unacceptably high bleeding risk,” they explained, adding that existing management guidelines for the use of immunosuppressive therapy “rely on registry findings and authors’ experience rather than on comparative studies.”

“Therefore, any valuable knowledge regarding clinical experience in managing this disorder should be helpful,” they wrote. “The rarity of the condition prompts the design of registries to compile as much information as possible concerning baseline status, diagnosis, treatment, and follow-up ... to continuously update guidelines on disease management procedures.”

Indeed, the AHASR is “a good-sized registry” and these data are valuable, Dr. Key said.

“I like the fact that they focused on a couple of things here to do with outcomes, particularly analyzing the causes of death,” he said, noting that the reported death is not remarkably different from what has been reported previously, but it does “raise the question of morbidity also related to the therapy – particularly infection.”

The data are especially useful with respect to use of immunosuppressive regimens, he said.

“These are, for the most part, old or frail patients. ... They can’t just be put on cyclophosphamide and sent away without monitoring blood counts and being given advice about what to look out for regarding infection and when to seek treatment,” he said, adding that immunosuppressive regimens are “given for very good and necessary reasons, but are not benign.”

“There ought to be consideration, if necessary, of advice from an infectious disease specialist,” he added, noting that “rheumatologists deal with this all the time, but hematologists often underestimate the infectious morbidity of [immunosuppressive therapy].”

The study authors reported having no conflicts of interest to disclose. Dr. Key has served at the chair of a grant committee for Novo Nordisk.

[email protected]

The first report from a Spanish registry of patients with acquired hemophilia A shows a strikingly high rate of infection-related deaths among older patients in the 2 months after they start immunosuppressive therapy.

The findings also indicate that an unusually large proportion of patients were on antithrombotic therapy, which may have led to misdiagnosis or delayed diagnosis of acquired hemophilia A (AHA) in some cases, Marıa-Eva Mingot-Castellano, MD, PhD, of Hospital Universitario Virgen del Rocıo, Seville, Spain, and Hospital Regional Universitario de Malaga (Spain) and colleagues reported on behalf of the Acquired Haemophilia-A Spanish Registry (AHASR).

The report was published online in Blood Advances.

These data provide useful clinical information about a rare disease, and they underscore the need for vigilance when prescribing immunosuppressive therapy for frail, elderly patients with AHA, hematologist Nigel Key, MD, said in an interview.

“The findings point to the fact that we still have a high death rate with this disorder, whether directly or indirectly related,” said Dr. Key, the Harold R. Roberts Distinguished Professor and vice chief for research in the division of hematology at the University of North Carolina at Chapel Hill. “[AHA] is still a high-morbidity, high-mortality condition, and these are very high-risk patients.”



The Spanish AHA registry data

The authors retrospectively collected data on 154 patients who were diagnosed with AHA at 36 Spanish hospitals from May 2014 through September 2020 and followed for a median of 12 months.

The patients were mostly men (56.3%) and had a median age of 74 years at diagnosis.

A third were on antithrombotic therapy at diagnosis, and hemostatic treatment was used in 70% of cases.

“Only one patient did not achieve control of hemorrhage. Complete remission (CR) was achieved by 84.2% of cases after immunosuppressive therapy,” the authors wrote, noting that “steroids alone were less efficient than the other strategies (68.2% vs. 87.2%), whereas no differences existed among these (steroids/cyclophosphamide, 88.5%; vs. steroids/calcineurin inhibitors, 81.2%; vs. rituximab-based regimens, 87.5%).

Women and those with high inhibitor levels were less likely to achieve CR, they said.

Of the 154 registry participants, 36 died, and 15 (9.9%) of those died as a result of infection, the leading cause of death. Five (3.3%) died as a result of hemorrhage. All of the hemorrhage-related deaths and half of the infection-related deaths occurred within 2 months of diagnosis, they noted, adding that “prior antithrombotic therapy was inversely associated with survival, irrespective of age.”

The median age of nonsurvivors was significantly higher than that of survivors (79 vs. 73 years), and the median age of those who died from infection was significantly higher than that of patients who died from other causes (85 vs. 78 years).



Additional insights

“One remarkable finding, not described before in AHA, was the high proportion of patients on antithrombotic therapy in the days before AHA diagnosis, namely one-third of the whole series,” the authors wrote. “This proportion is comparable to that of the Spanish population of similar age groups.”

Further, the use of antithrombotic therapy prior to AHA diagnosis was associated with mortality during follow-up in patients aged 75 years and older, they noted.

The older age and comorbidity burden among affected patients underscores their vulnerability and the importance of prompt diagnosis, they added, explaining how misdiagnosis might occur: “Attributing the bleeding episode to a hemostatic imbalance caused by the antithrombotic therapy may entail a risk of misdiagnosis. Frail patients could be admitted to hospital shortly after having been administered anticoagulants. In these cases, misdiagnosis would prevent early [immunosuppressive therapy], and patients could be exposed to potentially life-threatening bleedings.”

Delayed diagnoses have also been described in other registries. For example, in the China Acquired Hemophilia Registry (CARE), nearly half of participants had a delayed diagnosis, and younger patients were more likely than older patients to be referred for consultation, the authors explained.

“Interestingly, antiplatelet therapy has been described to delay AHA diagnosis or lead to misdiagnosis of AHA patients. Furthermore, the underlying diseases that prompted antithrombotic therapy highlight the vulnerability of these patients and could contribute to a negative outcome,” they noted.

Given the high rate of fatal infection in the first months of immunosuppressive therapy in the series, and the association between antithrombotic therapy and mortality, particular care should be taken to avoid misdiagnosis, the authors stressed.

They noted, however, that the study has some important limitations inherent in retrospective analyses and studies with limited sample size and missing data.

Still, the findings add value, they said.

“AHA is not well-known among clinicians unfamiliar with hemostatic disorders. Lack of awareness may preclude early diagnosis, thus exposing patients to an unacceptably high bleeding risk,” they explained, adding that existing management guidelines for the use of immunosuppressive therapy “rely on registry findings and authors’ experience rather than on comparative studies.”

“Therefore, any valuable knowledge regarding clinical experience in managing this disorder should be helpful,” they wrote. “The rarity of the condition prompts the design of registries to compile as much information as possible concerning baseline status, diagnosis, treatment, and follow-up ... to continuously update guidelines on disease management procedures.”

Indeed, the AHASR is “a good-sized registry” and these data are valuable, Dr. Key said.

“I like the fact that they focused on a couple of things here to do with outcomes, particularly analyzing the causes of death,” he said, noting that the reported death is not remarkably different from what has been reported previously, but it does “raise the question of morbidity also related to the therapy – particularly infection.”

The data are especially useful with respect to use of immunosuppressive regimens, he said.

“These are, for the most part, old or frail patients. ... They can’t just be put on cyclophosphamide and sent away without monitoring blood counts and being given advice about what to look out for regarding infection and when to seek treatment,” he said, adding that immunosuppressive regimens are “given for very good and necessary reasons, but are not benign.”

“There ought to be consideration, if necessary, of advice from an infectious disease specialist,” he added, noting that “rheumatologists deal with this all the time, but hematologists often underestimate the infectious morbidity of [immunosuppressive therapy].”

The study authors reported having no conflicts of interest to disclose. Dr. Key has served at the chair of a grant committee for Novo Nordisk.

[email protected]

The success of chimeric antigen receptor T (CAR T)-cell therapy for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) has garnered much attention, but the field is still in its infancy – with toxicity and relapse rates remaining unacceptably high.

These and other observations from a review of published data on using CAR T cells for B-ALL shine a spotlight on areas that need optimization in the use of the therapy in this setting, according to review authors Vanessa A. Fabrizio, MD, a fellow at Duke University, Durham, N.C., and Kevin J. Curran, MD, a pediatric oncologist at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.

Based on their review of early pivotal clinical trials, relapse data, toxicities, and mechanisms to optimize CAR T-cell therapy, Dr. Fabrizio and Dr. Curran outlined several “practice points” and proposed a research agenda aimed at optimizing the use of CAR T-cell therapy for B-ALL (Best Pract Res Clin Haematol. 2021 Aug 27. doi: 10.1016/j.beha.2021.101305).
 

Practice points

CAR T-cell therapy has transformed the treatment of both pediatric and adult patients with relapsed/refractory (R/R) B-ALL, the authors said, adding that “[c]linical trial results across multiple institutions with different CAR constructs report significant response rates in treated patients.”

Dr. Fabrizio and Dr. Curran specifically note that only one product (tisagenlecleucel) is currently approved for the treatment of R/R B-ALL in patients under age 26 years. Further, the successful application of this therapy is limited by high relapse rates, significant toxicity in some cases, and challenges related to collection and production issues.

They contend that areas in which optimization of CAR T-cell therapy can occur include apheresis, production, chemotherapy bridging, pretreatment disease burden management, toxicity management, disease monitoring after therapy, and use of consolidative allogeneic hematopoietic stem cell transplantation.
 

Research agenda

Key ways to heighten the success of CAR T-cell therapy for B-ALL are the development of off-the-shelf CAR T-cell products and the selection of optimal T cells to enhance apheresis and production, they said, adding that research is needed on the use of bridging chemotherapy to reduce tumor burden.

Bridging chemotherapy has been shown to impact outcomes while minimizing toxicity, but it remains undefined.

“Prospective trials are required to determine if the optimization of lymphodepleting chemotherapy can improve outcomes, and if consolidative therapy with transplantation should be considered in select patients,” they wrote. “Continued efforts to improve this technology for patients is ongoing while remaining questions are being investigated.”

The authors acknowledge that CAR T-cell therapy has transformed the treatment landscape for both pediatric and adult patients with R/R B-ALL, but this extensive review of all published data on the subject shows that “the incidence of relapse among responders is unacceptably high, demonstrating the need to improve this therapy.”

In conclusion, they wrote: “To be effective following infusion, CAR T cells must expand, persist, exhibit enduring anti-tumor cytotoxicity, withstand and/or counteract an immunosuppressive tumor microenvironment, and overcome targeted tumor antigen escape. In designing CAR T cells for cancer immunotherapy, all of these factors must be harmonized to generate the optimal therapy,” noting that “[t]oxicity management and, ideally the prediction of toxicity in individualized patients, should continue to be a focus of ongoing efforts.”

Dr. Curran has received research support from Juno Therapeutics and Novartis, and has consulted, participated in advisory boards, or taken part in educational seminars for Juno Therapeutics, Novartis, and Mesoblast. Dr. Fabrizio reported having no conflict of interests.

[email protected]

The success of chimeric antigen receptor T (CAR T)-cell therapy for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) has garnered much attention, but the field is still in its infancy – with toxicity and relapse rates remaining unacceptably high.

These and other observations from a review of published data on using CAR T cells for B-ALL shine a spotlight on areas that need optimization in the use of the therapy in this setting, according to review authors Vanessa A. Fabrizio, MD, a fellow at Duke University, Durham, N.C., and Kevin J. Curran, MD, a pediatric oncologist at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.

Based on their review of early pivotal clinical trials, relapse data, toxicities, and mechanisms to optimize CAR T-cell therapy, Dr. Fabrizio and Dr. Curran outlined several “practice points” and proposed a research agenda aimed at optimizing the use of CAR T-cell therapy for B-ALL (Best Pract Res Clin Haematol. 2021 Aug 27. doi: 10.1016/j.beha.2021.101305).
 

Practice points

CAR T-cell therapy has transformed the treatment of both pediatric and adult patients with relapsed/refractory (R/R) B-ALL, the authors said, adding that “[c]linical trial results across multiple institutions with different CAR constructs report significant response rates in treated patients.”

Dr. Fabrizio and Dr. Curran specifically note that only one product (tisagenlecleucel) is currently approved for the treatment of R/R B-ALL in patients under age 26 years. Further, the successful application of this therapy is limited by high relapse rates, significant toxicity in some cases, and challenges related to collection and production issues.

They contend that areas in which optimization of CAR T-cell therapy can occur include apheresis, production, chemotherapy bridging, pretreatment disease burden management, toxicity management, disease monitoring after therapy, and use of consolidative allogeneic hematopoietic stem cell transplantation.
 

Research agenda

Key ways to heighten the success of CAR T-cell therapy for B-ALL are the development of off-the-shelf CAR T-cell products and the selection of optimal T cells to enhance apheresis and production, they said, adding that research is needed on the use of bridging chemotherapy to reduce tumor burden.

Bridging chemotherapy has been shown to impact outcomes while minimizing toxicity, but it remains undefined.

“Prospective trials are required to determine if the optimization of lymphodepleting chemotherapy can improve outcomes, and if consolidative therapy with transplantation should be considered in select patients,” they wrote. “Continued efforts to improve this technology for patients is ongoing while remaining questions are being investigated.”

The authors acknowledge that CAR T-cell therapy has transformed the treatment landscape for both pediatric and adult patients with R/R B-ALL, but this extensive review of all published data on the subject shows that “the incidence of relapse among responders is unacceptably high, demonstrating the need to improve this therapy.”

In conclusion, they wrote: “To be effective following infusion, CAR T cells must expand, persist, exhibit enduring anti-tumor cytotoxicity, withstand and/or counteract an immunosuppressive tumor microenvironment, and overcome targeted tumor antigen escape. In designing CAR T cells for cancer immunotherapy, all of these factors must be harmonized to generate the optimal therapy,” noting that “[t]oxicity management and, ideally the prediction of toxicity in individualized patients, should continue to be a focus of ongoing efforts.”

Dr. Curran has received research support from Juno Therapeutics and Novartis, and has consulted, participated in advisory boards, or taken part in educational seminars for Juno Therapeutics, Novartis, and Mesoblast. Dr. Fabrizio reported having no conflict of interests.

[email protected]

The success of chimeric antigen receptor T (CAR T)-cell therapy for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) has garnered much attention, but the field is still in its infancy – with toxicity and relapse rates remaining unacceptably high.

These and other observations from a review of published data on using CAR T cells for B-ALL shine a spotlight on areas that need optimization in the use of the therapy in this setting, according to review authors Vanessa A. Fabrizio, MD, a fellow at Duke University, Durham, N.C., and Kevin J. Curran, MD, a pediatric oncologist at Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York.

Based on their review of early pivotal clinical trials, relapse data, toxicities, and mechanisms to optimize CAR T-cell therapy, Dr. Fabrizio and Dr. Curran outlined several “practice points” and proposed a research agenda aimed at optimizing the use of CAR T-cell therapy for B-ALL (Best Pract Res Clin Haematol. 2021 Aug 27. doi: 10.1016/j.beha.2021.101305).
 

Practice points

CAR T-cell therapy has transformed the treatment of both pediatric and adult patients with relapsed/refractory (R/R) B-ALL, the authors said, adding that “[c]linical trial results across multiple institutions with different CAR constructs report significant response rates in treated patients.”

Dr. Fabrizio and Dr. Curran specifically note that only one product (tisagenlecleucel) is currently approved for the treatment of R/R B-ALL in patients under age 26 years. Further, the successful application of this therapy is limited by high relapse rates, significant toxicity in some cases, and challenges related to collection and production issues.

They contend that areas in which optimization of CAR T-cell therapy can occur include apheresis, production, chemotherapy bridging, pretreatment disease burden management, toxicity management, disease monitoring after therapy, and use of consolidative allogeneic hematopoietic stem cell transplantation.
 

Research agenda

Key ways to heighten the success of CAR T-cell therapy for B-ALL are the development of off-the-shelf CAR T-cell products and the selection of optimal T cells to enhance apheresis and production, they said, adding that research is needed on the use of bridging chemotherapy to reduce tumor burden.

Bridging chemotherapy has been shown to impact outcomes while minimizing toxicity, but it remains undefined.

“Prospective trials are required to determine if the optimization of lymphodepleting chemotherapy can improve outcomes, and if consolidative therapy with transplantation should be considered in select patients,” they wrote. “Continued efforts to improve this technology for patients is ongoing while remaining questions are being investigated.”

The authors acknowledge that CAR T-cell therapy has transformed the treatment landscape for both pediatric and adult patients with R/R B-ALL, but this extensive review of all published data on the subject shows that “the incidence of relapse among responders is unacceptably high, demonstrating the need to improve this therapy.”

In conclusion, they wrote: “To be effective following infusion, CAR T cells must expand, persist, exhibit enduring anti-tumor cytotoxicity, withstand and/or counteract an immunosuppressive tumor microenvironment, and overcome targeted tumor antigen escape. In designing CAR T cells for cancer immunotherapy, all of these factors must be harmonized to generate the optimal therapy,” noting that “[t]oxicity management and, ideally the prediction of toxicity in individualized patients, should continue to be a focus of ongoing efforts.”

Dr. Curran has received research support from Juno Therapeutics and Novartis, and has consulted, participated in advisory boards, or taken part in educational seminars for Juno Therapeutics, Novartis, and Mesoblast. Dr. Fabrizio reported having no conflict of interests.

[email protected]

Targeted agents for the treatment of diffuse large B-cell lymphoma (DLBCL) should be used in the context of oncogenic addictions within the lymphoma cells, and a thorough molecular analysis should be conducted prior to using specific agents, a review of the relevant literature suggests.

“In addition ... single-agent regimens are most likely not efficient enough to substantially improve the outcome of patients with DLBCL,” Wendan Xu and colleagues at University Hospital Munster, Germany, concluded, based on their review.

Indeed, novel combinations that include B-cell receptor (BCR) signaling and phosphatidylinositol 3-kinase (PI3K) inhibitors are needed for DLBCL treatment, and treatment should also include conventional chemoimmunotherapeutic regimens as well as other targeted agents and novel immunologic approaches, they wrote. Such novel combinations could overcome mechanisms of resistance and increase cure rates in individuals with DLBCL, they contended.

The authors’ observations are based on a search of the available data, from which they summarized the “current understanding of BCR signaling with a special focus on the PI3K pathway and its role in the pathogenesis of DLBCL.”

The addition of the anti-CD20 antibody rituximab to the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) significantly improved outcomes for patients with DLBCL, but about a third of patients are not cured by the rituximab-CHOP (R-CHOP) regimen and subsequent therapies, they said, explaining their rationale for the review.

“A better understanding of the molecular pathogenesis is warranted to use novel targeted agents in an optimal manner,” they said.

The authors also addressed clinical implications of the findings, and mechanisms of resistance to PI3k inhibitors. For example, they noted that:

–Bruton’s tyrosine kinase (BTK) inhibitors may be beneficial when added to R-CHOP.

In the randomized phase 3 PHOENIX trial, ibrutinib plus R-CHOP versus R-CHOP alone in patients with non–germinal center B-cell (non-GCB) DLBCL showed a survival benefit in patients over 60 years of age, which suggests a possible role for “an intensified R-CHOP regimen that includes a BTK inhibitor” in these patients, they said. They added that confirmatory trials are under way, including the ESCALADE trial looking at the second-generation BTK inhibitor acalabrutinib combined with R-CHOP versus R-CHOP alone in patients with untreated DLBCL.

–Results have been mixed with PI3K inhibitors.

Various PI3K inhibitors have been evaluated for the treatment of patients with DLBCL.

Idelalisib, a first-in-class PI3K-specific inhibitor approved for treatment of relapsed/refractory (r/r) follicular lymphoma, small lymphocytic lymphoma, and chronic lymphocytic leukemia (CLL), showed only modest activity in preclinical DLBCL models, and no responses were detectable in a small trial of patients with r/r DLBCL, the authors said. “Severe toxic side effects and treatment-related deaths occurred in several clinical trials that tested idelalisib in combination with antibodies alone or with antibodies and chemotherapy, leading to the premature discontinuation of some of these studies,” they noted.

Other studies investigating idelalisib plus lenalidomide and rituximab or the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with r/r CLL or lymphoma were also halted because of “overwhelming, immune-mediated pulmonary and/or hepatic toxicities.”

Copanlisib, an intravenous pan-class I PI3K inhibitor with preferential inhibition of PI3Ka and PI3Kd, showed some promise as monotherapy in a phase 2 trial of patients with r/r DLBCL. The overall response rate was about 20%, and response was “numerically higher” in activated B-cell like (ABC) DLBCL, compared with GCB DLBCL (32% vs. 13%), confirming preclinical data that showed PI3Ka/d inhibition effectiveness mainly in ABC DLBCL.

“Compared with idelalisib, copanlisib appears to have a more favorable toxicity profile, with a lower incidence of severe complications,” they said, adding that a phase 2 trial of copanlisib plus R-CHOP as first-line therapy for patients with DLBCL is under way.

Further, monotherapy with buparlisib, a pan-class I PI3K inhibitor, was associated with a low response rate of 11.5% in a DLBCL subcohort in a phase 2 study, whereas parsaclisib, a next-generation inhibitor with specificity to the PI3Kd isoform, showed efficacy as a monotherapy in patients with r/r DLBCL in a phase 2 study (overall response rate, 25.5%), they said, adding that other PI3K inhibitors with additional inhibitory effects are under clinical development.

–Various molecular mechanisms of resistance to PI3K inhibitors have been described preclinically and clinically.

In an unbiased exploratory analysis of samples from patients treated with copanlisib, a 16-gene mutation signature that separated responders from nonresponders was identified, the authors said.

The finding suggests that genetic aberrations dictate response to PI3K inhibitors, they noted.

“This 16-gene signature included TNFAIP3, CREBBP, and PRDM1, which are known to be important in the molecular pathogenesis of DLBCL,” they wrote. A composite score was developed to reflect the numerical presence or absence of mutations in the gene set, they explained, adding that patients with a high composite score had a significantly higher overall response rate and longer progression-free survival than did patients with a lower score.

In addition, idelalisib treatment resulted in a feedback activation of PI3Ka in ABC DLBCL cells.

“This rebound of PI3K activity was overcome by subsequent PI3Ka inhibition in preclinical DLBCL models, further underscoring the necessity of inhibiting both PI3Ka and PI3Kd to achieve responses in ABC DLBCL,” they wrote, adding that “[i]n ABC DLBCL models treated with the PI3Ka/PI3Kd inhibitor AZD8835, activated CARD11 mutations were identified as a mechanism of resistance.”

Investigations looking at various treatment combinations to overcome resistance to PI3K inhibition and improve the efficacy of targeted approaches are under way, they said.

For example, copanlisib plus the BCL-2 inhibitor venetoclax showed “synergistic activity in BCR-dependent DLBCLs, with genetic bases for BCL-2 dysregulation in vitro and in vivo,” and combination treatment with umbralisib and the proteasome inhibitor carfilzomib showed synergistic cytotoxicity in B-cell lymphoma, they said, noting that the latter combination is currently being evaluated in patients with DLBCL.

This work was supported by a research grant from the Deutsche Krebshilfe. Dr. Xu reported having no financial disclosures.

[email protected]

Targeted agents for the treatment of diffuse large B-cell lymphoma (DLBCL) should be used in the context of oncogenic addictions within the lymphoma cells, and a thorough molecular analysis should be conducted prior to using specific agents, a review of the relevant literature suggests.

“In addition ... single-agent regimens are most likely not efficient enough to substantially improve the outcome of patients with DLBCL,” Wendan Xu and colleagues at University Hospital Munster, Germany, concluded, based on their review.

Indeed, novel combinations that include B-cell receptor (BCR) signaling and phosphatidylinositol 3-kinase (PI3K) inhibitors are needed for DLBCL treatment, and treatment should also include conventional chemoimmunotherapeutic regimens as well as other targeted agents and novel immunologic approaches, they wrote. Such novel combinations could overcome mechanisms of resistance and increase cure rates in individuals with DLBCL, they contended.

The authors’ observations are based on a search of the available data, from which they summarized the “current understanding of BCR signaling with a special focus on the PI3K pathway and its role in the pathogenesis of DLBCL.”

The addition of the anti-CD20 antibody rituximab to the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) significantly improved outcomes for patients with DLBCL, but about a third of patients are not cured by the rituximab-CHOP (R-CHOP) regimen and subsequent therapies, they said, explaining their rationale for the review.

“A better understanding of the molecular pathogenesis is warranted to use novel targeted agents in an optimal manner,” they said.

The authors also addressed clinical implications of the findings, and mechanisms of resistance to PI3k inhibitors. For example, they noted that:

–Bruton’s tyrosine kinase (BTK) inhibitors may be beneficial when added to R-CHOP.

In the randomized phase 3 PHOENIX trial, ibrutinib plus R-CHOP versus R-CHOP alone in patients with non–germinal center B-cell (non-GCB) DLBCL showed a survival benefit in patients over 60 years of age, which suggests a possible role for “an intensified R-CHOP regimen that includes a BTK inhibitor” in these patients, they said. They added that confirmatory trials are under way, including the ESCALADE trial looking at the second-generation BTK inhibitor acalabrutinib combined with R-CHOP versus R-CHOP alone in patients with untreated DLBCL.

–Results have been mixed with PI3K inhibitors.

Various PI3K inhibitors have been evaluated for the treatment of patients with DLBCL.

Idelalisib, a first-in-class PI3K-specific inhibitor approved for treatment of relapsed/refractory (r/r) follicular lymphoma, small lymphocytic lymphoma, and chronic lymphocytic leukemia (CLL), showed only modest activity in preclinical DLBCL models, and no responses were detectable in a small trial of patients with r/r DLBCL, the authors said. “Severe toxic side effects and treatment-related deaths occurred in several clinical trials that tested idelalisib in combination with antibodies alone or with antibodies and chemotherapy, leading to the premature discontinuation of some of these studies,” they noted.

Other studies investigating idelalisib plus lenalidomide and rituximab or the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with r/r CLL or lymphoma were also halted because of “overwhelming, immune-mediated pulmonary and/or hepatic toxicities.”

Copanlisib, an intravenous pan-class I PI3K inhibitor with preferential inhibition of PI3Ka and PI3Kd, showed some promise as monotherapy in a phase 2 trial of patients with r/r DLBCL. The overall response rate was about 20%, and response was “numerically higher” in activated B-cell like (ABC) DLBCL, compared with GCB DLBCL (32% vs. 13%), confirming preclinical data that showed PI3Ka/d inhibition effectiveness mainly in ABC DLBCL.

“Compared with idelalisib, copanlisib appears to have a more favorable toxicity profile, with a lower incidence of severe complications,” they said, adding that a phase 2 trial of copanlisib plus R-CHOP as first-line therapy for patients with DLBCL is under way.

Further, monotherapy with buparlisib, a pan-class I PI3K inhibitor, was associated with a low response rate of 11.5% in a DLBCL subcohort in a phase 2 study, whereas parsaclisib, a next-generation inhibitor with specificity to the PI3Kd isoform, showed efficacy as a monotherapy in patients with r/r DLBCL in a phase 2 study (overall response rate, 25.5%), they said, adding that other PI3K inhibitors with additional inhibitory effects are under clinical development.

–Various molecular mechanisms of resistance to PI3K inhibitors have been described preclinically and clinically.

In an unbiased exploratory analysis of samples from patients treated with copanlisib, a 16-gene mutation signature that separated responders from nonresponders was identified, the authors said.

The finding suggests that genetic aberrations dictate response to PI3K inhibitors, they noted.

“This 16-gene signature included TNFAIP3, CREBBP, and PRDM1, which are known to be important in the molecular pathogenesis of DLBCL,” they wrote. A composite score was developed to reflect the numerical presence or absence of mutations in the gene set, they explained, adding that patients with a high composite score had a significantly higher overall response rate and longer progression-free survival than did patients with a lower score.

In addition, idelalisib treatment resulted in a feedback activation of PI3Ka in ABC DLBCL cells.

“This rebound of PI3K activity was overcome by subsequent PI3Ka inhibition in preclinical DLBCL models, further underscoring the necessity of inhibiting both PI3Ka and PI3Kd to achieve responses in ABC DLBCL,” they wrote, adding that “[i]n ABC DLBCL models treated with the PI3Ka/PI3Kd inhibitor AZD8835, activated CARD11 mutations were identified as a mechanism of resistance.”

Investigations looking at various treatment combinations to overcome resistance to PI3K inhibition and improve the efficacy of targeted approaches are under way, they said.

For example, copanlisib plus the BCL-2 inhibitor venetoclax showed “synergistic activity in BCR-dependent DLBCLs, with genetic bases for BCL-2 dysregulation in vitro and in vivo,” and combination treatment with umbralisib and the proteasome inhibitor carfilzomib showed synergistic cytotoxicity in B-cell lymphoma, they said, noting that the latter combination is currently being evaluated in patients with DLBCL.

This work was supported by a research grant from the Deutsche Krebshilfe. Dr. Xu reported having no financial disclosures.

[email protected]

Targeted agents for the treatment of diffuse large B-cell lymphoma (DLBCL) should be used in the context of oncogenic addictions within the lymphoma cells, and a thorough molecular analysis should be conducted prior to using specific agents, a review of the relevant literature suggests.

“In addition ... single-agent regimens are most likely not efficient enough to substantially improve the outcome of patients with DLBCL,” Wendan Xu and colleagues at University Hospital Munster, Germany, concluded, based on their review.

Indeed, novel combinations that include B-cell receptor (BCR) signaling and phosphatidylinositol 3-kinase (PI3K) inhibitors are needed for DLBCL treatment, and treatment should also include conventional chemoimmunotherapeutic regimens as well as other targeted agents and novel immunologic approaches, they wrote. Such novel combinations could overcome mechanisms of resistance and increase cure rates in individuals with DLBCL, they contended.

The authors’ observations are based on a search of the available data, from which they summarized the “current understanding of BCR signaling with a special focus on the PI3K pathway and its role in the pathogenesis of DLBCL.”

The addition of the anti-CD20 antibody rituximab to the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) significantly improved outcomes for patients with DLBCL, but about a third of patients are not cured by the rituximab-CHOP (R-CHOP) regimen and subsequent therapies, they said, explaining their rationale for the review.

“A better understanding of the molecular pathogenesis is warranted to use novel targeted agents in an optimal manner,” they said.

The authors also addressed clinical implications of the findings, and mechanisms of resistance to PI3k inhibitors. For example, they noted that:

–Bruton’s tyrosine kinase (BTK) inhibitors may be beneficial when added to R-CHOP.

In the randomized phase 3 PHOENIX trial, ibrutinib plus R-CHOP versus R-CHOP alone in patients with non–germinal center B-cell (non-GCB) DLBCL showed a survival benefit in patients over 60 years of age, which suggests a possible role for “an intensified R-CHOP regimen that includes a BTK inhibitor” in these patients, they said. They added that confirmatory trials are under way, including the ESCALADE trial looking at the second-generation BTK inhibitor acalabrutinib combined with R-CHOP versus R-CHOP alone in patients with untreated DLBCL.

–Results have been mixed with PI3K inhibitors.

Various PI3K inhibitors have been evaluated for the treatment of patients with DLBCL.

Idelalisib, a first-in-class PI3K-specific inhibitor approved for treatment of relapsed/refractory (r/r) follicular lymphoma, small lymphocytic lymphoma, and chronic lymphocytic leukemia (CLL), showed only modest activity in preclinical DLBCL models, and no responses were detectable in a small trial of patients with r/r DLBCL, the authors said. “Severe toxic side effects and treatment-related deaths occurred in several clinical trials that tested idelalisib in combination with antibodies alone or with antibodies and chemotherapy, leading to the premature discontinuation of some of these studies,” they noted.

Other studies investigating idelalisib plus lenalidomide and rituximab or the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with r/r CLL or lymphoma were also halted because of “overwhelming, immune-mediated pulmonary and/or hepatic toxicities.”

Copanlisib, an intravenous pan-class I PI3K inhibitor with preferential inhibition of PI3Ka and PI3Kd, showed some promise as monotherapy in a phase 2 trial of patients with r/r DLBCL. The overall response rate was about 20%, and response was “numerically higher” in activated B-cell like (ABC) DLBCL, compared with GCB DLBCL (32% vs. 13%), confirming preclinical data that showed PI3Ka/d inhibition effectiveness mainly in ABC DLBCL.

“Compared with idelalisib, copanlisib appears to have a more favorable toxicity profile, with a lower incidence of severe complications,” they said, adding that a phase 2 trial of copanlisib plus R-CHOP as first-line therapy for patients with DLBCL is under way.

Further, monotherapy with buparlisib, a pan-class I PI3K inhibitor, was associated with a low response rate of 11.5% in a DLBCL subcohort in a phase 2 study, whereas parsaclisib, a next-generation inhibitor with specificity to the PI3Kd isoform, showed efficacy as a monotherapy in patients with r/r DLBCL in a phase 2 study (overall response rate, 25.5%), they said, adding that other PI3K inhibitors with additional inhibitory effects are under clinical development.

–Various molecular mechanisms of resistance to PI3K inhibitors have been described preclinically and clinically.

In an unbiased exploratory analysis of samples from patients treated with copanlisib, a 16-gene mutation signature that separated responders from nonresponders was identified, the authors said.

The finding suggests that genetic aberrations dictate response to PI3K inhibitors, they noted.

“This 16-gene signature included TNFAIP3, CREBBP, and PRDM1, which are known to be important in the molecular pathogenesis of DLBCL,” they wrote. A composite score was developed to reflect the numerical presence or absence of mutations in the gene set, they explained, adding that patients with a high composite score had a significantly higher overall response rate and longer progression-free survival than did patients with a lower score.

In addition, idelalisib treatment resulted in a feedback activation of PI3Ka in ABC DLBCL cells.

“This rebound of PI3K activity was overcome by subsequent PI3Ka inhibition in preclinical DLBCL models, further underscoring the necessity of inhibiting both PI3Ka and PI3Kd to achieve responses in ABC DLBCL,” they wrote, adding that “[i]n ABC DLBCL models treated with the PI3Ka/PI3Kd inhibitor AZD8835, activated CARD11 mutations were identified as a mechanism of resistance.”

Investigations looking at various treatment combinations to overcome resistance to PI3K inhibition and improve the efficacy of targeted approaches are under way, they said.

For example, copanlisib plus the BCL-2 inhibitor venetoclax showed “synergistic activity in BCR-dependent DLBCLs, with genetic bases for BCL-2 dysregulation in vitro and in vivo,” and combination treatment with umbralisib and the proteasome inhibitor carfilzomib showed synergistic cytotoxicity in B-cell lymphoma, they said, noting that the latter combination is currently being evaluated in patients with DLBCL.

This work was supported by a research grant from the Deutsche Krebshilfe. Dr. Xu reported having no financial disclosures.

[email protected]

The overall survival benefit with durvalumab plus etoposide and cisplatin/carboplatin versus EP alone for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) as demonstrated in the phase 3 CASPIAN trial was sustained beyond 3 years, according to a planned exploratory analysis.

The durable overall survival (OS) benefit and the well-tolerated safety profile of the durvalumab with EP therapy further establishes the combination as the standard of care for the first-line treatment of ES-SCLC, Luis Paz-Ares, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 18 (abstract LBA61).

At 3 years, there is more than three times the survival in patients with durvalumab and EP versus EP, and at the same time, the adverse-event profile continues to be favorable,” said Dr. Paz-Ares of Universidad Complutense & Ciberonc, Madrid.

This is the longest follow-up reported to date for a phase 3 trial of a programmed death–ligand 1 inhibitor and EP in this setting, he said.

The CASPIAN trial included 805 treatment-naive patients with ES-SCLC who were randomized 1:1:1 to receive 1,500 mg of durvalumab with EP every 3 weeks, 1,500 mg of durvalumab at 75 mg of tremelimumab and EP every 3 weeks, or EP alone. Patients in the durvalumab arms received four cycles of treatment followed by maintenance durvalumab, and those in the EP-only arm received up to six cycles of EP.

Primary outcomes data from the trial showed a significant overall survival benefit with durvalumab and EP versus EP alone (hazard ratio, 0.73), as did a subsequent analysis after a median follow-up of 25.1 mo (HR, 0.75).

Durvalumab with tremelimumab and EP numerically improved overall survival versus EP (HR, 0.82), but did not reach statistical significance.

At median follow up of 39.4 months, the durvalumab and EP combination showed sustained improvement in overall survival versus EP alone (HR, 0.71).

Median overall survival was 12.9 versus 10.5 months. OS was 22.9% versus 13.9% at 24 months, and 17.6% versus 5.8% at 36 months with durvalumab with EP versus EP, respectively, Dr. Paz-Ares said.

Durvalumab plus tremelimumab plus EP continued to numerically improve overall survival, compared with EP alone (HR, 0.81); median OS in that arm was 10.4 months, and 15.3% of patients were alive at 36 months, he noted.

Serious adverse events occurred in 32.5%, 47.4%, and 36.5% of patients in the durvalumab with EP, durvalumab plus tremelimumab plus EP, and EP arms respectively, and adverse events leading to death occurred in 5.3%, 10.9%, and 6.0%, respectively.

The findings are “really encouraging and unprecedented, frankly,” said session chair Alfredo Addeo, MD, of University Hospital, Geneva.

“They are setting the bar for competitors,” he said, referencing the IMpower 133 trial looking at atezolizumab with chemotherapy in ES-SCLC.

The CASPIAN study was funded by AstraZeneca. Dr. Paz-Ares reported relationships with multiple pharmaceutical companies.

[email protected]

The overall survival benefit with durvalumab plus etoposide and cisplatin/carboplatin versus EP alone for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) as demonstrated in the phase 3 CASPIAN trial was sustained beyond 3 years, according to a planned exploratory analysis.

The durable overall survival (OS) benefit and the well-tolerated safety profile of the durvalumab with EP therapy further establishes the combination as the standard of care for the first-line treatment of ES-SCLC, Luis Paz-Ares, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 18 (abstract LBA61).

At 3 years, there is more than three times the survival in patients with durvalumab and EP versus EP, and at the same time, the adverse-event profile continues to be favorable,” said Dr. Paz-Ares of Universidad Complutense & Ciberonc, Madrid.

This is the longest follow-up reported to date for a phase 3 trial of a programmed death–ligand 1 inhibitor and EP in this setting, he said.

The CASPIAN trial included 805 treatment-naive patients with ES-SCLC who were randomized 1:1:1 to receive 1,500 mg of durvalumab with EP every 3 weeks, 1,500 mg of durvalumab at 75 mg of tremelimumab and EP every 3 weeks, or EP alone. Patients in the durvalumab arms received four cycles of treatment followed by maintenance durvalumab, and those in the EP-only arm received up to six cycles of EP.

Primary outcomes data from the trial showed a significant overall survival benefit with durvalumab and EP versus EP alone (hazard ratio, 0.73), as did a subsequent analysis after a median follow-up of 25.1 mo (HR, 0.75).

Durvalumab with tremelimumab and EP numerically improved overall survival versus EP (HR, 0.82), but did not reach statistical significance.

At median follow up of 39.4 months, the durvalumab and EP combination showed sustained improvement in overall survival versus EP alone (HR, 0.71).

Median overall survival was 12.9 versus 10.5 months. OS was 22.9% versus 13.9% at 24 months, and 17.6% versus 5.8% at 36 months with durvalumab with EP versus EP, respectively, Dr. Paz-Ares said.

Durvalumab plus tremelimumab plus EP continued to numerically improve overall survival, compared with EP alone (HR, 0.81); median OS in that arm was 10.4 months, and 15.3% of patients were alive at 36 months, he noted.

Serious adverse events occurred in 32.5%, 47.4%, and 36.5% of patients in the durvalumab with EP, durvalumab plus tremelimumab plus EP, and EP arms respectively, and adverse events leading to death occurred in 5.3%, 10.9%, and 6.0%, respectively.

The findings are “really encouraging and unprecedented, frankly,” said session chair Alfredo Addeo, MD, of University Hospital, Geneva.

“They are setting the bar for competitors,” he said, referencing the IMpower 133 trial looking at atezolizumab with chemotherapy in ES-SCLC.

The CASPIAN study was funded by AstraZeneca. Dr. Paz-Ares reported relationships with multiple pharmaceutical companies.

[email protected]

The overall survival benefit with durvalumab plus etoposide and cisplatin/carboplatin versus EP alone for the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) as demonstrated in the phase 3 CASPIAN trial was sustained beyond 3 years, according to a planned exploratory analysis.

The durable overall survival (OS) benefit and the well-tolerated safety profile of the durvalumab with EP therapy further establishes the combination as the standard of care for the first-line treatment of ES-SCLC, Luis Paz-Ares, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 18 (abstract LBA61).

At 3 years, there is more than three times the survival in patients with durvalumab and EP versus EP, and at the same time, the adverse-event profile continues to be favorable,” said Dr. Paz-Ares of Universidad Complutense & Ciberonc, Madrid.

This is the longest follow-up reported to date for a phase 3 trial of a programmed death–ligand 1 inhibitor and EP in this setting, he said.

The CASPIAN trial included 805 treatment-naive patients with ES-SCLC who were randomized 1:1:1 to receive 1,500 mg of durvalumab with EP every 3 weeks, 1,500 mg of durvalumab at 75 mg of tremelimumab and EP every 3 weeks, or EP alone. Patients in the durvalumab arms received four cycles of treatment followed by maintenance durvalumab, and those in the EP-only arm received up to six cycles of EP.

Primary outcomes data from the trial showed a significant overall survival benefit with durvalumab and EP versus EP alone (hazard ratio, 0.73), as did a subsequent analysis after a median follow-up of 25.1 mo (HR, 0.75).

Durvalumab with tremelimumab and EP numerically improved overall survival versus EP (HR, 0.82), but did not reach statistical significance.

At median follow up of 39.4 months, the durvalumab and EP combination showed sustained improvement in overall survival versus EP alone (HR, 0.71).

Median overall survival was 12.9 versus 10.5 months. OS was 22.9% versus 13.9% at 24 months, and 17.6% versus 5.8% at 36 months with durvalumab with EP versus EP, respectively, Dr. Paz-Ares said.

Durvalumab plus tremelimumab plus EP continued to numerically improve overall survival, compared with EP alone (HR, 0.81); median OS in that arm was 10.4 months, and 15.3% of patients were alive at 36 months, he noted.

Serious adverse events occurred in 32.5%, 47.4%, and 36.5% of patients in the durvalumab with EP, durvalumab plus tremelimumab plus EP, and EP arms respectively, and adverse events leading to death occurred in 5.3%, 10.9%, and 6.0%, respectively.

The findings are “really encouraging and unprecedented, frankly,” said session chair Alfredo Addeo, MD, of University Hospital, Geneva.

“They are setting the bar for competitors,” he said, referencing the IMpower 133 trial looking at atezolizumab with chemotherapy in ES-SCLC.

The CASPIAN study was funded by AstraZeneca. Dr. Paz-Ares reported relationships with multiple pharmaceutical companies.

[email protected]

Patients with hematologic malignancies who are seronegative after full SARS-CoV-2 vaccination may benefit from a booster, but breakthrough infections will remain a risk, particularly in those with B-cell malignancies, an observational study suggests.

The findings, based on a review of COVID-19 booster vaccine recipients with B cell–derived hematologic malignancies from the prospective Leukemia & Lymphoma Society National Registry, provide valuable information about booster vaccinations in this vulnerable population, according to LLS chief medical officer and lead study author Gwen Nichols, MD.
 

The LLS Registry data

Of 49 patients included in the review, 38 failed to make antispike (anti-S) antibodies after full vaccination, and of those, 21 seroconverted after booster vaccination and 11 experienced seroelevation after the booster.

The patients who did not seroconvert were seronegative after initial vaccination and experienced no change in antibody level after the booster vaccination. In contrast, the 21 who seroconverted had a median 23.1 AU/ml increase in antibody level, Dr. Nichols, along with LLS chief scientific officer Lee M. Greenberger, PhD,and their colleagues reported online Sept. 6, 2021, in Cancer Cell.

Similar proportions of seroconverted patients had low-level responses between 2.2 and 23.1 AU/mL and robust response between 125 and 2,500 AU/mL, they noted. The 11 patients with seroelevation were seropositive after full vaccination and demonstrated a median increase of 2,128 AU/mL in antibody level after the booster vaccination.
 

Therapy effects on vaccine response

Outcomes of the current analysis also confirmed the authors’ previous finding, which suggested that “both disease and therapies can affect the serological response to vaccination,” they wrote, explaining that, among the 12 patients who received no malignancy-targeted treatments in the past 2 years, only 1 was a nonresponder, 7 demonstrated seroconversion, and 4 demonstrated seroelevation.

“In contrast, among the 21 patients who completed therapy with anti-CD20 antibodies either alone or in combination with other therapies, 12 patients were nonresponders, 7 patients demonstrated seroconversion, and 2 patients demonstrated seroelevation,” they added.

The authors also noted that five of seven patients who completed anti-CD20 antibody therapy alone or in combination with chemotherapy at least 7 months prior to the booster vaccination demonstrated seroconversion or seroelevation, whereas many of the patients with recent or maintenance anti-CD20 antibody therapy before the booster vaccination failed to seroconvert afterward.

In light of previous findings showing B-cell recovery begins 6-9 months after rituximab therapy, these data suggest that recent anti-CD20 antibody-containing treatment regimens may suppress booster vaccination response, the authors wrote.

The current data also support the group’s prior finding that use of a Bruton tyrosine kinase inhibitor may suppress vaccine response: Of the patients in the current study who experienced seroelevation and were treated with a BTKi, two discontinued BTKi therapy 7-23 months prior to booster vaccination, one maintained a low dose of ibrutinib before booster vaccination, one maintained BTKi therapy continuously before and after the booster, and the two who experienced marked seroconversion after booster vaccination stopped BTKi therapy at least 4 months prior.

Conversely, five patients with a very weak seroconversion and two patients with moderate seroconversion maintained BTKi therapy during booster vaccination.

“These data suggest that BTKi therapy can interfere with a response to booster vaccination,” they wrote, noting, however, that “it is encouraging that seven patients ... maintained on a BTKi seroconverted or experienced seroelevation after booster vaccination and [this] is consistent with a previous report on one patient.”
 

Study limitations and lessons

Although the findings of this study are limited by the small number of patients, the fact that treatment and disease were patient reported, and a lack of data on “antibody responses, particularly to the delta variant, B-cell memory, or T-cell responses,” they nevertheless provide encouraging news, Dr. Nichols told this news organization.

“Many blood cancer patients are getting boosters and a good number are able to make antibody with an additional dose. This is giving us much needed information about boosters,” she said. “Through the LLS National Patient Registry, we anticipate having data on hundreds of more patients over the course of the next few months.”

The information is needed because data suggest that up to 25% of patients with hematologic malignancies fail to make anti-S antibodies after full COVID-19 vaccination and that seronegative patients may be especially vulnerable to breakthrough infections, she and her colleagues noted.

Patients with B-cell malignancies are at the highest risk, and this is particularly concerning as some patients with blood cancer who contracted COVID-19 in the prevaccine period of the pandemic had “prolonged, severe infections; generated variant strains; and demonstrated significantly higher mortality rates compared to the general population,” they said.

However, a recently published placebo-controlled trial that demonstrated a booster vaccination–mediated increase in anti-S antibodies and neutralizing antibodies in immunosuppressed patients, and the current review, which focused on patients who obtained booster vaccinations prior to Aug. 12, 2021 (when the Food and Drug Administration granted emergency use authorization for booster doses in immunocompromised people), offer findings that suggest these patients may benefit from receiving COVID-19 boosters.

“We conclude that some patients with hematologic malignancies who are seronegative after a full course of vaccination may benefit from a booster,” the authors wrote. They added a warning: “Regulators, patients, and health care providers should be aware that a sizable subset of patients with blood cancer may remain at risk of breakthrough COVID-19 infections after full vaccination followed by booster vaccination.”

Dr. Nichols stressed that the findings “do not in any way suggest that blood cancer patients should stop therapy to get an antibody response to the vaccinations.”

“LLS is encouraging blood cancer patients to get vaccinated and to continue taking preventive measures such as wearing masks, social distancing, hand washing, and avoiding crowds and poorly ventilated indoor spaces,” she said.

Sergio Giralt, MD, professor and deputy head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center, New York, further emphasized the importance of preventive measures.

“I think the extra booster will go a long way to protect our patients at this time but should not be used as a replacement for masking indoors and continued social distancing in this vulnerable patient population,” he said.

This study was supported by the LLS.

[email protected]

Patients with hematologic malignancies who are seronegative after full SARS-CoV-2 vaccination may benefit from a booster, but breakthrough infections will remain a risk, particularly in those with B-cell malignancies, an observational study suggests.

The findings, based on a review of COVID-19 booster vaccine recipients with B cell–derived hematologic malignancies from the prospective Leukemia & Lymphoma Society National Registry, provide valuable information about booster vaccinations in this vulnerable population, according to LLS chief medical officer and lead study author Gwen Nichols, MD.
 

The LLS Registry data

Of 49 patients included in the review, 38 failed to make antispike (anti-S) antibodies after full vaccination, and of those, 21 seroconverted after booster vaccination and 11 experienced seroelevation after the booster.

The patients who did not seroconvert were seronegative after initial vaccination and experienced no change in antibody level after the booster vaccination. In contrast, the 21 who seroconverted had a median 23.1 AU/ml increase in antibody level, Dr. Nichols, along with LLS chief scientific officer Lee M. Greenberger, PhD,and their colleagues reported online Sept. 6, 2021, in Cancer Cell.

Similar proportions of seroconverted patients had low-level responses between 2.2 and 23.1 AU/mL and robust response between 125 and 2,500 AU/mL, they noted. The 11 patients with seroelevation were seropositive after full vaccination and demonstrated a median increase of 2,128 AU/mL in antibody level after the booster vaccination.
 

Therapy effects on vaccine response

Outcomes of the current analysis also confirmed the authors’ previous finding, which suggested that “both disease and therapies can affect the serological response to vaccination,” they wrote, explaining that, among the 12 patients who received no malignancy-targeted treatments in the past 2 years, only 1 was a nonresponder, 7 demonstrated seroconversion, and 4 demonstrated seroelevation.

“In contrast, among the 21 patients who completed therapy with anti-CD20 antibodies either alone or in combination with other therapies, 12 patients were nonresponders, 7 patients demonstrated seroconversion, and 2 patients demonstrated seroelevation,” they added.

The authors also noted that five of seven patients who completed anti-CD20 antibody therapy alone or in combination with chemotherapy at least 7 months prior to the booster vaccination demonstrated seroconversion or seroelevation, whereas many of the patients with recent or maintenance anti-CD20 antibody therapy before the booster vaccination failed to seroconvert afterward.

In light of previous findings showing B-cell recovery begins 6-9 months after rituximab therapy, these data suggest that recent anti-CD20 antibody-containing treatment regimens may suppress booster vaccination response, the authors wrote.

The current data also support the group’s prior finding that use of a Bruton tyrosine kinase inhibitor may suppress vaccine response: Of the patients in the current study who experienced seroelevation and were treated with a BTKi, two discontinued BTKi therapy 7-23 months prior to booster vaccination, one maintained a low dose of ibrutinib before booster vaccination, one maintained BTKi therapy continuously before and after the booster, and the two who experienced marked seroconversion after booster vaccination stopped BTKi therapy at least 4 months prior.

Conversely, five patients with a very weak seroconversion and two patients with moderate seroconversion maintained BTKi therapy during booster vaccination.

“These data suggest that BTKi therapy can interfere with a response to booster vaccination,” they wrote, noting, however, that “it is encouraging that seven patients ... maintained on a BTKi seroconverted or experienced seroelevation after booster vaccination and [this] is consistent with a previous report on one patient.”
 

Study limitations and lessons

Although the findings of this study are limited by the small number of patients, the fact that treatment and disease were patient reported, and a lack of data on “antibody responses, particularly to the delta variant, B-cell memory, or T-cell responses,” they nevertheless provide encouraging news, Dr. Nichols told this news organization.

“Many blood cancer patients are getting boosters and a good number are able to make antibody with an additional dose. This is giving us much needed information about boosters,” she said. “Through the LLS National Patient Registry, we anticipate having data on hundreds of more patients over the course of the next few months.”

The information is needed because data suggest that up to 25% of patients with hematologic malignancies fail to make anti-S antibodies after full COVID-19 vaccination and that seronegative patients may be especially vulnerable to breakthrough infections, she and her colleagues noted.

Patients with B-cell malignancies are at the highest risk, and this is particularly concerning as some patients with blood cancer who contracted COVID-19 in the prevaccine period of the pandemic had “prolonged, severe infections; generated variant strains; and demonstrated significantly higher mortality rates compared to the general population,” they said.

However, a recently published placebo-controlled trial that demonstrated a booster vaccination–mediated increase in anti-S antibodies and neutralizing antibodies in immunosuppressed patients, and the current review, which focused on patients who obtained booster vaccinations prior to Aug. 12, 2021 (when the Food and Drug Administration granted emergency use authorization for booster doses in immunocompromised people), offer findings that suggest these patients may benefit from receiving COVID-19 boosters.

“We conclude that some patients with hematologic malignancies who are seronegative after a full course of vaccination may benefit from a booster,” the authors wrote. They added a warning: “Regulators, patients, and health care providers should be aware that a sizable subset of patients with blood cancer may remain at risk of breakthrough COVID-19 infections after full vaccination followed by booster vaccination.”

Dr. Nichols stressed that the findings “do not in any way suggest that blood cancer patients should stop therapy to get an antibody response to the vaccinations.”

“LLS is encouraging blood cancer patients to get vaccinated and to continue taking preventive measures such as wearing masks, social distancing, hand washing, and avoiding crowds and poorly ventilated indoor spaces,” she said.

Sergio Giralt, MD, professor and deputy head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center, New York, further emphasized the importance of preventive measures.

“I think the extra booster will go a long way to protect our patients at this time but should not be used as a replacement for masking indoors and continued social distancing in this vulnerable patient population,” he said.

This study was supported by the LLS.

[email protected]

Patients with hematologic malignancies who are seronegative after full SARS-CoV-2 vaccination may benefit from a booster, but breakthrough infections will remain a risk, particularly in those with B-cell malignancies, an observational study suggests.

The findings, based on a review of COVID-19 booster vaccine recipients with B cell–derived hematologic malignancies from the prospective Leukemia & Lymphoma Society National Registry, provide valuable information about booster vaccinations in this vulnerable population, according to LLS chief medical officer and lead study author Gwen Nichols, MD.
 

The LLS Registry data

Of 49 patients included in the review, 38 failed to make antispike (anti-S) antibodies after full vaccination, and of those, 21 seroconverted after booster vaccination and 11 experienced seroelevation after the booster.

The patients who did not seroconvert were seronegative after initial vaccination and experienced no change in antibody level after the booster vaccination. In contrast, the 21 who seroconverted had a median 23.1 AU/ml increase in antibody level, Dr. Nichols, along with LLS chief scientific officer Lee M. Greenberger, PhD,and their colleagues reported online Sept. 6, 2021, in Cancer Cell.

Similar proportions of seroconverted patients had low-level responses between 2.2 and 23.1 AU/mL and robust response between 125 and 2,500 AU/mL, they noted. The 11 patients with seroelevation were seropositive after full vaccination and demonstrated a median increase of 2,128 AU/mL in antibody level after the booster vaccination.
 

Therapy effects on vaccine response

Outcomes of the current analysis also confirmed the authors’ previous finding, which suggested that “both disease and therapies can affect the serological response to vaccination,” they wrote, explaining that, among the 12 patients who received no malignancy-targeted treatments in the past 2 years, only 1 was a nonresponder, 7 demonstrated seroconversion, and 4 demonstrated seroelevation.

“In contrast, among the 21 patients who completed therapy with anti-CD20 antibodies either alone or in combination with other therapies, 12 patients were nonresponders, 7 patients demonstrated seroconversion, and 2 patients demonstrated seroelevation,” they added.

The authors also noted that five of seven patients who completed anti-CD20 antibody therapy alone or in combination with chemotherapy at least 7 months prior to the booster vaccination demonstrated seroconversion or seroelevation, whereas many of the patients with recent or maintenance anti-CD20 antibody therapy before the booster vaccination failed to seroconvert afterward.

In light of previous findings showing B-cell recovery begins 6-9 months after rituximab therapy, these data suggest that recent anti-CD20 antibody-containing treatment regimens may suppress booster vaccination response, the authors wrote.

The current data also support the group’s prior finding that use of a Bruton tyrosine kinase inhibitor may suppress vaccine response: Of the patients in the current study who experienced seroelevation and were treated with a BTKi, two discontinued BTKi therapy 7-23 months prior to booster vaccination, one maintained a low dose of ibrutinib before booster vaccination, one maintained BTKi therapy continuously before and after the booster, and the two who experienced marked seroconversion after booster vaccination stopped BTKi therapy at least 4 months prior.

Conversely, five patients with a very weak seroconversion and two patients with moderate seroconversion maintained BTKi therapy during booster vaccination.

“These data suggest that BTKi therapy can interfere with a response to booster vaccination,” they wrote, noting, however, that “it is encouraging that seven patients ... maintained on a BTKi seroconverted or experienced seroelevation after booster vaccination and [this] is consistent with a previous report on one patient.”
 

Study limitations and lessons

Although the findings of this study are limited by the small number of patients, the fact that treatment and disease were patient reported, and a lack of data on “antibody responses, particularly to the delta variant, B-cell memory, or T-cell responses,” they nevertheless provide encouraging news, Dr. Nichols told this news organization.

“Many blood cancer patients are getting boosters and a good number are able to make antibody with an additional dose. This is giving us much needed information about boosters,” she said. “Through the LLS National Patient Registry, we anticipate having data on hundreds of more patients over the course of the next few months.”

The information is needed because data suggest that up to 25% of patients with hematologic malignancies fail to make anti-S antibodies after full COVID-19 vaccination and that seronegative patients may be especially vulnerable to breakthrough infections, she and her colleagues noted.

Patients with B-cell malignancies are at the highest risk, and this is particularly concerning as some patients with blood cancer who contracted COVID-19 in the prevaccine period of the pandemic had “prolonged, severe infections; generated variant strains; and demonstrated significantly higher mortality rates compared to the general population,” they said.

However, a recently published placebo-controlled trial that demonstrated a booster vaccination–mediated increase in anti-S antibodies and neutralizing antibodies in immunosuppressed patients, and the current review, which focused on patients who obtained booster vaccinations prior to Aug. 12, 2021 (when the Food and Drug Administration granted emergency use authorization for booster doses in immunocompromised people), offer findings that suggest these patients may benefit from receiving COVID-19 boosters.

“We conclude that some patients with hematologic malignancies who are seronegative after a full course of vaccination may benefit from a booster,” the authors wrote. They added a warning: “Regulators, patients, and health care providers should be aware that a sizable subset of patients with blood cancer may remain at risk of breakthrough COVID-19 infections after full vaccination followed by booster vaccination.”

Dr. Nichols stressed that the findings “do not in any way suggest that blood cancer patients should stop therapy to get an antibody response to the vaccinations.”

“LLS is encouraging blood cancer patients to get vaccinated and to continue taking preventive measures such as wearing masks, social distancing, hand washing, and avoiding crowds and poorly ventilated indoor spaces,” she said.

Sergio Giralt, MD, professor and deputy head of the division of hematologic malignancies at Memorial Sloan Kettering Cancer Center, New York, further emphasized the importance of preventive measures.

“I think the extra booster will go a long way to protect our patients at this time but should not be used as a replacement for masking indoors and continued social distancing in this vulnerable patient population,” he said.

This study was supported by the LLS.

[email protected]

The extent of pathological response to neoadjuvant immune checkpoint inhibition independently predicted overall survival (OS) and disease-free survival (DFS) in patients with early-stage non–small cell lung cancer (NSCLC) in the phase 2 IFCT-1601 IONESCO trial.

Although major pathological response after neoadjuvant cisplatin-based chemotherapy has been shown to predict survival in patients with early-stage NSCLC, this is the first time a similar association has been demonstrated with neoadjuvant immune checkpoint inhibition, Marie Wislez, MD, PhD, a researcher at Hopital Cochin, Paris, reported at the 2021 European Society of Medical Oncology Congress.

Primary outcomes of the multicenter trial showed 12- and 18-month OS of 89.1%, and 12- and 18-month DFS of 78.3% and 73.7%, respectively, in 46 patients treated with preoperative durvalumab. Median OS and DFS were not reached.

Major pathological response was observed in eight patients (18.6%), with three patients experiencing complete pathological response. No deaths or recurrences were observed in patients in this group. A significant association was observed between major pathological response and DFS. However, the study was stopped early because of excessive 90-day postoperative mortality, which the authors said were most likely related to comorbidities.

The current post hoc analysis of data from the study showed poorer overall survival and disease-free survival with increasing percentage of residual viable tumor (RVT) cells on multivariate prognostic analysis (hazard ratio, 1.05 and 1.06; P = .04 and .02, respectively), Dr. Wislez said in her presentation made on Sept. 18 (abstract 1151MO).

“For each 10% increase of RVT, you have an increased risk of death of 64% and increased risk of recurrence of 71%,” she said.

Study subjects, who were enrolled between April 2017 and August 2019, had a median age of 61 years, 67.4% were men, 98% were smokers or former smokes, and all had Eastern Cooperative Oncology Group performance status scores of 0-1. The median percentage of RVT cells was 36.11.

Of the 50 patients enrolled, 46 were eligible for and received durvalumab and 43 underwent surgery. Those with stages IB and 4 cm or greater tumor size to stage IIIA non-N2 NSCLC received three cycles of durvalumab before surgery. Durvalumab was given intravenously at a dose of 750 mg on days 1, 15, and 29, and surgery was performed 2-14 days after the last infusion.

Tissue specimens from patients who underwent neoadjuvant durvalumab and complete surgical resection were retrospectively evaluated by two pathologists blinded to patient outcomes, Dr. Wislez noted.

Session chair Michael Thomas, MD, of Thoraxklinik-Heidelberg at Heidelberg (Germany) University Hospital, described the study as “hypotheses generating,” and noted that it suggests incremental step-wise assessment of pathological response could be an additional tool for subgrouping of patients in upcoming trials.

Indeed, this novel finding suggests that the extent of pathological response could be considered as a surrogate marker for neoadjuvant treatment trials, although the use of a continuous variable would be challenging in the trial setting, Dr. Wislez agreed.

“But it’s a demonstration that [with] immunotherapy monotherapy ... the extent of pathological response is associated with overall survival,” she said.

This study was funded by AstraZeneca. Dr. Wislez reported honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche, Novartis, Merck, and MSD.

[email protected]

The extent of pathological response to neoadjuvant immune checkpoint inhibition independently predicted overall survival (OS) and disease-free survival (DFS) in patients with early-stage non–small cell lung cancer (NSCLC) in the phase 2 IFCT-1601 IONESCO trial.

Although major pathological response after neoadjuvant cisplatin-based chemotherapy has been shown to predict survival in patients with early-stage NSCLC, this is the first time a similar association has been demonstrated with neoadjuvant immune checkpoint inhibition, Marie Wislez, MD, PhD, a researcher at Hopital Cochin, Paris, reported at the 2021 European Society of Medical Oncology Congress.

Primary outcomes of the multicenter trial showed 12- and 18-month OS of 89.1%, and 12- and 18-month DFS of 78.3% and 73.7%, respectively, in 46 patients treated with preoperative durvalumab. Median OS and DFS were not reached.

Major pathological response was observed in eight patients (18.6%), with three patients experiencing complete pathological response. No deaths or recurrences were observed in patients in this group. A significant association was observed between major pathological response and DFS. However, the study was stopped early because of excessive 90-day postoperative mortality, which the authors said were most likely related to comorbidities.

The current post hoc analysis of data from the study showed poorer overall survival and disease-free survival with increasing percentage of residual viable tumor (RVT) cells on multivariate prognostic analysis (hazard ratio, 1.05 and 1.06; P = .04 and .02, respectively), Dr. Wislez said in her presentation made on Sept. 18 (abstract 1151MO).

“For each 10% increase of RVT, you have an increased risk of death of 64% and increased risk of recurrence of 71%,” she said.

Study subjects, who were enrolled between April 2017 and August 2019, had a median age of 61 years, 67.4% were men, 98% were smokers or former smokes, and all had Eastern Cooperative Oncology Group performance status scores of 0-1. The median percentage of RVT cells was 36.11.

Of the 50 patients enrolled, 46 were eligible for and received durvalumab and 43 underwent surgery. Those with stages IB and 4 cm or greater tumor size to stage IIIA non-N2 NSCLC received three cycles of durvalumab before surgery. Durvalumab was given intravenously at a dose of 750 mg on days 1, 15, and 29, and surgery was performed 2-14 days after the last infusion.

Tissue specimens from patients who underwent neoadjuvant durvalumab and complete surgical resection were retrospectively evaluated by two pathologists blinded to patient outcomes, Dr. Wislez noted.

Session chair Michael Thomas, MD, of Thoraxklinik-Heidelberg at Heidelberg (Germany) University Hospital, described the study as “hypotheses generating,” and noted that it suggests incremental step-wise assessment of pathological response could be an additional tool for subgrouping of patients in upcoming trials.

Indeed, this novel finding suggests that the extent of pathological response could be considered as a surrogate marker for neoadjuvant treatment trials, although the use of a continuous variable would be challenging in the trial setting, Dr. Wislez agreed.

“But it’s a demonstration that [with] immunotherapy monotherapy ... the extent of pathological response is associated with overall survival,” she said.

This study was funded by AstraZeneca. Dr. Wislez reported honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche, Novartis, Merck, and MSD.

[email protected]

The extent of pathological response to neoadjuvant immune checkpoint inhibition independently predicted overall survival (OS) and disease-free survival (DFS) in patients with early-stage non–small cell lung cancer (NSCLC) in the phase 2 IFCT-1601 IONESCO trial.

Although major pathological response after neoadjuvant cisplatin-based chemotherapy has been shown to predict survival in patients with early-stage NSCLC, this is the first time a similar association has been demonstrated with neoadjuvant immune checkpoint inhibition, Marie Wislez, MD, PhD, a researcher at Hopital Cochin, Paris, reported at the 2021 European Society of Medical Oncology Congress.

Primary outcomes of the multicenter trial showed 12- and 18-month OS of 89.1%, and 12- and 18-month DFS of 78.3% and 73.7%, respectively, in 46 patients treated with preoperative durvalumab. Median OS and DFS were not reached.

Major pathological response was observed in eight patients (18.6%), with three patients experiencing complete pathological response. No deaths or recurrences were observed in patients in this group. A significant association was observed between major pathological response and DFS. However, the study was stopped early because of excessive 90-day postoperative mortality, which the authors said were most likely related to comorbidities.

The current post hoc analysis of data from the study showed poorer overall survival and disease-free survival with increasing percentage of residual viable tumor (RVT) cells on multivariate prognostic analysis (hazard ratio, 1.05 and 1.06; P = .04 and .02, respectively), Dr. Wislez said in her presentation made on Sept. 18 (abstract 1151MO).

“For each 10% increase of RVT, you have an increased risk of death of 64% and increased risk of recurrence of 71%,” she said.

Study subjects, who were enrolled between April 2017 and August 2019, had a median age of 61 years, 67.4% were men, 98% were smokers or former smokes, and all had Eastern Cooperative Oncology Group performance status scores of 0-1. The median percentage of RVT cells was 36.11.

Of the 50 patients enrolled, 46 were eligible for and received durvalumab and 43 underwent surgery. Those with stages IB and 4 cm or greater tumor size to stage IIIA non-N2 NSCLC received three cycles of durvalumab before surgery. Durvalumab was given intravenously at a dose of 750 mg on days 1, 15, and 29, and surgery was performed 2-14 days after the last infusion.

Tissue specimens from patients who underwent neoadjuvant durvalumab and complete surgical resection were retrospectively evaluated by two pathologists blinded to patient outcomes, Dr. Wislez noted.

Session chair Michael Thomas, MD, of Thoraxklinik-Heidelberg at Heidelberg (Germany) University Hospital, described the study as “hypotheses generating,” and noted that it suggests incremental step-wise assessment of pathological response could be an additional tool for subgrouping of patients in upcoming trials.

Indeed, this novel finding suggests that the extent of pathological response could be considered as a surrogate marker for neoadjuvant treatment trials, although the use of a continuous variable would be challenging in the trial setting, Dr. Wislez agreed.

“But it’s a demonstration that [with] immunotherapy monotherapy ... the extent of pathological response is associated with overall survival,” she said.

This study was funded by AstraZeneca. Dr. Wislez reported honoraria from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche, Novartis, Merck, and MSD.

[email protected]

Checkpoint inhibition for consolidation after chemoradiotherapy (CRT) showed promising survival benefit in patients with unresectable stage III non–small cell lung cancer (NSCLC) in two recent studies, including one looking at the investigational agent sugemalimab and one assessing durvalumab in a real-world setting.

Statistically significant and clinically meaningful improvement in progression-free survival (PFS) was observed with sugemalimab versus placebo in the randomized, phase 3 GEMSTONE-301 study, and consolidation durvalumab showed effectiveness in a real-world cohort in the PACIFIC-R study.

Findings from both studies were presented at the 2021 European Society for Medical Oncology Congress.
 

GEMSTONE-301

Median progression-free survival among 381 patients randomized 2:1 to receive 1,200 mg of sugemalimab or placebo every 3 weeks after either concurrent or sequential chemoradiotherapy was 9.0 versus 5.8 months, in the treatment arms, respectively (hazard ratio, 0.64) (Abstract LBA43), reported Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.

Patients were recruited from 50 sites, and one-third had received sequential CRT. Progression-free survival was assessed at median follow up of 14 months.

“The 12- and 18-month PFS rates were 45% vs. 26% and 39% vs. 23%, respectively,” Dr. Wu said.

Of note, the PFS benefit was observed both for patients who underwent sequential CRT (median PFS, 8.1 vs. 4.1 months with sugemalimab vs. placebo; hazard ratio, 0.59) and for those who received concurrent CRT (median PFS, 10.5 vs. 6.4 months; HR, 0.66).

Overall survival (OS) data were not mature at the time of the presentation, but a trend favoring sugemalimab was observed (HR, 0.44) he noted.

Sugemalimab, an investigational anti–programmed death-ligand 1 (PD-L1 )monoclonal antibody, was well tolerated; grade 3 or higher treatment-emergent adverse events (AEs) occurred in 24.3% of patients in the sugemalimab group and in 23.8% in the placebo group.

Concurrent chemoradiotherapy followed by immunotherapy is the standard of care for patients with unresectable stage III NSCLC, but nearly half undergo sequential CRT because they can’t tolerate concurrent treatment, Dr. Wu explained, describing the rationale for the study – the first phase 3 trial looking at both concurrent and sequential CRT in this patient population.

The results provide evidence for sugemalimab as a consolidation treatment for those who did not progress following either approach to CRT, he concluded.
 

PACIFIC-R study

The large, international, observational PACIFIC-R study also looked at consolidation in a real-world setting, and confirmed a PFS benefit with durvalumab in stage III NSCLC patients who had completed concurrent or sequential platinum-based CRT within the previous 12 weeks without evidence of disease progression (Abstract 1171MO).

“The median real-world PFS in this cohort was 21.7 months, which is higher than that in the durvalumab arm in the PACIFIC trial, which was 16.9 months,” reported Nicolas Girard, MD, a professor at Institut Curie, Paris.

The PACIFIC trial set the standard for durvalumab-based consolidation after CRT, and ongoing survival benefit was confirmed by 5-year follow-up data, he noted.

The PACIFIC-R trial included 1,399 patients from 11 countries who were treated as part of an expanded-access program following the PACIFIC trial.

Median time to durvalumab initiation after the end of radiotherapy in the cohort was 56 days. Overall median durvalumab treatment duration was 11 months, and the median number of infusions was 22, Dr. Girard said.

Pneumonitis was the most common adverse event leading to discontinuation: 214 (18.5%) patients experienced any-grade pneumonitis and/or interstitial lung disease, and 9.5 discontinued the study as a result. Most cases were mild or moderate, he said.

Subgroup analyses showed that real-world PFS was higher among patients with stage IIIa disease and those with PD-L1–positive tumors, those with nonsquamous disease histology, and those who received concurrent CRT.

“For example, in those with stage IIIa disease, the median real-world PFS was 23.7 months versus 19.2 months in patients with stage IIIb and c disease,” he said.

“PACIFIC-R demonstrated the efficacy of durvalumab consolidation in patients with unresectable stage III non–small cell lung cancer after completion of chemoradiotherapy,” said Dr. Girard. “The effectiveness of durvalumab was consistent among key subgroups, as was safety, when comparing the data with that of PACIFIC.

“The future read-outs of OS will further provide insight into the effectiveness of this regimen.”

Session chair Lizza E. Hendriks, MD, PhD, of Maastricht (the Netherlands) University, applauded the inclusion of patients undergoing sequential CRT in the GEMSTONE-301 and PACIFIC-R studies, noting that it is “very important to have data in sequential radiochemotherapy populations” given the substantial number of patients who require a sequential approach because of poor performance status, difficulty tolerating concurrent CRT, or logistical reasons, such as an inability to travel to receive concurrent CRT.

The GEMSTONE-301 study was funded by CStone Pharmaceuticals. Dr. Wu reported having no disclosures. The PACIFIC-R study was funded by AstraZeneca. Dr. Girard reported financial relationships with AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Hendriks reported financial relationships with numerous companies.

[email protected]

Checkpoint inhibition for consolidation after chemoradiotherapy (CRT) showed promising survival benefit in patients with unresectable stage III non–small cell lung cancer (NSCLC) in two recent studies, including one looking at the investigational agent sugemalimab and one assessing durvalumab in a real-world setting.

Statistically significant and clinically meaningful improvement in progression-free survival (PFS) was observed with sugemalimab versus placebo in the randomized, phase 3 GEMSTONE-301 study, and consolidation durvalumab showed effectiveness in a real-world cohort in the PACIFIC-R study.

Findings from both studies were presented at the 2021 European Society for Medical Oncology Congress.
 

GEMSTONE-301

Median progression-free survival among 381 patients randomized 2:1 to receive 1,200 mg of sugemalimab or placebo every 3 weeks after either concurrent or sequential chemoradiotherapy was 9.0 versus 5.8 months, in the treatment arms, respectively (hazard ratio, 0.64) (Abstract LBA43), reported Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.

Patients were recruited from 50 sites, and one-third had received sequential CRT. Progression-free survival was assessed at median follow up of 14 months.

“The 12- and 18-month PFS rates were 45% vs. 26% and 39% vs. 23%, respectively,” Dr. Wu said.

Of note, the PFS benefit was observed both for patients who underwent sequential CRT (median PFS, 8.1 vs. 4.1 months with sugemalimab vs. placebo; hazard ratio, 0.59) and for those who received concurrent CRT (median PFS, 10.5 vs. 6.4 months; HR, 0.66).

Overall survival (OS) data were not mature at the time of the presentation, but a trend favoring sugemalimab was observed (HR, 0.44) he noted.

Sugemalimab, an investigational anti–programmed death-ligand 1 (PD-L1 )monoclonal antibody, was well tolerated; grade 3 or higher treatment-emergent adverse events (AEs) occurred in 24.3% of patients in the sugemalimab group and in 23.8% in the placebo group.

Concurrent chemoradiotherapy followed by immunotherapy is the standard of care for patients with unresectable stage III NSCLC, but nearly half undergo sequential CRT because they can’t tolerate concurrent treatment, Dr. Wu explained, describing the rationale for the study – the first phase 3 trial looking at both concurrent and sequential CRT in this patient population.

The results provide evidence for sugemalimab as a consolidation treatment for those who did not progress following either approach to CRT, he concluded.
 

PACIFIC-R study

The large, international, observational PACIFIC-R study also looked at consolidation in a real-world setting, and confirmed a PFS benefit with durvalumab in stage III NSCLC patients who had completed concurrent or sequential platinum-based CRT within the previous 12 weeks without evidence of disease progression (Abstract 1171MO).

“The median real-world PFS in this cohort was 21.7 months, which is higher than that in the durvalumab arm in the PACIFIC trial, which was 16.9 months,” reported Nicolas Girard, MD, a professor at Institut Curie, Paris.

The PACIFIC trial set the standard for durvalumab-based consolidation after CRT, and ongoing survival benefit was confirmed by 5-year follow-up data, he noted.

The PACIFIC-R trial included 1,399 patients from 11 countries who were treated as part of an expanded-access program following the PACIFIC trial.

Median time to durvalumab initiation after the end of radiotherapy in the cohort was 56 days. Overall median durvalumab treatment duration was 11 months, and the median number of infusions was 22, Dr. Girard said.

Pneumonitis was the most common adverse event leading to discontinuation: 214 (18.5%) patients experienced any-grade pneumonitis and/or interstitial lung disease, and 9.5 discontinued the study as a result. Most cases were mild or moderate, he said.

Subgroup analyses showed that real-world PFS was higher among patients with stage IIIa disease and those with PD-L1–positive tumors, those with nonsquamous disease histology, and those who received concurrent CRT.

“For example, in those with stage IIIa disease, the median real-world PFS was 23.7 months versus 19.2 months in patients with stage IIIb and c disease,” he said.

“PACIFIC-R demonstrated the efficacy of durvalumab consolidation in patients with unresectable stage III non–small cell lung cancer after completion of chemoradiotherapy,” said Dr. Girard. “The effectiveness of durvalumab was consistent among key subgroups, as was safety, when comparing the data with that of PACIFIC.

“The future read-outs of OS will further provide insight into the effectiveness of this regimen.”

Session chair Lizza E. Hendriks, MD, PhD, of Maastricht (the Netherlands) University, applauded the inclusion of patients undergoing sequential CRT in the GEMSTONE-301 and PACIFIC-R studies, noting that it is “very important to have data in sequential radiochemotherapy populations” given the substantial number of patients who require a sequential approach because of poor performance status, difficulty tolerating concurrent CRT, or logistical reasons, such as an inability to travel to receive concurrent CRT.

The GEMSTONE-301 study was funded by CStone Pharmaceuticals. Dr. Wu reported having no disclosures. The PACIFIC-R study was funded by AstraZeneca. Dr. Girard reported financial relationships with AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Hendriks reported financial relationships with numerous companies.

[email protected]

Checkpoint inhibition for consolidation after chemoradiotherapy (CRT) showed promising survival benefit in patients with unresectable stage III non–small cell lung cancer (NSCLC) in two recent studies, including one looking at the investigational agent sugemalimab and one assessing durvalumab in a real-world setting.

Statistically significant and clinically meaningful improvement in progression-free survival (PFS) was observed with sugemalimab versus placebo in the randomized, phase 3 GEMSTONE-301 study, and consolidation durvalumab showed effectiveness in a real-world cohort in the PACIFIC-R study.

Findings from both studies were presented at the 2021 European Society for Medical Oncology Congress.
 

GEMSTONE-301

Median progression-free survival among 381 patients randomized 2:1 to receive 1,200 mg of sugemalimab or placebo every 3 weeks after either concurrent or sequential chemoradiotherapy was 9.0 versus 5.8 months, in the treatment arms, respectively (hazard ratio, 0.64) (Abstract LBA43), reported Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Guangzhou, China.

Patients were recruited from 50 sites, and one-third had received sequential CRT. Progression-free survival was assessed at median follow up of 14 months.

“The 12- and 18-month PFS rates were 45% vs. 26% and 39% vs. 23%, respectively,” Dr. Wu said.

Of note, the PFS benefit was observed both for patients who underwent sequential CRT (median PFS, 8.1 vs. 4.1 months with sugemalimab vs. placebo; hazard ratio, 0.59) and for those who received concurrent CRT (median PFS, 10.5 vs. 6.4 months; HR, 0.66).

Overall survival (OS) data were not mature at the time of the presentation, but a trend favoring sugemalimab was observed (HR, 0.44) he noted.

Sugemalimab, an investigational anti–programmed death-ligand 1 (PD-L1 )monoclonal antibody, was well tolerated; grade 3 or higher treatment-emergent adverse events (AEs) occurred in 24.3% of patients in the sugemalimab group and in 23.8% in the placebo group.

Concurrent chemoradiotherapy followed by immunotherapy is the standard of care for patients with unresectable stage III NSCLC, but nearly half undergo sequential CRT because they can’t tolerate concurrent treatment, Dr. Wu explained, describing the rationale for the study – the first phase 3 trial looking at both concurrent and sequential CRT in this patient population.

The results provide evidence for sugemalimab as a consolidation treatment for those who did not progress following either approach to CRT, he concluded.
 

PACIFIC-R study

The large, international, observational PACIFIC-R study also looked at consolidation in a real-world setting, and confirmed a PFS benefit with durvalumab in stage III NSCLC patients who had completed concurrent or sequential platinum-based CRT within the previous 12 weeks without evidence of disease progression (Abstract 1171MO).

“The median real-world PFS in this cohort was 21.7 months, which is higher than that in the durvalumab arm in the PACIFIC trial, which was 16.9 months,” reported Nicolas Girard, MD, a professor at Institut Curie, Paris.

The PACIFIC trial set the standard for durvalumab-based consolidation after CRT, and ongoing survival benefit was confirmed by 5-year follow-up data, he noted.

The PACIFIC-R trial included 1,399 patients from 11 countries who were treated as part of an expanded-access program following the PACIFIC trial.

Median time to durvalumab initiation after the end of radiotherapy in the cohort was 56 days. Overall median durvalumab treatment duration was 11 months, and the median number of infusions was 22, Dr. Girard said.

Pneumonitis was the most common adverse event leading to discontinuation: 214 (18.5%) patients experienced any-grade pneumonitis and/or interstitial lung disease, and 9.5 discontinued the study as a result. Most cases were mild or moderate, he said.

Subgroup analyses showed that real-world PFS was higher among patients with stage IIIa disease and those with PD-L1–positive tumors, those with nonsquamous disease histology, and those who received concurrent CRT.

“For example, in those with stage IIIa disease, the median real-world PFS was 23.7 months versus 19.2 months in patients with stage IIIb and c disease,” he said.

“PACIFIC-R demonstrated the efficacy of durvalumab consolidation in patients with unresectable stage III non–small cell lung cancer after completion of chemoradiotherapy,” said Dr. Girard. “The effectiveness of durvalumab was consistent among key subgroups, as was safety, when comparing the data with that of PACIFIC.

“The future read-outs of OS will further provide insight into the effectiveness of this regimen.”

Session chair Lizza E. Hendriks, MD, PhD, of Maastricht (the Netherlands) University, applauded the inclusion of patients undergoing sequential CRT in the GEMSTONE-301 and PACIFIC-R studies, noting that it is “very important to have data in sequential radiochemotherapy populations” given the substantial number of patients who require a sequential approach because of poor performance status, difficulty tolerating concurrent CRT, or logistical reasons, such as an inability to travel to receive concurrent CRT.

The GEMSTONE-301 study was funded by CStone Pharmaceuticals. Dr. Wu reported having no disclosures. The PACIFIC-R study was funded by AstraZeneca. Dr. Girard reported financial relationships with AstraZeneca, Bristol Myers Squibb, and Merck Sharp & Dohme. Dr. Hendriks reported financial relationships with numerous companies.

[email protected]

Foregoing chemotherapy in favor of cancer immunotherapy (CIT) alone for the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) and high programmed death–ligand 1 (PD-L1) expression did not impact survival outcomes in a retrospective cohort of U.S. patients – except in a subgroup of nonsmokers.

Median overall survival was similar at 21.0 months and 22.1 months in 169 patients who received cancer immunotherapy plus chemotherapy and 351 who received cancer immunotherapy monotherapy, respectively (adjusted hazard ratio, 1.03). Median real-world progression-free survival (PFS) was also similar in the two groups (10.8 vs. 11.5 months; aHR, 1.04), Solange Peters, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 17 (abstract VP2_2021).

However, in a small subgroup of 50 never-smokers, CIT plus chemotherapy showed significant and meaningful improvement in both overall survival and real-world progression-free survival, compared with CIT monotherapy, said Dr. Peters, ESMO president and professor and chair of medical oncology at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The hazard ratios for overall survival and progression-free survival, after adjusting for baseline characteristics, were 0.50 and 0.40 in this subgroup, Dr. Peters said.

She and her colleagues reviewed data from the nationwide Flatiron Health Electronic Health Record–derived deidentified database for patients with metastatic nonsquamous NSCLC with a PD-L1 tumor proportion score at least 50% expression who initiated first-line CIT monotherapy or CIT plus chemotherapy between Oct. 24, 2016, and Feb. 28, 2019.

Median follow-up was 23.5 and 19.9 months in the monotherapy and combination therapy groups, respectively.

The findings are notable because “this is a very important scientific question, which by the way, is a daily question we have,” Dr. Peters said during a plenary debate session at the conference.

“One in four patients [with metastatic nonsquamous NSCLC has] this high PDL expression,” she explained, noting that both treatment approaches are commonly used in the first-line setting in this patient population.

The findings highlight the value of “well-conducted real-world evidence trials” in the absence of randomized trial results, she said.

Invited discussant Marina Chiara Garassino, MBBS, professor of medicine at the University of Chicago, also acknowledged the importance of the findings, noting the “multiple possibilities” for treatment selection in the metastatic nonsquamous NSCLC patient population.

Although patients with PD-L1 expression below 50% derive clear benefit from combination versus single-agent therapy, treatment selection for those with high PD-L1 expression is “very tricky and debatable,” she said.

For those with high PD-L1 expression, the choice is less clear and wrought with uncertainties – particularly for certain subgroups like never-smokers and those with PD-L1 expression over 90%, she said.

The findings reinforce those seen in prior meta-analyses and other clinical trials, particularly with respect to the role of smoking history when making treatment decisions.

“After these results and previous subgroup analyses, in my opinion, in [patients with] PD-L1 expression over 50%, we should consider the combination of chemotherapy and immunotherapy,” she said.

Conversely, findings from this study showing no difference in outcomes between the treatment approaches in patients with brain or liver metastases are based on small numbers and lack power for drawing any conclusions, she said. It also remains unclear whether there is a differential effect for women and those with PD-L1 expression over 90%, high tumor mutation burden, performance score greater than 2, and age over 75 years.

Both Dr. Garassino and Dr. Peters said they are looking to the INSIGNA trial, which is currently recruiting patients in the United States to evaluate the timing of pembrolizumab alone or with chemotherapy as first-line treatment and maintenance in NSCLC, to provide more clarification regarding the best treatment approaches.

This study was funded by F. Hoffmann–La Roche. Dr. Peters and Dr. Garassino each disclosed personal and/or institutional financial relationships with numerous pharmaceutical companies.

[email protected]

Foregoing chemotherapy in favor of cancer immunotherapy (CIT) alone for the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) and high programmed death–ligand 1 (PD-L1) expression did not impact survival outcomes in a retrospective cohort of U.S. patients – except in a subgroup of nonsmokers.

Median overall survival was similar at 21.0 months and 22.1 months in 169 patients who received cancer immunotherapy plus chemotherapy and 351 who received cancer immunotherapy monotherapy, respectively (adjusted hazard ratio, 1.03). Median real-world progression-free survival (PFS) was also similar in the two groups (10.8 vs. 11.5 months; aHR, 1.04), Solange Peters, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 17 (abstract VP2_2021).

However, in a small subgroup of 50 never-smokers, CIT plus chemotherapy showed significant and meaningful improvement in both overall survival and real-world progression-free survival, compared with CIT monotherapy, said Dr. Peters, ESMO president and professor and chair of medical oncology at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The hazard ratios for overall survival and progression-free survival, after adjusting for baseline characteristics, were 0.50 and 0.40 in this subgroup, Dr. Peters said.

She and her colleagues reviewed data from the nationwide Flatiron Health Electronic Health Record–derived deidentified database for patients with metastatic nonsquamous NSCLC with a PD-L1 tumor proportion score at least 50% expression who initiated first-line CIT monotherapy or CIT plus chemotherapy between Oct. 24, 2016, and Feb. 28, 2019.

Median follow-up was 23.5 and 19.9 months in the monotherapy and combination therapy groups, respectively.

The findings are notable because “this is a very important scientific question, which by the way, is a daily question we have,” Dr. Peters said during a plenary debate session at the conference.

“One in four patients [with metastatic nonsquamous NSCLC has] this high PDL expression,” she explained, noting that both treatment approaches are commonly used in the first-line setting in this patient population.

The findings highlight the value of “well-conducted real-world evidence trials” in the absence of randomized trial results, she said.

Invited discussant Marina Chiara Garassino, MBBS, professor of medicine at the University of Chicago, also acknowledged the importance of the findings, noting the “multiple possibilities” for treatment selection in the metastatic nonsquamous NSCLC patient population.

Although patients with PD-L1 expression below 50% derive clear benefit from combination versus single-agent therapy, treatment selection for those with high PD-L1 expression is “very tricky and debatable,” she said.

For those with high PD-L1 expression, the choice is less clear and wrought with uncertainties – particularly for certain subgroups like never-smokers and those with PD-L1 expression over 90%, she said.

The findings reinforce those seen in prior meta-analyses and other clinical trials, particularly with respect to the role of smoking history when making treatment decisions.

“After these results and previous subgroup analyses, in my opinion, in [patients with] PD-L1 expression over 50%, we should consider the combination of chemotherapy and immunotherapy,” she said.

Conversely, findings from this study showing no difference in outcomes between the treatment approaches in patients with brain or liver metastases are based on small numbers and lack power for drawing any conclusions, she said. It also remains unclear whether there is a differential effect for women and those with PD-L1 expression over 90%, high tumor mutation burden, performance score greater than 2, and age over 75 years.

Both Dr. Garassino and Dr. Peters said they are looking to the INSIGNA trial, which is currently recruiting patients in the United States to evaluate the timing of pembrolizumab alone or with chemotherapy as first-line treatment and maintenance in NSCLC, to provide more clarification regarding the best treatment approaches.

This study was funded by F. Hoffmann–La Roche. Dr. Peters and Dr. Garassino each disclosed personal and/or institutional financial relationships with numerous pharmaceutical companies.

[email protected]

Foregoing chemotherapy in favor of cancer immunotherapy (CIT) alone for the first-line treatment of patients with metastatic nonsquamous non–small cell lung cancer (NSCLC) and high programmed death–ligand 1 (PD-L1) expression did not impact survival outcomes in a retrospective cohort of U.S. patients – except in a subgroup of nonsmokers.

Median overall survival was similar at 21.0 months and 22.1 months in 169 patients who received cancer immunotherapy plus chemotherapy and 351 who received cancer immunotherapy monotherapy, respectively (adjusted hazard ratio, 1.03). Median real-world progression-free survival (PFS) was also similar in the two groups (10.8 vs. 11.5 months; aHR, 1.04), Solange Peters, MD, reported at the 2021 European Society for Medical Oncology Congress on Sept. 17 (abstract VP2_2021).

However, in a small subgroup of 50 never-smokers, CIT plus chemotherapy showed significant and meaningful improvement in both overall survival and real-world progression-free survival, compared with CIT monotherapy, said Dr. Peters, ESMO president and professor and chair of medical oncology at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The hazard ratios for overall survival and progression-free survival, after adjusting for baseline characteristics, were 0.50 and 0.40 in this subgroup, Dr. Peters said.

She and her colleagues reviewed data from the nationwide Flatiron Health Electronic Health Record–derived deidentified database for patients with metastatic nonsquamous NSCLC with a PD-L1 tumor proportion score at least 50% expression who initiated first-line CIT monotherapy or CIT plus chemotherapy between Oct. 24, 2016, and Feb. 28, 2019.

Median follow-up was 23.5 and 19.9 months in the monotherapy and combination therapy groups, respectively.

The findings are notable because “this is a very important scientific question, which by the way, is a daily question we have,” Dr. Peters said during a plenary debate session at the conference.

“One in four patients [with metastatic nonsquamous NSCLC has] this high PDL expression,” she explained, noting that both treatment approaches are commonly used in the first-line setting in this patient population.

The findings highlight the value of “well-conducted real-world evidence trials” in the absence of randomized trial results, she said.

Invited discussant Marina Chiara Garassino, MBBS, professor of medicine at the University of Chicago, also acknowledged the importance of the findings, noting the “multiple possibilities” for treatment selection in the metastatic nonsquamous NSCLC patient population.

Although patients with PD-L1 expression below 50% derive clear benefit from combination versus single-agent therapy, treatment selection for those with high PD-L1 expression is “very tricky and debatable,” she said.

For those with high PD-L1 expression, the choice is less clear and wrought with uncertainties – particularly for certain subgroups like never-smokers and those with PD-L1 expression over 90%, she said.

The findings reinforce those seen in prior meta-analyses and other clinical trials, particularly with respect to the role of smoking history when making treatment decisions.

“After these results and previous subgroup analyses, in my opinion, in [patients with] PD-L1 expression over 50%, we should consider the combination of chemotherapy and immunotherapy,” she said.

Conversely, findings from this study showing no difference in outcomes between the treatment approaches in patients with brain or liver metastases are based on small numbers and lack power for drawing any conclusions, she said. It also remains unclear whether there is a differential effect for women and those with PD-L1 expression over 90%, high tumor mutation burden, performance score greater than 2, and age over 75 years.

Both Dr. Garassino and Dr. Peters said they are looking to the INSIGNA trial, which is currently recruiting patients in the United States to evaluate the timing of pembrolizumab alone or with chemotherapy as first-line treatment and maintenance in NSCLC, to provide more clarification regarding the best treatment approaches.

This study was funded by F. Hoffmann–La Roche. Dr. Peters and Dr. Garassino each disclosed personal and/or institutional financial relationships with numerous pharmaceutical companies.

[email protected]

Combination bevacizumab and osimertinib provided no progression-free survival benefit over osimertinib alone for the first-line treatment of advanced epidermal growth factor receptor (EGFR)–mutated nonsquamous non–small cell lung cancer (NSCLC) in patients in an open-label, phase 2 study.

Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).

“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.

However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.

Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.

Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.

The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.

Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.

Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.

The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.

“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.

“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”

The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”

This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.

This article was updated Sept. 24, 2021.

[email protected]

Combination bevacizumab and osimertinib provided no progression-free survival benefit over osimertinib alone for the first-line treatment of advanced epidermal growth factor receptor (EGFR)–mutated nonsquamous non–small cell lung cancer (NSCLC) in patients in an open-label, phase 2 study.

Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).

“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.

However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.

Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.

Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.

The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.

Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.

Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.

The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.

“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.

“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”

The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”

This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.

This article was updated Sept. 24, 2021.

[email protected]

Combination bevacizumab and osimertinib provided no progression-free survival benefit over osimertinib alone for the first-line treatment of advanced epidermal growth factor receptor (EGFR)–mutated nonsquamous non–small cell lung cancer (NSCLC) in patients in an open-label, phase 2 study.

Median progression-free survival (PFS) was 20.2 months in 61 patients in the osimertinib monotherapy arm and 22.1 months in 61 patients in the combination treatment arm (hazard ratio, 0.862), Hirotsugu Kenmotsu, MD, PhD, reported at the 2021 Congress of the European Society for Medical Oncology Sept. 18 (abstract LBA44).

“The study did not meet the primary endpoint,” said Dr. Kenmotsu of Shizuoka Cancer Center, Nagaizumi, Japan. “One-year progression-free survival was 63.7% and 73.8%, respectively.

However, subgroup analyses showed a trend toward improved PFS with combination bevacizumab and osimertinib in ever-smokers (HR, 0.481) and patients with Del19 mutations (HR, 0.622), he said.

Bevacizumab was also associated with a significant reduction in the risk of pneumonitis, an interstitial lung disease (ILD): Pneumonitis occurred in 18.3% of patients in the combination therapy arm, compared with 3.3% in the osimertinib monotherapy arm.

Study participants were untreated patients with advanced nonsquamous NSCLC harboring an EGFR-sensitizing mutation – either Del19 or L858R – without symptomatic brain metastases. They were enrolled between January 2018 and September 2018 and randomized to receive 80 mg of osimertinib daily, either alone or with 15 mg/kg of bevacizumab every 3 weeks.

The objective response rate was 82% in the combination therapy arm and 86% in osimertinib monotherapy arm, Dr. Kenmotsu said, adding that overall survival data are not yet mature.

Grade 3-4 adverse events occurred in 34 patients (56%) in the combination therapy arm and in 29 patients (48%) in the osimertinib monotherapy arm, he noted.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor has been a standard first-line treatment for NSCLC harboring activating EGFR mutations, he explained, noting that prior studies have shown promise for improved PFS with the addition of antivascular endothelial growth factor inhibitors to first-generation EGFR TKIs in this population.

Although the current study failed to show efficacy of the combination therapy versus osimertinib monotherapy for improving PFS in nonsquamous NSCLC harboring EGFR mutation, ever-smokers and patients with exon 19 deletions might benefit from the combination therapy as first-line treatment, and the combination might also reduce the risk of osimertinib-related pneumonitis, Dr. Kenmotsu said.

The study is among those that address “really important questions in lung cancer today,” said invited discussant Natasha B. Leighl, MD, professor of medicine at the University of Toronto’s Princess Margaret Cancer Center.

“I certainly agree with the authors that this study is a negative trial and bevacizumab does not improve PFS over the standard of osimertinib alone,” she said, acknowledging that the study is the first randomized comparison of the two treatment approaches in the first-line setting. She also agreed with the authors that the subgroup findings are intriguing.

“But ... what is the biomarker?” she asked, referring to the “very interesting” finding of a possible bevacizumab benefit among ever-smokers. “I’m looking forward to more correlative studies to help define this further.”

The novel finding of a significantly reduced risk of pneumonitis with the addition of bevacizumab, on the other hand, is “extremely exciting,” she said, explaining that the combination therapy approach could “perhaps [be used] as a potential therapy for patients with TKI-induced ILD and no other options, or those at very high risk of ILD, for example, perhaps, post immunotherapy or in high-risk populations.”

This study was funded by AstraZeneca. Dr. Kenmotsu and Dr. Leigh each disclosed financial relationships with numerous pharmaceutical companies.

This article was updated Sept. 24, 2021.

[email protected]

A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.

The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.

The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.

Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.

The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.

As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.

“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”

With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.

“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.

In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).

When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.

However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.

Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.

“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”

The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.

Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.

“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.

Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.

[email protected]

A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.

The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.

The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.

Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.

The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.

As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.

“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”

With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.

“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.

In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).

When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.

However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.

Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.

“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”

The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.

Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.

“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.

Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.

[email protected]

A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.

The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.

The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.

Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.

Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.

The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.

As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.

“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”

With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.

“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.

In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).

When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.

However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.

Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.

“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”

The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.

Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.

“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.

Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.

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