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In this edition of “How I will treat my next patient,” I take a look at two phase 2 trials in stage IV non–small cell lung cancer (NSCLC) patients that appeared recently in JAMA Oncology. One summarizes a trial in stage IV NSCLC with four or fewer sites of metastasis (oligometastatic disease or OM), in which pembrolizumab is added to locally ablative therapy (LAT). The other examines whether LAT potentiates the response to immuno-oncology (I/O) in distant sites that were unexposed to LAT.
I/O added to LAT in OM-NSCLC
Joshua M. Bauml, MD, of the University of Pennsylvania, Philadelphia, and colleagues, published findings from a nonrandomized phase 2 trial in OM-NSCLC in which patients could receive LAT by any technique (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449). Patients could have synchronous or metachronous OM-NSCLC, any histology, and any PD-L1 tumor proportion score. Patients with more than four sites of metastatic disease that regressed to OM-NSCLC after prior therapy (i.e., “oligoremnant NSCLC”) were excluded.
They reported on 51 patients who received conventional-dose pembrolizumab for eight cycles after LAT. Patients without toxicity or progression were allowed to receive up to eight additional cycles of pembrolizumab. The median progression-free survival (PFS) was 19.1 months (95% confidence interval, 9.4-28.7 months), significantly longer than the historical comparison group (median PFS, 6.6 months; P = .005). Additionally, the 24-month overall survival (OS) was 77.5%. With respect to safety, no quality of life decrement or new safety signals were seen.
What this means in practice
As Dr. Bauml and colleagues suggest, there is strong theoretical rationale for believing that OM-NSCLC represents a special, potentially curable, population of stage IV NSCLC patients. Like the recently published work of Daniel R. Gomez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues (J Clin Oncol. 2019 Jun 20;37[18]:1558-65), who studied LAT in comparison with consolidative/maintenance chemotherapy in a slightly different population of OM-NSCLC patients, the current trial moves clinical research forward.
Practically, this study has limitations that should temper a clinician’s enthusiasm for adopting the strategy of LAT, followed by I/O, as standard practice: small patient numbers, most with only one site of OM-NSCLC; comparison with historical controls; and no meaningful information about patient subsets who benefit from I/O and who do not. As the authors suggest, this study provides a strong rationale for a phase 3 trial with stratification for variables that could influence outcome. It does not inform clinical practice at the present time.
LAT added to I/O in stage IV NSCLC
We have limited ability to identify (the majority of) patients with metastatic NSCLC who will not benefit from I/O and no proven interventions to augment benefit in (the majority of) patients with low PD-L1 tumor proportion scores and/or low tumor mutation burden. However, the PEMBRO-RT study was designed to investigate whether LAT with stereotactic body radiation therapy (SBRT) could exploit the hypothesized increase in tumor antigen release and antigen presentation that could lead to better responses to I/O in untreated sites of disease among all patients with stage IV NSCLC.
As reported by Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam and colleagues, the PEMBRO-RT study randomized 76 patients with stage IV NSCLC to pembro following SBRT to a single metastatic site (the experimental arm of the trial) or pembrolizumab alone. Pembrolizumab was given in a conventional dose and schedule in both arms of the trial and was administered within 7 days after SBRT on the experimental arm (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1478).
The primary outcome was the overall response rate (ORR) at 12 weeks. Among patients on the experimental versus control arms, the ORR was 36% and 18%, respectively (P = .07). This did not meet the prespecified endpoint of improving ORR from 20% to 50% at 12 weeks. Additionally, although improved on the pembro plus SBRT arm of the trial, the median PFS and OS did not meet statistical criteria for improvement over the control arm, except among the 47 patients in the PD-L1 negative subset.
What this means in practice
There are a lot of potentially relevant variables in this small, randomized phase 2 study. As the authors discuss, if there is a dose and schedule of RT that facilitates antigen release and presentation and or an ideal latent period after radiotherapy that promotes an “abscopal effect” from I/O, it is unclear whether the ideal schema was used in the PEMBRO-RT trial.
At present, if a patient with stage IV NSCLC requires LAT for clinical reasons during I/O treatment, the patient can receive it safely, but without the expectation that the LAT will augment overall benefit from I/O. Additional preclinical work will need to help guide us about a rational way to design the next trial to test the concept of supra-additive benefit from these modalities. Not only is this combination “not ready for prime time” in clinical care, but it’s not ready for the large numbers of patients in a phase 3 clinical trial.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I take a look at two phase 2 trials in stage IV non–small cell lung cancer (NSCLC) patients that appeared recently in JAMA Oncology. One summarizes a trial in stage IV NSCLC with four or fewer sites of metastasis (oligometastatic disease or OM), in which pembrolizumab is added to locally ablative therapy (LAT). The other examines whether LAT potentiates the response to immuno-oncology (I/O) in distant sites that were unexposed to LAT.
I/O added to LAT in OM-NSCLC
Joshua M. Bauml, MD, of the University of Pennsylvania, Philadelphia, and colleagues, published findings from a nonrandomized phase 2 trial in OM-NSCLC in which patients could receive LAT by any technique (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449). Patients could have synchronous or metachronous OM-NSCLC, any histology, and any PD-L1 tumor proportion score. Patients with more than four sites of metastatic disease that regressed to OM-NSCLC after prior therapy (i.e., “oligoremnant NSCLC”) were excluded.
They reported on 51 patients who received conventional-dose pembrolizumab for eight cycles after LAT. Patients without toxicity or progression were allowed to receive up to eight additional cycles of pembrolizumab. The median progression-free survival (PFS) was 19.1 months (95% confidence interval, 9.4-28.7 months), significantly longer than the historical comparison group (median PFS, 6.6 months; P = .005). Additionally, the 24-month overall survival (OS) was 77.5%. With respect to safety, no quality of life decrement or new safety signals were seen.
What this means in practice
As Dr. Bauml and colleagues suggest, there is strong theoretical rationale for believing that OM-NSCLC represents a special, potentially curable, population of stage IV NSCLC patients. Like the recently published work of Daniel R. Gomez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues (J Clin Oncol. 2019 Jun 20;37[18]:1558-65), who studied LAT in comparison with consolidative/maintenance chemotherapy in a slightly different population of OM-NSCLC patients, the current trial moves clinical research forward.
Practically, this study has limitations that should temper a clinician’s enthusiasm for adopting the strategy of LAT, followed by I/O, as standard practice: small patient numbers, most with only one site of OM-NSCLC; comparison with historical controls; and no meaningful information about patient subsets who benefit from I/O and who do not. As the authors suggest, this study provides a strong rationale for a phase 3 trial with stratification for variables that could influence outcome. It does not inform clinical practice at the present time.
LAT added to I/O in stage IV NSCLC
We have limited ability to identify (the majority of) patients with metastatic NSCLC who will not benefit from I/O and no proven interventions to augment benefit in (the majority of) patients with low PD-L1 tumor proportion scores and/or low tumor mutation burden. However, the PEMBRO-RT study was designed to investigate whether LAT with stereotactic body radiation therapy (SBRT) could exploit the hypothesized increase in tumor antigen release and antigen presentation that could lead to better responses to I/O in untreated sites of disease among all patients with stage IV NSCLC.
As reported by Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam and colleagues, the PEMBRO-RT study randomized 76 patients with stage IV NSCLC to pembro following SBRT to a single metastatic site (the experimental arm of the trial) or pembrolizumab alone. Pembrolizumab was given in a conventional dose and schedule in both arms of the trial and was administered within 7 days after SBRT on the experimental arm (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1478).
The primary outcome was the overall response rate (ORR) at 12 weeks. Among patients on the experimental versus control arms, the ORR was 36% and 18%, respectively (P = .07). This did not meet the prespecified endpoint of improving ORR from 20% to 50% at 12 weeks. Additionally, although improved on the pembro plus SBRT arm of the trial, the median PFS and OS did not meet statistical criteria for improvement over the control arm, except among the 47 patients in the PD-L1 negative subset.
What this means in practice
There are a lot of potentially relevant variables in this small, randomized phase 2 study. As the authors discuss, if there is a dose and schedule of RT that facilitates antigen release and presentation and or an ideal latent period after radiotherapy that promotes an “abscopal effect” from I/O, it is unclear whether the ideal schema was used in the PEMBRO-RT trial.
At present, if a patient with stage IV NSCLC requires LAT for clinical reasons during I/O treatment, the patient can receive it safely, but without the expectation that the LAT will augment overall benefit from I/O. Additional preclinical work will need to help guide us about a rational way to design the next trial to test the concept of supra-additive benefit from these modalities. Not only is this combination “not ready for prime time” in clinical care, but it’s not ready for the large numbers of patients in a phase 3 clinical trial.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.
In this edition of “How I will treat my next patient,” I take a look at two phase 2 trials in stage IV non–small cell lung cancer (NSCLC) patients that appeared recently in JAMA Oncology. One summarizes a trial in stage IV NSCLC with four or fewer sites of metastasis (oligometastatic disease or OM), in which pembrolizumab is added to locally ablative therapy (LAT). The other examines whether LAT potentiates the response to immuno-oncology (I/O) in distant sites that were unexposed to LAT.
I/O added to LAT in OM-NSCLC
Joshua M. Bauml, MD, of the University of Pennsylvania, Philadelphia, and colleagues, published findings from a nonrandomized phase 2 trial in OM-NSCLC in which patients could receive LAT by any technique (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449). Patients could have synchronous or metachronous OM-NSCLC, any histology, and any PD-L1 tumor proportion score. Patients with more than four sites of metastatic disease that regressed to OM-NSCLC after prior therapy (i.e., “oligoremnant NSCLC”) were excluded.
They reported on 51 patients who received conventional-dose pembrolizumab for eight cycles after LAT. Patients without toxicity or progression were allowed to receive up to eight additional cycles of pembrolizumab. The median progression-free survival (PFS) was 19.1 months (95% confidence interval, 9.4-28.7 months), significantly longer than the historical comparison group (median PFS, 6.6 months; P = .005). Additionally, the 24-month overall survival (OS) was 77.5%. With respect to safety, no quality of life decrement or new safety signals were seen.
What this means in practice
As Dr. Bauml and colleagues suggest, there is strong theoretical rationale for believing that OM-NSCLC represents a special, potentially curable, population of stage IV NSCLC patients. Like the recently published work of Daniel R. Gomez, MD, of the University of Texas MD Anderson Cancer Center, Houston, and colleagues (J Clin Oncol. 2019 Jun 20;37[18]:1558-65), who studied LAT in comparison with consolidative/maintenance chemotherapy in a slightly different population of OM-NSCLC patients, the current trial moves clinical research forward.
Practically, this study has limitations that should temper a clinician’s enthusiasm for adopting the strategy of LAT, followed by I/O, as standard practice: small patient numbers, most with only one site of OM-NSCLC; comparison with historical controls; and no meaningful information about patient subsets who benefit from I/O and who do not. As the authors suggest, this study provides a strong rationale for a phase 3 trial with stratification for variables that could influence outcome. It does not inform clinical practice at the present time.
LAT added to I/O in stage IV NSCLC
We have limited ability to identify (the majority of) patients with metastatic NSCLC who will not benefit from I/O and no proven interventions to augment benefit in (the majority of) patients with low PD-L1 tumor proportion scores and/or low tumor mutation burden. However, the PEMBRO-RT study was designed to investigate whether LAT with stereotactic body radiation therapy (SBRT) could exploit the hypothesized increase in tumor antigen release and antigen presentation that could lead to better responses to I/O in untreated sites of disease among all patients with stage IV NSCLC.
As reported by Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam and colleagues, the PEMBRO-RT study randomized 76 patients with stage IV NSCLC to pembro following SBRT to a single metastatic site (the experimental arm of the trial) or pembrolizumab alone. Pembrolizumab was given in a conventional dose and schedule in both arms of the trial and was administered within 7 days after SBRT on the experimental arm (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1478).
The primary outcome was the overall response rate (ORR) at 12 weeks. Among patients on the experimental versus control arms, the ORR was 36% and 18%, respectively (P = .07). This did not meet the prespecified endpoint of improving ORR from 20% to 50% at 12 weeks. Additionally, although improved on the pembro plus SBRT arm of the trial, the median PFS and OS did not meet statistical criteria for improvement over the control arm, except among the 47 patients in the PD-L1 negative subset.
What this means in practice
There are a lot of potentially relevant variables in this small, randomized phase 2 study. As the authors discuss, if there is a dose and schedule of RT that facilitates antigen release and presentation and or an ideal latent period after radiotherapy that promotes an “abscopal effect” from I/O, it is unclear whether the ideal schema was used in the PEMBRO-RT trial.
At present, if a patient with stage IV NSCLC requires LAT for clinical reasons during I/O treatment, the patient can receive it safely, but without the expectation that the LAT will augment overall benefit from I/O. Additional preclinical work will need to help guide us about a rational way to design the next trial to test the concept of supra-additive benefit from these modalities. Not only is this combination “not ready for prime time” in clinical care, but it’s not ready for the large numbers of patients in a phase 3 clinical trial.
Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.