Correspondence
Biomarkers for immune checkpoint inhibitors We read with interest Luana Calabrò and colleagues’1 phase 2 study, which investigated the efficacy, safety, and immunological activity of tremelimumab, an anti-CTLA4 monoclonal antibody, in patients with advanced malignant mesothelioma.1,2 They noted disease control in nine (31%) of the 29 enrolled patients, and proposed CD4-positive, ICOS-positive T cells as a predictive marker of treatment outcome. Although these results are promising, we believe that studies concerning biomarkers for immune checkpoint inhibitors should take another direction. Different checkpoint-targeting drugs have been developed and investigated to overcome the inhibitory signalling pathways that switch off T cells. Besides treatments that act on CTLA4, drugs targeting the programmed death (PD) protein 1 or its ligands PD-L1 and PD-L2, LAG3, HAVCR2, IDO1, CD276, and VTCN1 have now been tested for a wide variety of different cancers.3 However, in view of the low response rates and potential serious side-effects, the development of robust predictive biomarkers is needed. The authors made a clear effort to identify lymphocyte subsets as biomarkers of response. Intriguingly, the increase in peripheral CD4positive, ICOS-positive T cells 30 days after treatment was shown to be a potential predictive marker of tremelimumab treatment outcomes in patients with mesothelioma. An increase in peripheral CD4positive, ICOS-positive T cells after treatment with tremelimumab provides information regarding the T-cell activation induced by CTLA4 blockade. Differences in these T-cell counts after treatment imply differences in the proportion of immunosuppression attributable to CTLA4 expression. www.thelancet.com/oncology Vol 15 January 2014
However, in the present approach the underlying cause of differences in peripheral T-cell activation after treatment with tremelimumab remains unclear and this result can only be obtained after the start of therapy. The investigators did investigate several lymphocyte subgroups at baseline, but the selected populations are non-specific and are not related to the treatment approach. It would have been very informative if the investigators had reported data regarding CTLA4 expression in the tumour or peripheral blood before treatment to gain insights into the mechanisms of treatment response. Without a doubt, biomarkers that can predict response to these checkpoint inhibitors before use are desirable. The part played by different immunosuppressive mechanisms can change during treatment and disease progression dependent on cellular interactions and local signals, clearly affecting the efficacy of any immunotherapy.4 Proper biomarkers for the different immune checkpoint inhibitors enable the selection of the appropriate inhibitors for an optimised, patient-tailored treatment.5 The search for these biomarkers is now warranted by the encouraging clinical activity of tremelimumab in patients with chemotherapy-resistant advanced malignant mesothelioma. We declare that we have no conflicts of interest.
Lysanne A Lievense, Joost P J J Hegmans, *Joachim G J V Aerts [email protected] Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, Netherlands 1
2
3
Calabrò L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 2013; 14: 1104–11. Nowak AK. Immunological checkpoint inhibitors enter adolescence. Lancet Oncol 2013; 14: 1035–07. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252–64.
4
5
Aerts JG, Hegmans JP. Tumor-specific cytotoxic T cells are crucial for efficacy of immunomodulatory antibodies in patients with lung cancer. Cancer Res 2013; 73: 2381–88. Hegmans JP, Aerts JG. Immunological profiling as a means to invigorate personalized cancer therapy. Oncoimmunology 2013; 2: e25236.
Authors’ reply As Lysanne Lievense and colleagues correctly point out, the search for biomarkers that are predictive of response to immune-checkpointblocking monoclonal antibodies is an area of active investigation; however, despite these efforts, no markers to select patients who respond well to treatment with this new category of therapeutic antibodies have yet been identified. Expression of programmed cell death (PD) ligand 1 (PD-L1) by tumour cells seemed to represent an absolute biomarker predictive of response to PD1 and PD-L1 blockade,1 but a sizeable proportion of patients with PD-L1-negative tumours efficiently respond to blocking of PD1 and PD-L1.2 With regards to CTLA4 expression by tumour cells, to the best of our knowledge, no clear-cut data have been reported for cell-surface expression on neoplastic cells; we also investigated the expression of CTLA4 on a panel of nine human mesothelioma cell lines, without identifying it (Calabrò L, Maio M, unpublished data). Nevertheless, even if CTLA4 was expressed on the mesothelioma cells of patients treated in our study, it probably would not have given any therapeutic advantage because of the IgG2 isotype of tremelimumab, which prevents efficient antibody-dependent and complement-dependent cytotoxicity. We have thoroughly investigated the expression of CTLA4 on peripheral blood mononuclear cells collected at baseline from patients with cutaneous melanoma treated with the anti-CTLA4 drug ipilimumab, and did not note any correlation with clinical outcome (Calabrò L, Maio M, unpublished data). e1
Correspondence
We clearly have to continue to explore the complexities of the immune system to identify biomarkers predictive of response to blocking of immune checkpoints, helping to select the best candidates to such treatments. Nevertheless, the specific targeting of immune cells by these antibodies makes these drugs totally different from other therapeutic monoclonal antibodies that bind to antigens on tumour cells; therefore, prediction of patients’ response to such drugs through investigation of dynamic rather than static biomarkers is probably needed. Along these lines, our finding that absolute numbers of circulating CD4-positive, ICOS-positive T cells correlate with a more favourable prognosis in the course of treatment with tremelimumab in patients with mesothelioma identifies a dynamic biomarker, possibly useful to monitor treatment with CTLA4 blockade.3 Additionally, because the absolute number of circulating CD4-positive, ICOS-positive T cells is an early marker in the course of treatment,3 as we also noted in patients with melanoma treated with ipilimumab,4 this marker might eventually become useful to drive treatment continuation or discontinuation with an anti-CTLA4 monoclonal antibody. There are undoubtedly many directions that need to be explored to take full advantage of immune-checkpointblockade therapies, but we have to first acknowledge that these drugs represent a so-called paradigm shift in our immunological and clinical beliefs. MM has served as a consultant, adviser, or both, to Bristol-Myers Squibb, Roche-Genetech, and Medimmune. LC declares that she has no conflicts of interest.
Luana Calabrò, *Michele Maio [email protected] Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, 53100 Siena, Italy 1
e2
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443–54.
2
3
4
Callahan M, Horak CE, Curran MA, et al. Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab. Proc Am Soc Clin Oncol 2013; 31 (suppl): abstr 3003. Calabrò L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 2013; 14: 1104–11. Di Giacomo AM, Calabrò L, Danielli R, et al. Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme. Cancer Immunol Immunother 2013; 62: 1021–28.
Rechallenge with imatinib in GIST: is more always RIGHT? We read with interest the RIGHT study,1 a commendable undertaking in which a statistically significant improvement in progression-free survival (PFS) from 0·9 to 1·8 months was reported for the re-introduction of imatinib, compared with placebo, after progression on treatment with at least imatinib and sunitinib, a practice already recommended in many treatment guidelines. The idea of re-introduction of previous regimens after disease progression, although not entirely new, challenges some longstanding notions in medical oncology. However, we believe that this study shows another more important, and often overlooked, notion within the oncology community—separation of clinically meaningful significance from statistical significance. In the RIGHT trial, although the hazard ratio was impressive (0·46, 95% CI 0·27–0·78, p=0·005), the reported improvement in median PFS was 25 days. The authors attributed the lack of benefit seen for overall survival to the fact that 93% of patients in the placebo group crossed over to imatinib at progression, although any survival benefit could be reasonably assumed to be less than the PFS benefit.
Other measures of potential benefit were also disappointing. More than 90% of patients retreated with imatinib progressed within 4 months, and although the confidence interval around the estimate of PFS suggested that a small number of patients might achieve more meaningful benefit, every patient experienced disease progression by 7 months. Furthermore, no objective responses were reported, although this finding might not accurately reflect treatment activity; adjustment of radiological response criteria or use of PET instead of CT might be an approach worthy of further study in this area. Importantly, the toxicity of the treatment (although manageable) was not trivial, with half of patients reporting grade 3 or 4 toxicity, including 10% with severe (grade 3) or disabling (grade 4) fatigue. That such results are viewed as clearly effective, rather than merely statistically significant (a view also held by the accompanying Comment2), is increasingly common in oncology. The addition of erlotinib to gemcitabine in advanced pancreatic cancer resulted in a statistically significant benefit of only 10 days, but was deemed sufficient to receive approval by the US Food and Drug Administration.3 Although patients with cancer might accept smaller benefits than do physicians,4 clinicians have the responsibility of discussing trial-reported benefits in a meaningful context. The increasing cost of cancer drugs that seem to have limited efficacy is an issue that needs to be addressed by society. Because of the potential cost of delivering imatinib, estimated at up to US$100 000 per year,5 a critical eye is needed to assess whether the costs (financial, toxicity, and opportunity) outweigh the clinical benefit. We await formal estimation of cost-per-qualityadjusted-life-year data, which will be important in considering societal subsidies of this drug. www.thelancet.com/oncology Vol 15 January 2014
Biomarkers for immune checkpoint inhibitors We read with interest Luana Calabrò and colleagues’1 phase 2 study, which investigated the efficacy, safety, and immunological activity of tremelimumab, an anti-CTLA4 monoclonal antibody, in patients with advanced malignant mesothelioma.1,2 They noted disease control in nine (31%) of the 29 enrolled patients, and proposed CD4-positive, ICOS-positive T cells as a predictive marker of treatment outcome. Although these results are promising, we believe that studies concerning biomarkers for immune checkpoint inhibitors should take another direction. Different checkpoint-targeting drugs have been developed and investigated to overcome the inhibitory signalling pathways that switch off T cells. Besides treatments that act on CTLA4, drugs targeting the programmed death (PD) protein 1 or its ligands PD-L1 and PD-L2, LAG3, HAVCR2, IDO1, CD276, and VTCN1 have now been tested for a wide variety of different cancers.3 However, in view of the low response rates and potential serious side-effects, the development of robust predictive biomarkers is needed. The authors made a clear effort to identify lymphocyte subsets as biomarkers of response. Intriguingly, the increase in peripheral CD4positive, ICOS-positive T cells 30 days after treatment was shown to be a potential predictive marker of tremelimumab treatment outcomes in patients with mesothelioma. An increase in peripheral CD4positive, ICOS-positive T cells after treatment with tremelimumab provides information regarding the T-cell activation induced by CTLA4 blockade. Differences in these T-cell counts after treatment imply differences in the proportion of immunosuppression attributable to CTLA4 expression. www.thelancet.com/oncology Vol 15 January 2014
However, in the present approach the underlying cause of differences in peripheral T-cell activation after treatment with tremelimumab remains unclear and this result can only be obtained after the start of therapy. The investigators did investigate several lymphocyte subgroups at baseline, but the selected populations are non-specific and are not related to the treatment approach. It would have been very informative if the investigators had reported data regarding CTLA4 expression in the tumour or peripheral blood before treatment to gain insights into the mechanisms of treatment response. Without a doubt, biomarkers that can predict response to these checkpoint inhibitors before use are desirable. The part played by different immunosuppressive mechanisms can change during treatment and disease progression dependent on cellular interactions and local signals, clearly affecting the efficacy of any immunotherapy.4 Proper biomarkers for the different immune checkpoint inhibitors enable the selection of the appropriate inhibitors for an optimised, patient-tailored treatment.5 The search for these biomarkers is now warranted by the encouraging clinical activity of tremelimumab in patients with chemotherapy-resistant advanced malignant mesothelioma. We declare that we have no conflicts of interest.
Lysanne A Lievense, Joost P J J Hegmans, *Joachim G J V Aerts [email protected] Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Rotterdam, Netherlands 1
2
3
Calabrò L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 2013; 14: 1104–11. Nowak AK. Immunological checkpoint inhibitors enter adolescence. Lancet Oncol 2013; 14: 1035–07. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12: 252–64.
4
5
Aerts JG, Hegmans JP. Tumor-specific cytotoxic T cells are crucial for efficacy of immunomodulatory antibodies in patients with lung cancer. Cancer Res 2013; 73: 2381–88. Hegmans JP, Aerts JG. Immunological profiling as a means to invigorate personalized cancer therapy. Oncoimmunology 2013; 2: e25236.
Authors’ reply As Lysanne Lievense and colleagues correctly point out, the search for biomarkers that are predictive of response to immune-checkpointblocking monoclonal antibodies is an area of active investigation; however, despite these efforts, no markers to select patients who respond well to treatment with this new category of therapeutic antibodies have yet been identified. Expression of programmed cell death (PD) ligand 1 (PD-L1) by tumour cells seemed to represent an absolute biomarker predictive of response to PD1 and PD-L1 blockade,1 but a sizeable proportion of patients with PD-L1-negative tumours efficiently respond to blocking of PD1 and PD-L1.2 With regards to CTLA4 expression by tumour cells, to the best of our knowledge, no clear-cut data have been reported for cell-surface expression on neoplastic cells; we also investigated the expression of CTLA4 on a panel of nine human mesothelioma cell lines, without identifying it (Calabrò L, Maio M, unpublished data). Nevertheless, even if CTLA4 was expressed on the mesothelioma cells of patients treated in our study, it probably would not have given any therapeutic advantage because of the IgG2 isotype of tremelimumab, which prevents efficient antibody-dependent and complement-dependent cytotoxicity. We have thoroughly investigated the expression of CTLA4 on peripheral blood mononuclear cells collected at baseline from patients with cutaneous melanoma treated with the anti-CTLA4 drug ipilimumab, and did not note any correlation with clinical outcome (Calabrò L, Maio M, unpublished data). e1
Correspondence
We clearly have to continue to explore the complexities of the immune system to identify biomarkers predictive of response to blocking of immune checkpoints, helping to select the best candidates to such treatments. Nevertheless, the specific targeting of immune cells by these antibodies makes these drugs totally different from other therapeutic monoclonal antibodies that bind to antigens on tumour cells; therefore, prediction of patients’ response to such drugs through investigation of dynamic rather than static biomarkers is probably needed. Along these lines, our finding that absolute numbers of circulating CD4-positive, ICOS-positive T cells correlate with a more favourable prognosis in the course of treatment with tremelimumab in patients with mesothelioma identifies a dynamic biomarker, possibly useful to monitor treatment with CTLA4 blockade.3 Additionally, because the absolute number of circulating CD4-positive, ICOS-positive T cells is an early marker in the course of treatment,3 as we also noted in patients with melanoma treated with ipilimumab,4 this marker might eventually become useful to drive treatment continuation or discontinuation with an anti-CTLA4 monoclonal antibody. There are undoubtedly many directions that need to be explored to take full advantage of immune-checkpointblockade therapies, but we have to first acknowledge that these drugs represent a so-called paradigm shift in our immunological and clinical beliefs. MM has served as a consultant, adviser, or both, to Bristol-Myers Squibb, Roche-Genetech, and Medimmune. LC declares that she has no conflicts of interest.
Luana Calabrò, *Michele Maio [email protected] Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, 53100 Siena, Italy 1
e2
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443–54.
2
3
4
Callahan M, Horak CE, Curran MA, et al. Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab. Proc Am Soc Clin Oncol 2013; 31 (suppl): abstr 3003. Calabrò L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol 2013; 14: 1104–11. Di Giacomo AM, Calabrò L, Danielli R, et al. Long-term survival and immunological parameters in metastatic melanoma patients who responded to ipilimumab 10 mg/kg within an expanded access programme. Cancer Immunol Immunother 2013; 62: 1021–28.
Rechallenge with imatinib in GIST: is more always RIGHT? We read with interest the RIGHT study,1 a commendable undertaking in which a statistically significant improvement in progression-free survival (PFS) from 0·9 to 1·8 months was reported for the re-introduction of imatinib, compared with placebo, after progression on treatment with at least imatinib and sunitinib, a practice already recommended in many treatment guidelines. The idea of re-introduction of previous regimens after disease progression, although not entirely new, challenges some longstanding notions in medical oncology. However, we believe that this study shows another more important, and often overlooked, notion within the oncology community—separation of clinically meaningful significance from statistical significance. In the RIGHT trial, although the hazard ratio was impressive (0·46, 95% CI 0·27–0·78, p=0·005), the reported improvement in median PFS was 25 days. The authors attributed the lack of benefit seen for overall survival to the fact that 93% of patients in the placebo group crossed over to imatinib at progression, although any survival benefit could be reasonably assumed to be less than the PFS benefit.
Other measures of potential benefit were also disappointing. More than 90% of patients retreated with imatinib progressed within 4 months, and although the confidence interval around the estimate of PFS suggested that a small number of patients might achieve more meaningful benefit, every patient experienced disease progression by 7 months. Furthermore, no objective responses were reported, although this finding might not accurately reflect treatment activity; adjustment of radiological response criteria or use of PET instead of CT might be an approach worthy of further study in this area. Importantly, the toxicity of the treatment (although manageable) was not trivial, with half of patients reporting grade 3 or 4 toxicity, including 10% with severe (grade 3) or disabling (grade 4) fatigue. That such results are viewed as clearly effective, rather than merely statistically significant (a view also held by the accompanying Comment2), is increasingly common in oncology. The addition of erlotinib to gemcitabine in advanced pancreatic cancer resulted in a statistically significant benefit of only 10 days, but was deemed sufficient to receive approval by the US Food and Drug Administration.3 Although patients with cancer might accept smaller benefits than do physicians,4 clinicians have the responsibility of discussing trial-reported benefits in a meaningful context. The increasing cost of cancer drugs that seem to have limited efficacy is an issue that needs to be addressed by society. Because of the potential cost of delivering imatinib, estimated at up to US$100 000 per year,5 a critical eye is needed to assess whether the costs (financial, toxicity, and opportunity) outweigh the clinical benefit. We await formal estimation of cost-per-qualityadjusted-life-year data, which will be important in considering societal subsidies of this drug. www.thelancet.com/oncology Vol 15 January 2014
