- Email: [email protected]
Immune-checkpoint inhibition for digestive cancers
Comment
Oesophageal cancer, squamous-cell carcinoma, or adenocarcinoma, are frequently diagnosed at advanced stages and have poor prognosis. Despite decreasing incidence in squamous-cell carcinoma in many countries, the incidence of oesophageal cancer has not changed over time due to a rise in incidence of adenocarcinoma.1 Thus, oesophageal cancer remains the eighth most frequent cancer and the sixth most common cause of death from cancer worldwide.1 At the locally advanced or metastatic stages, curative therapy is not feasible, and only palliative treatments are available. Two chemotherapy schemes are effective and are used routinely as palliative treatments: platinum and fluorouracil-based regimens or taxane-based regimens (docetaxel or paclitaxel). The expected median overall survival is 8–12 months.2 Several targeted therapies have been tested, mostly in patients with refractory oesophageal cancer that has not responded to at least one standard chemotherapy regimen. Most of these strategies, however, have led to no3 or moderate4 increases in overall survival. New effective therapies are urgently needed. Immune-checkpoint inhibitors offer a new therapeutic approach against cancer. These drugs have shown excellent results in some cancers, such as melanoma, squamous non-small-cell lung cancer, non-squamous non-small-cell lung cancer, Hodgkin’s lymphoma, and renal-cell carcinoma. Some preliminary studies have now shown promising results for digestive cancers, such as a phase 1b study in which eight (22%) of 36 patients with gastric cancers overexpressing programmed cell death protein 1 (PD-1) ligand 1 had overall responses to pembrolizumab.5 Several other studies are underway, including two assessing treatment of cholangiocarcinoma with pembrolizumab (NCT02702401) and hepatocellular carcinoma with nivolumab (NCT02576509). In The Lancet Oncology, Toshihiro Kudo and colleagues6 present a single-arm, phase 2 study of nivolumab, an immune-checkpoint inhibitor of PD-1, used to treat Japanese patients with treatment-refractory squamouscell oesophageal cancer with encouraging results. Of note, the study had no comparison group, because no third-line strategies have been validated. 65 patients were treated with nivolumab after having no response
to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. At a median followup of 10·8 months (IQR 4·9–14·3), 11 (17%, 95% CI 10–28) of 64 patients had achieved a centrally assessed objective response (the primary endpoint). Median overall survival, a secondary endpoint, was 10·8 months (95% CI 7·4–13·3). Adverse events were seen in 55 (85%) patients, and were grade 3–4 in 17 (26%) and the most common adverse events were diarrhoea, decreased appetite, constipation, rash, and fatigue. Five patients developed treatment-related interstitial lung disease (three adverse events and two serious adverse events), but resolved with supportive care after nivolumab was discontinued. 11 treatment-related serious adverse events were reported overall, but there were no treatment-related deaths. As in previous studies in other cancers, the response to nivolumab seems to be sustainable. The results of Kudo and colleagues suggest promising future opportunities for the palliative management of oesophageal cancer. Confirmation in a phase 3 randomised controlled study that compares nivolumab, alone or in combination with chemotherapy, with standard chemotherapy is needed. Immune-check point therapy induces new adverse events rarely seen with standard chemotherapy that clinicians will have to learn to manage, such as endocrine disorders (eg, hypothyroidism), interstitial lung disease, pneumonitis, and eosinophilic pneumonia,6 and other less common immune disorders (eg, pemphigoid).5 Assessment of the response to immune-checkpoint inhibitors with the Response Evaluation Criteria In Solid Tumors (RECIST) might not be suitable, and will probably have to change to include routine assessment of immune response, such as with the immune-related response evaluation criteria. This approach is supported by a 2009 study in which some patients had pseudoprogression when assessed with the RECIST criteria, but also had longer overall survival that in patients with favourable responses with the immune-related response evaluation criteria.7 Another study showed that the benefit of pembrolizumab was underestimated in around 15% of patients when assessed with RECIST compared with the immune-related response evaluation criteria.8
www.thelancet.com/oncology Published online March 14, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30188-2
Antonio Romero/Science Photo Library
Immune-checkpoint inhibition for digestive cancers
Lancet Oncol 2017 Published Online March 14, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30188-2 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(17)30181-X
1
Comment
Immune-checkpoint inhibitors are showing promising results in digestive cancers. Further research must be done to validate this approach for the treatment of oesophageal cancer and to define predictive factors for response, such as overexpression of PD-1 ligand 1.5 *Sylvain Manfredi, Antoine Drouillard Hepato-Gastroenterology and Digestive Oncology Department, Digestive Cancer Registry, University Hospital Dijon, INSERM U866, Dijon 21000, France [email protected] We declare no competing interests 1 2
2
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359–86. Mitry E, Taïeb J, Artu P, et al. Combination of folinic acid. 5-fluorouracil bolus and infusion, and cisplatin (LV5FU2-P regimen) in patients with advanced gastric of gatroesophpageal junction carcinoma. Ann Oncol 2004; 15: 765–69.
3 4
5 6
7 8
Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol 2013; 14: 627–37. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014; 15: 1224–35. Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 2016; 17: 717–26. Kudo T, Hamamoto Y, Kato K, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol 2017; published online March 14. http://dx.doi.org/10.1016/ S1470-2045(17)30181-X. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15: 7412–20. Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 2016; 34: 1510–17.
www.thelancet.com/oncology Published online March 14, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30188-2
Oesophageal cancer, squamous-cell carcinoma, or adenocarcinoma, are frequently diagnosed at advanced stages and have poor prognosis. Despite decreasing incidence in squamous-cell carcinoma in many countries, the incidence of oesophageal cancer has not changed over time due to a rise in incidence of adenocarcinoma.1 Thus, oesophageal cancer remains the eighth most frequent cancer and the sixth most common cause of death from cancer worldwide.1 At the locally advanced or metastatic stages, curative therapy is not feasible, and only palliative treatments are available. Two chemotherapy schemes are effective and are used routinely as palliative treatments: platinum and fluorouracil-based regimens or taxane-based regimens (docetaxel or paclitaxel). The expected median overall survival is 8–12 months.2 Several targeted therapies have been tested, mostly in patients with refractory oesophageal cancer that has not responded to at least one standard chemotherapy regimen. Most of these strategies, however, have led to no3 or moderate4 increases in overall survival. New effective therapies are urgently needed. Immune-checkpoint inhibitors offer a new therapeutic approach against cancer. These drugs have shown excellent results in some cancers, such as melanoma, squamous non-small-cell lung cancer, non-squamous non-small-cell lung cancer, Hodgkin’s lymphoma, and renal-cell carcinoma. Some preliminary studies have now shown promising results for digestive cancers, such as a phase 1b study in which eight (22%) of 36 patients with gastric cancers overexpressing programmed cell death protein 1 (PD-1) ligand 1 had overall responses to pembrolizumab.5 Several other studies are underway, including two assessing treatment of cholangiocarcinoma with pembrolizumab (NCT02702401) and hepatocellular carcinoma with nivolumab (NCT02576509). In The Lancet Oncology, Toshihiro Kudo and colleagues6 present a single-arm, phase 2 study of nivolumab, an immune-checkpoint inhibitor of PD-1, used to treat Japanese patients with treatment-refractory squamouscell oesophageal cancer with encouraging results. Of note, the study had no comparison group, because no third-line strategies have been validated. 65 patients were treated with nivolumab after having no response
to fluoropyrimidine-based, platinum-based, and taxane-based chemotherapy. At a median followup of 10·8 months (IQR 4·9–14·3), 11 (17%, 95% CI 10–28) of 64 patients had achieved a centrally assessed objective response (the primary endpoint). Median overall survival, a secondary endpoint, was 10·8 months (95% CI 7·4–13·3). Adverse events were seen in 55 (85%) patients, and were grade 3–4 in 17 (26%) and the most common adverse events were diarrhoea, decreased appetite, constipation, rash, and fatigue. Five patients developed treatment-related interstitial lung disease (three adverse events and two serious adverse events), but resolved with supportive care after nivolumab was discontinued. 11 treatment-related serious adverse events were reported overall, but there were no treatment-related deaths. As in previous studies in other cancers, the response to nivolumab seems to be sustainable. The results of Kudo and colleagues suggest promising future opportunities for the palliative management of oesophageal cancer. Confirmation in a phase 3 randomised controlled study that compares nivolumab, alone or in combination with chemotherapy, with standard chemotherapy is needed. Immune-check point therapy induces new adverse events rarely seen with standard chemotherapy that clinicians will have to learn to manage, such as endocrine disorders (eg, hypothyroidism), interstitial lung disease, pneumonitis, and eosinophilic pneumonia,6 and other less common immune disorders (eg, pemphigoid).5 Assessment of the response to immune-checkpoint inhibitors with the Response Evaluation Criteria In Solid Tumors (RECIST) might not be suitable, and will probably have to change to include routine assessment of immune response, such as with the immune-related response evaluation criteria. This approach is supported by a 2009 study in which some patients had pseudoprogression when assessed with the RECIST criteria, but also had longer overall survival that in patients with favourable responses with the immune-related response evaluation criteria.7 Another study showed that the benefit of pembrolizumab was underestimated in around 15% of patients when assessed with RECIST compared with the immune-related response evaluation criteria.8
www.thelancet.com/oncology Published online March 14, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30188-2
Antonio Romero/Science Photo Library
Immune-checkpoint inhibition for digestive cancers
Lancet Oncol 2017 Published Online March 14, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30188-2 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(17)30181-X
1
Comment
Immune-checkpoint inhibitors are showing promising results in digestive cancers. Further research must be done to validate this approach for the treatment of oesophageal cancer and to define predictive factors for response, such as overexpression of PD-1 ligand 1.5 *Sylvain Manfredi, Antoine Drouillard Hepato-Gastroenterology and Digestive Oncology Department, Digestive Cancer Registry, University Hospital Dijon, INSERM U866, Dijon 21000, France [email protected] We declare no competing interests 1 2
2
Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359–86. Mitry E, Taïeb J, Artu P, et al. Combination of folinic acid. 5-fluorouracil bolus and infusion, and cisplatin (LV5FU2-P regimen) in patients with advanced gastric of gatroesophpageal junction carcinoma. Ann Oncol 2004; 15: 765–69.
3 4
5 6
7 8
Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol 2013; 14: 627–37. Wilke H, Muro K, Van Cutsem E, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 2014; 15: 1224–35. Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 2016; 17: 717–26. Kudo T, Hamamoto Y, Kato K, et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol 2017; published online March 14. http://dx.doi.org/10.1016/ S1470-2045(17)30181-X. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15: 7412–20. Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 2016; 34: 1510–17.
www.thelancet.com/oncology Published online March 14, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30188-2