- Email: [email protected]
Missing a GOLDen opportunity in gastric cancer
Comment
Advanced gastric cancer has a poor prognosis; currently available palliative treatments result in survival of less than 18 months for most patients. Although immune checkpoint blockade has shown promise in chemorefractory gastric cancer, the modest benefit associated with anti-PD-1 therapy means that alternative gastric cancer vulnerabilities should continue to be explored.1 Defective homologous recombination, classically found in BRCA-mutated tumours, has been successfully exploited by poly-ADP-ribose polymerase (PARP) inhibitors in ovarian, breast, and prostate cancer. BRCA mutation is rare in gastric cancer; however, loss of ataxia-telangiectasia mutated protein (ATM-negative) occurs in 16–22% of tumours.2 Since ATM loss results in a homologous recombination deficient (HRD) state, PARP inhibition theoretically seems to be an attractive target in gastric cancer. The randomised, double-blind, placebo-controlled, phase 3 GOLD study presented by Yung-Jue Bang and colleagues3 in The Lancet Oncology randomly assigned 525 patients with advanced previously treated gastric cancer to weekly paclitaxel plus olaparib (n=263) or paclitaxel plus placebo (n=262), followed by olaparib or placebo maintenance monotherapy. The design of GOLD was based on the promising overall survival results of Study 39, 4 a randomised phase 2 trial, which showed statistically superior overall survival for patients treated with olaparib plus paclitaxel in both overall and ATMnegative patient populations. Despite these apparently sound foundations, the GOLD trial is negative for its co-primary endpoints of improved overall survival in either the overall patient population (HR 0·79 [97·5% CI 0·63–1·00]; p=0·026) or ATM-negative population (0·73 [0·40–1·34]; p=0·25). The negative results of GOLD will not change clinical practice; however, do these findings justify abandoning PARP as a target in gastric cancer? There are key differences between GOLD and Study 39, which might explain these disappointing results. Study 39 prospectively enriched for ATM-negative status, resulting in a 51% (63 of 124) prevalence of ATM-negative patients in that trial. In GOLD, only 18% (94 of 525) of patients were ATM-negative, reflecting the population prevalence of ATM loss in gastric cancer. The promising overall survival of olaparib-treated ATMnegative patients in Study 39 might have inflated the
results for the overall population, leading to an overoptimistic prediction of the benefit from olaparib in GOLD. Specifically, because PARP inhibitors are effective in tumours with a defined molecular dependency, it might have been unrealistic to expect efficacy from olaparib in an unenriched or non-biomarker selected population. However, perhaps surprisingly, the provocative survival results associated with olaparib in ATM-negative patients in Study 39 were not repeated in GOLD either. Plausible explanations for this finding include absence of biomarker standardisation, heterogenous ATM expression, confounding of ATM results by mismatch repair deficiency or PD-L1 expression (with which ATM loss is strongly associated), TP53 mutation status, or immaturity of the overall survival results in the ATM-negative subgroup.5 In particular, 19 (40%) of 48 ATM-negative patients treated with olaparib were censored in GOLD; this fact is relevant because the adjusted proportion of ATMnegative patient treated with olaparib who achieved an objective radiological response in GOLD is more than twice that of the ATM-negative group treated with paclitaxel (38% vs 16·%). Conversely, it is also possible that the results of Study 39 were a chance finding in a relatively small trial, which did not show an advantage in objective response or progression-free survival for patients treated with olaparib compared with those given placebo, and that ATM loss is not a robust predictive biomarker for efficacy of PARP inhibition in gastric cancer. Importantly, ATM loss is only one of several mechanisms by which gastric cancer converges on the HRD phenotype. The common, chromosomally unstable TCGA subtype of gastric and oesophageal adenocarcinoma is characterised by genomic instability, which can lead to acquired HRD and accumulation of genomic scar.6 HRD-associated genomic scar is quantifiable using next-generation sequencing signatures, some of which have been developed as diagnostics predictive of sensitivity to platinum chemotherapy and PARP inhibition.7,8 For example, although BRCA-mutated tumours provided the PARPsensitive HRD archetype, a non-BRCA HRD biomarker has been validated as a predictor of rucaparib efficacy in ovarian cancer.7 Thus, although ATM loss
www.thelancet.com/oncology Published online November 2, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30719-2
GJLP/Science Photo Library
Missing a GOLDen opportunity in gastric cancer
Lancet Oncol 2017 Published Online November 2, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30719-2 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(17)30682-4
1
Comment
represents the original gastric cancer HRD model, other complementary HRD populations might be identified using genomic or transcriptomic signatures and these patients could be sensitive to PARP inhibitor therapy.9,10 Finally, in the future, because mechanistic synergy is not anticipated between PARP inhibition and taxanes, the true value of PARP inhibition might be better assessed with maximally dosed PARP inhibitors without cytotoxic chemotherapy in a biomarker-refined population or in rational combination therapies. Trial enrichment using platinum sensitivity as a surrogate for HRD is one straightforward option, since PARP inhibition has been most successful as a single-agent maintenance therapy in patients with platinum-sensitive ovarian cancer. Elizabeth Smyth Gastrointestinal Oncology & Lymphoma Unit, Royal Marsden Hospital, London & Sutton SW3 6JJ, UK [email protected] ES has received honoraria for an advisory role from Five Prime Therapeutics, Bristol Meyer Squibb, and Gritstone Oncology. ES acknowledges the funding support of the National Institute for Cancer Research Royal Marsden/Institute for Cancer Research Biomedical Research Centre (NIHR RM/ICR BRC). 1
2
2
Kim HS, Kim MA, Hodgson D, et al. Concordance of ATM (ataxia telangiectasia mutated) immunohistochemistry between biopsy or metastatic tumor samples and primary tumors in gastric cancer patients. Pathobiology 2013; 80: 127–37. 3 Bang Y-J, Xu R-H, Chin K, et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following firstline therapy (GOLD): a double-blind, randomised , placebo-controlled, phase 3 trial. Lancet Oncol 2017; published online Nov 2. http://dx.doi. org/10.1016/S1470-2045(17)30682-4. 4 Bang YJ, Im SA, Lee KW, et al. Randomized, double-blind phase II trial with prospective classification by atm protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol 2015; 33: 3858–65. 5 Kim JW, Im SA, Kim MA, et al. Ataxia-telangiectasia-mutated protein expression with microsatellite instability in gastric cancer as prognostic marker. Int J Cancer 2014; 134: 72–80. 6 The Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature 2017; 541: 169–75. 7 Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinumsensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017; 18: 75–87. 8 Telli ML, Timms KM, Reid J, et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 2016; 22: 3764–73. 9 Cafferkey C, Smyth E, Loehr A, et al. Genomic loss of heterozygosity (LOH) and survival in patients (pts) treated with epirubicin, oxaliplatin, capecitabine (EOC) ± panitumumab (P) in the REAL3 trial. Ann Oncol 2016; 27: 207–42. 10 Secrier M, Li X, de Silva N, et al. utational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat Genet 2016; 48: 1131–41.
Kang Y-K, Satoh T, Ryu M-H, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): a double-blinded, randomized, phase III trial. Proc Am Soc Clin Oncol 2017; 35 (abstr): 4.
www.thelancet.com/oncology Published online November 2, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30719-2
Advanced gastric cancer has a poor prognosis; currently available palliative treatments result in survival of less than 18 months for most patients. Although immune checkpoint blockade has shown promise in chemorefractory gastric cancer, the modest benefit associated with anti-PD-1 therapy means that alternative gastric cancer vulnerabilities should continue to be explored.1 Defective homologous recombination, classically found in BRCA-mutated tumours, has been successfully exploited by poly-ADP-ribose polymerase (PARP) inhibitors in ovarian, breast, and prostate cancer. BRCA mutation is rare in gastric cancer; however, loss of ataxia-telangiectasia mutated protein (ATM-negative) occurs in 16–22% of tumours.2 Since ATM loss results in a homologous recombination deficient (HRD) state, PARP inhibition theoretically seems to be an attractive target in gastric cancer. The randomised, double-blind, placebo-controlled, phase 3 GOLD study presented by Yung-Jue Bang and colleagues3 in The Lancet Oncology randomly assigned 525 patients with advanced previously treated gastric cancer to weekly paclitaxel plus olaparib (n=263) or paclitaxel plus placebo (n=262), followed by olaparib or placebo maintenance monotherapy. The design of GOLD was based on the promising overall survival results of Study 39, 4 a randomised phase 2 trial, which showed statistically superior overall survival for patients treated with olaparib plus paclitaxel in both overall and ATMnegative patient populations. Despite these apparently sound foundations, the GOLD trial is negative for its co-primary endpoints of improved overall survival in either the overall patient population (HR 0·79 [97·5% CI 0·63–1·00]; p=0·026) or ATM-negative population (0·73 [0·40–1·34]; p=0·25). The negative results of GOLD will not change clinical practice; however, do these findings justify abandoning PARP as a target in gastric cancer? There are key differences between GOLD and Study 39, which might explain these disappointing results. Study 39 prospectively enriched for ATM-negative status, resulting in a 51% (63 of 124) prevalence of ATM-negative patients in that trial. In GOLD, only 18% (94 of 525) of patients were ATM-negative, reflecting the population prevalence of ATM loss in gastric cancer. The promising overall survival of olaparib-treated ATMnegative patients in Study 39 might have inflated the
results for the overall population, leading to an overoptimistic prediction of the benefit from olaparib in GOLD. Specifically, because PARP inhibitors are effective in tumours with a defined molecular dependency, it might have been unrealistic to expect efficacy from olaparib in an unenriched or non-biomarker selected population. However, perhaps surprisingly, the provocative survival results associated with olaparib in ATM-negative patients in Study 39 were not repeated in GOLD either. Plausible explanations for this finding include absence of biomarker standardisation, heterogenous ATM expression, confounding of ATM results by mismatch repair deficiency or PD-L1 expression (with which ATM loss is strongly associated), TP53 mutation status, or immaturity of the overall survival results in the ATM-negative subgroup.5 In particular, 19 (40%) of 48 ATM-negative patients treated with olaparib were censored in GOLD; this fact is relevant because the adjusted proportion of ATMnegative patient treated with olaparib who achieved an objective radiological response in GOLD is more than twice that of the ATM-negative group treated with paclitaxel (38% vs 16·%). Conversely, it is also possible that the results of Study 39 were a chance finding in a relatively small trial, which did not show an advantage in objective response or progression-free survival for patients treated with olaparib compared with those given placebo, and that ATM loss is not a robust predictive biomarker for efficacy of PARP inhibition in gastric cancer. Importantly, ATM loss is only one of several mechanisms by which gastric cancer converges on the HRD phenotype. The common, chromosomally unstable TCGA subtype of gastric and oesophageal adenocarcinoma is characterised by genomic instability, which can lead to acquired HRD and accumulation of genomic scar.6 HRD-associated genomic scar is quantifiable using next-generation sequencing signatures, some of which have been developed as diagnostics predictive of sensitivity to platinum chemotherapy and PARP inhibition.7,8 For example, although BRCA-mutated tumours provided the PARPsensitive HRD archetype, a non-BRCA HRD biomarker has been validated as a predictor of rucaparib efficacy in ovarian cancer.7 Thus, although ATM loss
www.thelancet.com/oncology Published online November 2, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30719-2
GJLP/Science Photo Library
Missing a GOLDen opportunity in gastric cancer
Lancet Oncol 2017 Published Online November 2, 2017 http://dx.doi.org/10.1016/ S1470-2045(17)30719-2 See Online/Articles http://dx.doi.org/10.1016/ S1470-2045(17)30682-4
1
Comment
represents the original gastric cancer HRD model, other complementary HRD populations might be identified using genomic or transcriptomic signatures and these patients could be sensitive to PARP inhibitor therapy.9,10 Finally, in the future, because mechanistic synergy is not anticipated between PARP inhibition and taxanes, the true value of PARP inhibition might be better assessed with maximally dosed PARP inhibitors without cytotoxic chemotherapy in a biomarker-refined population or in rational combination therapies. Trial enrichment using platinum sensitivity as a surrogate for HRD is one straightforward option, since PARP inhibition has been most successful as a single-agent maintenance therapy in patients with platinum-sensitive ovarian cancer. Elizabeth Smyth Gastrointestinal Oncology & Lymphoma Unit, Royal Marsden Hospital, London & Sutton SW3 6JJ, UK [email protected] ES has received honoraria for an advisory role from Five Prime Therapeutics, Bristol Meyer Squibb, and Gritstone Oncology. ES acknowledges the funding support of the National Institute for Cancer Research Royal Marsden/Institute for Cancer Research Biomedical Research Centre (NIHR RM/ICR BRC). 1
2
2
Kim HS, Kim MA, Hodgson D, et al. Concordance of ATM (ataxia telangiectasia mutated) immunohistochemistry between biopsy or metastatic tumor samples and primary tumors in gastric cancer patients. Pathobiology 2013; 80: 127–37. 3 Bang Y-J, Xu R-H, Chin K, et al. Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following firstline therapy (GOLD): a double-blind, randomised , placebo-controlled, phase 3 trial. Lancet Oncol 2017; published online Nov 2. http://dx.doi. org/10.1016/S1470-2045(17)30682-4. 4 Bang YJ, Im SA, Lee KW, et al. Randomized, double-blind phase II trial with prospective classification by atm protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer. J Clin Oncol 2015; 33: 3858–65. 5 Kim JW, Im SA, Kim MA, et al. Ataxia-telangiectasia-mutated protein expression with microsatellite instability in gastric cancer as prognostic marker. Int J Cancer 2014; 134: 72–80. 6 The Cancer Genome Atlas Research Network. Integrated genomic characterization of oesophageal carcinoma. Nature 2017; 541: 169–75. 7 Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinumsensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017; 18: 75–87. 8 Telli ML, Timms KM, Reid J, et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 2016; 22: 3764–73. 9 Cafferkey C, Smyth E, Loehr A, et al. Genomic loss of heterozygosity (LOH) and survival in patients (pts) treated with epirubicin, oxaliplatin, capecitabine (EOC) ± panitumumab (P) in the REAL3 trial. Ann Oncol 2016; 27: 207–42. 10 Secrier M, Li X, de Silva N, et al. utational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat Genet 2016; 48: 1131–41.
Kang Y-K, Satoh T, Ryu M-H, et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after second or later-line chemotherapy for advanced gastric or gastro-esophageal junction cancer (AGC): a double-blinded, randomized, phase III trial. Proc Am Soc Clin Oncol 2017; 35 (abstr): 4.
www.thelancet.com/oncology Published online November 2, 2017 http://dx.doi.org/10.1016/S1470-2045(17)30719-2