The intense rivalry between competing anti-PD-1/PD-L1 antibodies in lung cancer has overshadowed their development in other solid tumours. This could change in the wake of the publication of the first positive phase III study of any checkpoint inhibitor, Bristol-Myers Squibb’s Opdivo, in advanced gastric cancer.
The ONO-4538-12 study, conducted by Bristol’s partner and the product’s originator, Ono Pharmaceutical, had already been reported as having hit its primary endpoint last November. However, no details were disclosed at the time, so the data were the highlight of the first day of the Asco-GI cancer symposium in San Francisco yesterday (see tables).
The 493-patient, placebo-controlled study is the first with any type of agent to show a survival improvement for patients with previously treated advanced or recurrent gastric cancer who are refractory to or intolerant of standard therapy.
Opdivo conferred a 37% reduction in risk of death and a 40% reduction in risk of disease progression, in both cases to high levels of statistical significance (p<0.0001). However, the absolute levels of benefit in the extremely poor prognosis patient group might at first seem modest: just 1.2 months, at the median, for overall survival and less than five days for progression-free survival.
|Phase III results of Opdivo in advanced gastric cancer|
|Median OS||5.32 mth||4.14 mth||HR=0.63; p<0.0001|
|Objective response rate||11.2%||0%||p<0.0001|
|PFS||1.61 mth||1.45 mth||HR=0.60; p<0.0001|
Nevertheless, the study will surely form the basis of a regulatory submission, as well as justifying further investment in studies in earlier-stage gastric cancer. Notable was the fact the trial did not analyse outcomes on the basis of levels of PD-L1 expression, and therefore Opdivo could have had a greater effect in the higher expressers than lower ones, as is the case in NSCLC.
Of course, NSCLC is a separate headache for Bristol, which has recently seen Opdivo comprehensively outflanked by Merck & Co’s Keytruda in the first-line setting.
Bristol and Ono have three other large studies under way with Opdivo in gastric cancer, a condition that is highly prevalent in East Asia but relatively rare in Western markets. One is Checkmate-649, a phase III testing dual checkpoint blockade with Yervoy against oxaliplatin plus fluoropyrimidine in the first-line setting, expected to read out in 2019.
Meanwhile, Ono is about to start recruitment into a phase III study with Opdivo versus placebo in the post-operative adjuvant setting, on top of standard chemotherapy of tegafur-gimeracil-oteracil (S-1) or capecitabine plus oxaliplatin. Bristol is also conducting a large phase II study called Fraction-GC that compares Opdivo and Yervoy versus Opdivo and its investigational anti-Lag3 antibody BMS-986016.
However, Bristol’s headstart over other checkpoint blockers in gastric cancer could be short lived.
Merck KgaA and Pfizer are testing avelumab in the third-line setting in the Javelin Gastric 300 study, due to read out in August. Moreover, another avelumab study, Javelin Gastric 100, is ongoing in the first-line maintenance setting, and could be the first of any anti-PD-1/PD-L1 to render results here.
Merck & Co is also active with Keytruda and has the Keynote-061 study in second-line patients due to render results in December, and another in first-line patients that is on track for readout in early 2019.
|Key studies of anti-PD-1/PD-L1 agents in gastric cancer|
|Checkmate-649||Opdivo + Yervoy vs chemo||First line||1,266||NCT02872116||Jul 2019|
|ONO-4538-38||Opdivo vs placebo on top of S-1 or CapeOX||Adjuvant||700||NCT03006705||Jun 2021|
|Fraction-GC||Opdivo + Yervoy vs Opdivo + BMS-986016||Advanced||910||NCT02935634||Nov 2021|
|Keynote-061||Keytruda vs paclitaxel||Second line||720||NCT02370498||Dec 2017|
|Keynote-062||Keytruda +/- cisplatin + 5-FU vs cisplatin + 5-FU||First line||750||NCT02494583||Jan 2019|
|Keynote-063||Keytruda vs paclitaxel||Second line/Asian||360||NCT03019588||Jan 2019|
|Javelin Gastric 300||Avelumab vs chemo||Third line||330||NCT02625623||Aug 2017|
|Javelin Gastric 100||Avelumab vs continuation of chemo||First-line maintenance||666||NCT02625610||Nov 2018|
|Note: all phase III, except Fraction-GC (phase II).|
Neither Astrazeneca nor Roche have any registration studies under way with durvalumab or Tecentriq respectively, so gastric cancer could be unusual if the market is split three ways. While this cancer might not be as valuable as other indications it has a number of study readouts over the next few years that could give it a higher profile with investors.