Despite having barely seen a positive trial result since 2004 when the last product – Lilly’s Alimta – was approved, thoracic oncologists are hoping for some long-awaited progress in the rare and extremely poorly treated indication of mesothelioma.
Reviewing developments in the field at the European Lung Cancer Conference, Dr Sanjay Popat of the UK’s Royal Marsden Hospital highlighted the potential for a breakthrough with checkpoint inhibitors in mesothelioma this year. This is despite the fact that the only phase III trial of such a project to have been conducted to date – the Determine study of Astrazeneca’s CTLA4 antagonist tremelimumab – failed.
One of the sources of Dr Popat’s optimism could be the Maps-2 investigator-sponsored phase II study testing Bristol-Myers Squibb’s Opdivo and Yervoy as a second/third-line treatment. Data are due at Asco in a late-breaking abstract (LBA8507), one of a small number of studies to have been highlighted in advance by that organisation.
Formally, this study’s design can only show whether Yervoy provides an additive benefit over Opdivo. Investors will therefore look to across-trial comparisons, most likely with the Determine study, which enrolled similar second and third-line patients. The Maps-2 result could also provide some positive read-across for the ongoing Checkmate-743 study, which tests the Opdivo/Yervoy combo directly against pemetrexed/cisplatin in the first-line setting.
Checkmate-743 is the only industry-sponsored phase III with a checkpoint inhibitor in mesothelioma, but there are two collaborative group-sponsored studies under way: Promise-Meso with Keytruda in first-line disease and Confirm with Opdivo in the third-line setting. Both test these agents as monotherapies.
|Phase III and randomised phase II studies in mesothelioma|
|Boehringer Ingelheim||Vargatef||Lume-meso||pem/cis +/- Vargatef||1L||NCT01907100||Oct 2019|
|Bristol-Myers Squibb||Opdivo + Yervoy||Checkmate-743||Opdivo + Yervoy vs pem/cis||1L||NCT02899299||Oct 2020|
|Merck & Co||Keytruda||Promise-meso*||Keytruda vs pem/cis||1L||NCT02991482||Dec 2020|
|Bristol-Myers Squibb||Opdivo||Confirm*||Opdivo vs placebo||>3L||NCT03063450||Jun 2021|
|Eisai||amatuximab||Artemis||pem/cis +/- amatuximab||1L||NCT02357147||Sep 2017|
|Polaris Group||ADI-PEG 20||Atomic-meso||pem/cis +/- Adi-Peg 20||1L, low ASS1 expression||NCT02709512||Apr 2018|
|Bristol-Myers Squibb||Opdivo + Yervoy||Maps-2*||Opdivo +/- Yervoy||2-3L||NCT02716272||Asco|
|Pharmamar/J&J||Yondelis||Atreus||Yondelis (no control)||2L||NCT02194231||Asco|
|Bayer||anetumab ravtansine||-||anetumab ravtansine vs vinorelbine||2L||NCT02610140||Nov 2017|
|Merck & Co||Keytruda||*||pem/cis +/- Keytruda vs Keytruda||1L||NCT02784171||May 2019|
|Pem/cis = pemetrexed/cisplatin; *Investigator or collaborative group-sponsored study.|
Early studies with anti-PD-1/PD-L1 antibodies have shown single-agent activity for Keytruda, Opdivo and Pfizer/Merck KGaA’s Bavencio in mesothelioma, with one phase Ib study of Keytruda showing a disease control rate of 76%.
Asco will also see updated survival results with Boehringer Ingelheim’s Vargatef in the first-line setting in the Lume-Meso phase II trial (Abstract 8506).
Immature data from this relatively small phase II trial have shown a significant PFS benefit with a numerical difference on OS, and the hope must be that a significant OS result might emerge. This is important as Boehringer is conducting a large phase III study, also called Lume-Meso, in the same setting, that could support a guideline recommendation.
Asco will also see the outcome of the single-arm Atreus phase II study with J&J/Pharmamar’s Yondelis in the second-line setting (Abstract 8513). Activity here could prompt development of either this agent or – more likely – its follow-up, lurbinectedin.
Meanwhile, Roche has filed Avastin for use with pemetrexed/cisplatin as a first-line therapy, based on the Maps study conducted by the French Cooperative Thoracic Intergroup, which reported in 2015, showing a solid improvement in PFS and OS. The drug is already recommended by National Comprehensive Cancer Network guidelines.
Hail Mary filing
The only other company seeking an approval in mesothelioma is the Italian biotech Molmed, which filed its vascular-disrupting agent NGR-hTNF in the EU in December for fast-progressing patients. This is something of a long shot, being based on a subgroup derived from a negative phase III study.
Another hotly awaited readout in mesothelioma this year is that of a large phase II study with Bayer’s antibody-drug conjugate anetumab ravtansine in November. This study has been enlarged, so if its results are sufficiently strong it could support a registration application.
One thing is certain: in this indication progress cannot came too soon.
|Recent study results in mesothelioma|
|Company, project||Study, setting||Design||mPFS (months)||HR for PFS||mOS (months)||HR for OS|
|Roche, Avastin||Maps, 1L, n=448||pem/cis +/- Avastin||9.59 vs 7.48||0.61, p<0.0001||8.8 vs 16.1||0.77; p=0·0167|
|Boehringer Ingelheim, Vargatef||Lume-Meso phase II, 1L, n=87||pem/cis +/- Vargatef||9.4 vs 5.7||0.56, p=0.0174||18.3 vs 14.5||HR=0.78, p=0.4132*|
|Astrazeneca, tremelimumab||Determine, 2-3L, n=571||Vs placebo||-||-||7.7 vs 7.3||0.92 (0.76–1.12) p=0.408|
|Molmed, NGR-hTNF||NGR015, 2L, short TFI subset , n=198||Best investigator choice +/- NGR-hTNF||-||-||9.0 vs 6.3||0.69, p=0.02 (stratified)
0.65, p=0.01 (unstratified)
|Pem/cis = pemetrexed + cisplatin; TFI = treatment-free interval; *preliminary data, mature data are due at Asco (Abstract 8506).|