ELCC – Physicians look for progress in mesothelioma

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
Company Project Acronym Design Setting Trial ID Data
Phase III
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
Phase II
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%.

Hope

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).

To contact the writer of this story email Robin Davison at the ELCC in Geneva at robind@epvantage.com or follow @RobinDavison2 on Twitter

Share This Article