Esmo 2017 – A chance for Astra to save face in lung cancer

Imfinzi’s failure in the first cut of Mystic, the all-important first-line lung cancer study, dealt Astrazeneca a body blow, but data from two other trials presented at Esmo suggest that the company should perhaps not be written off in this disease just yet.

Pacific might open up an early lung cancer setting that Imfinzi could make its own if it acts quickly, while Flaura shows how Tagrisso could grab a large chunk of the first-line space. It is now up to Astra to seize the opportunity to carve out a niche – for instance by driving a push to increase genetic diagnosis and lung cancer screening.

Encouraging screening could be vital; Pacific looked at stage III NSCLC – an early stage of the disease that Dr Luis Paz-Ares, of the Hospital Universitario 12 de Octubre in Madrid, said accounted for up to a third of lung cancer patients. Earlier diagnosis could clearly open up this opportunity.

Dr Paz-Ares told this morning’s Esmo press briefing that Pacific was the first randomised phase III trial to study checkpoint blockade in stage III NSCLC, a disease that has not seen an advance in years, and is currently treated with chemoradiotherapy. Other agents’ trials are less advanced, and interestingly show little sponsorship interest from industry originators.

While some of these studies do have associated industry involvement the reluctance of companies beyond Astra to lead here raises questions about how seriously this NSCLC setting is seen as an opportunity.

Trials of anti-PD-(L)1 agents in stage III NSCLC
Product Primary sponsor Study Primary endpoint(s) Trial ID Readout
Imfinzi Astrazeneca Pacific OS & PFS NCT02125461 PFS reported
Keytruda Hoosier Group OS & PFS NCT02343952 Mar 2018
Keytruda Rutgers Safety NCT02621398 Sep 2018
Tecentriq MD Anderson Safety NCT02525757 Jan 2019
Opdivo European Thoracic Oncology Platform Nicolas Safety NCT02434081 Aug 2020
Opdivo RTOG Foundation RTOG 3505 OS & PFS NCT02768558 Oct 2022

Dr Paz-Ares also dismissed the possibility of Pacific guiding immediate use in stage III disease of a rival anti-PD-(L)1 agent that is already approved for NSCLC – such as Merck & Co’s Keytruda – saying: “You typically need agency approval, particularly to get reimbursement. I tend to use the drugs that have proven efficacy in [each] setting.”

Median PFS with Imfinzi came out at 16.8 months, easily beating placebo at 5.6 months, with an impressive 48% reduction in risk of progression (p<0.0001). The benefit was driven by patients with >25% PD-L1 expression, and the placebo arm performed a little less well than is typical: Dr Paz-Ares said median PFS with chemoradiation was 8-10 months.

As for the other co-primary, overall survival, Dr Paz-Ares said the data were not mature, and moreover that no analysis had been done; the dataset remains blinded to OS, and as such he did not show the current survival plot, which would have indicated the extent to which the curves were separating at this point.

OS readout remains a major risk to the Pacific dataset, since all patients, including placebo recipients, whose lung cancer advances could presumably get an approved second-line drug like Keytruda or Opdivo. If this sequencing of therapy negates what would otherwise have been an OS advantage it will cast serious doubt over Imfinzi's ability to show a real-world benefit.

Flaura blooms

Meanwhile, the Flaura trial represents Astra’s attempt to move its small-molecule drug Tagrisso to front-line use specifically in EGFR-mutated NSCLC; the drug is already approved in patients who have progressed on Iressa or Tarceva.

Flaura hit its primary endpoint, showing median PFS of 18.9 months, versus 10.2 months with Iressa or Tarceva. Risk of progression was cut by an impressive 54%, with p<0.0001; Leerink analysts had earlier written that Flaura replicating its phase I PFS benefit of around 19 months should be enough to drive first-line use over current EGFR inhibitors.

Presenting the data at Esmo Emory University's Dr Suresh Ramalingam stated that Tagrisso “should be considered as a new standard of care for first-line therapy” in EGFR-mutated NSCLC.

Taken together with Pacific this could result in Astra still having a significant lung cancer presence, notwithstanding its Mystic failure. Moreover, the stage III opportunity could be disproportionately large, since Imfinzi here might be given for two years, versus a median of 18 months seen in Keytruda’s first-line study Keynote-021G.

Dr Enriqueta Felip Font, Esmo’s independent commentator from the Vall d'Hebron University Hospital, called Pacific a very well-designed study that had yielded “pretty promising” results, adding: “We need to wait until the overall survival results, but this is a very relevant trial.”

Around 10% of NSCLC patients present with an EGFR mutation, while stage III disease could account for up to a third of current incidence. If Imfinzi next year shows some kind of benefit in future cuts of Mystic that would be the icing on the cake.

To contact the writer of this story email Jacob Plieth in Madrid at [email protected] or follow @JacobPlieth on Twitter

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