Esmo 2021 – Astra coasts towards a new lung cancer combo

Two new immuno-oncology mechanisms post encouraging data, giving a boost to small developers including Innate and Corvus.

Imfinzi is the standard of care for post-chemo stage III non-small cell lung cancer, but rivals have been snapping at its heels for some time. Data presented at Esmo last week might give Imfinzi a new edge in this setting, thanks to combination approaches.

An interim analysis of the mid-stage Coast trial showed that adding Astra’s own anti-CD73 antibody oleclumab, or the Innate Pharma-originated anti-NKG2A monalizumab, to Imfinzi boosted response rates and progression-free survival. Astra is already looking beyond NSCLC with these new mechanisms, and other anti-CD73 developers are also riding high.

Coast, conducted in 189 patients with unresectable, stage III NSCLC who had not progressed after concurrent chemoradiation, met its primary endpoint, the oleclumab and monalizumab combos boosting objective response rate significantly compared with Imfinzi alone. 

Source: Esmo 2021 and Dr Alex Martinez-Marti.

The monalizumab arm was the better of the two combos on ORR, but the oleclumab combo was more impressive on progression-free survival. After a median follow-up of 11.5 months, addition of oleclumab to Imfinzi reduced the risk of disease progression or death by 56%, and addition of monalizumab by 35%, over Imfinzi alone. 

On the measure of 10-month PFS rate, however, the monalizumab arm came out ahead, on 72.7% versus 64.8% for the oleclumab combination and 39.2% with Imfinzi monotherapy.

Safety was similar across the trial’s arms with no new signals seen for either combination. Incidence of grade 3 or higher treatment-emergent adverse events was 39.4% with Imfinzi monotherapy, 40.7% in the oleclumab combo arm and 27.9% in the monalizumab combo arm. Grade 3/4 pneumonitis was seen in one patient (1.6%), who received Imfinzi plus monalizumab.

Source: Esmo 2021.

This signals obviously need replicating in larger studies and Astra plans a registrational trial for the two combinations.

But the real winner from Coast was Innate, whose stock jumped 41% on Friday. Innate acquired rights to monalizumab from Novo Nordisk in 2014, and then partnered it with Astra a year later, an agreement that was deepened in 2018 (Astrazeneca asset swap kickstarts Innate's independence, October 23, 2018). According to SVB Leerink analysts, the start of a pivotal trial using the asset could mean Astra making a milestone payment to Innate.

Monalizumab targets NKG2A receptors, expressed on tumour-infiltrating cytotoxic CD8+ T cells and NK cells. The only other project with this mechanism to have reached the clinic appears to be Bristol Myers Squibb’s BMS-986315, which is in a phase 1/2 trial as monotherapy and in combination with Opdivo or Erbitux. The solid tumours study is expected to run until 2023. 

As for anti-CD73 MAbs – oleclumab’s category – the pipeline is more crowded. The project itself is in a total of 22 active, early to mid-stage clinical trials, many of which Astra is conducting in combination with Imfinzi. 

None of the other anti-CD73s have yet made it past phase 1; Eli Lilly abandoned work on a CD73 inhibitor earlier this year. But the Coast data was enough for some investors: Corvus’s stock more than doubled on Friday, with Arcus, Surface Oncology and I-Mab posting notable gains.

Should further encouraging data emerge from oleclumab's extensive clinical programme, perhaps hopes will rise further. 

Selected clinical-stage anti-CD73 projects
Company CD73 Details
Astrazeneca Oleclumab Ph2 in NSCLC, pancreatic, sarcoma, prostate, breast, colorectal; ph1 in bladder. Most trials incl combo w Imfinzi
Corvus CPI-006 Ph1 in solid tumours as monotherapy & combos, incl w Keytruda (NCT03454451)
Arcus AB680 Ph1 as monotherapy and in combo with PD-1 or Tigit (NCT04262856)
Surface Oncology/
Ph1 as monotherapy & combo, incl w spartalizumab (NCT03549000 & NCT04237649)
Bristol-Myers Squibb BMS-986179 Ph1 monotherapy & combo w Opdivo (NCT02754141)
I-Mab/Tracon Uliledlimab
Ph1 combo w Tecentriq (NCT03835949)
All trials in solid tumours unless specified. Source: Evaluate Pharma.

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