Despite progress made in oncology small-cell lung cancer remains a highly intractable disease, with second-line topotecan being the last drug to get US approval – 21 years ago. Presentations at Esmo this weekend from Pharmamar and Abbvie showed that industry has not given up just yet.
The most important readout for Abbvie’s Rova-T is still awaited, but Esmo saw an update of a phase I trial that backs use in DLL3-high patients but also shows that safety needs to be watched. Pharmamar’s focus is on Zepsyre, which could supersede its ageing marketed cell cycle inhibitor Yondelis, and its early data hint at a possible window of opportunity, though the march of immuno-oncology complicates matters.
The threat of immuno-oncology is important. Though data are very limited IO drugs have been recommended for SCLC in US National Comprehensive Cancer Network guidelines. If their use becomes routine it could affect the design of some ongoing studies.
Pharmamar wants to await results of a randomised phase III study before filing Zepsyre; SCLC is one of two late-stage shots on goal, the other being ovarian cancer. While according to EvaluatePharma sellside consensus Yondelis, which has been on the market for 10 years, is expected to generate revenues of $138m in 2022, Zepsyre is seen hitting $362m.
The group’s Esmo data concerned an update of uncontrolled studies in the second and third-line SCLC setting. This encompassed several dosing regimens – combinations with doxorubicin or taxotere, and a single-agent phase II basket trial.
Across these cohorts Zepsyre showed overall remissions of 36-71%, with progression-free survival in platinum-sensitive subjects of up to 6 months.
|Combined uncontrolled data from 3 phase I/II studies|
|Patients||ORR in all-comers||PFS in platinum-sensitives|
|Zepsyre + doxorubicin||48||50%||6.0 mth|
|Zepsyre + taxotere||7||71%||3.9 mth|
|Zepsyre single agent||36||36%||4.6 mth|
Of course, these being early data, the only comparison is across trials: topotecan’s registrational study showed around three months of PFS, while Rova-T worryingly gave even less, at 2.8 months, though based on its mechanism – Rova-T is an anti-DLL3 antibody-drug conjugate – Abbvie is relying on efficacy in DLL3-high patients, where PFS was 4.3 months.
It is important to bear in mind that there are different settings here; most of the subjects in Pharmamar’s trial were second line, meaning that they had largely not received topotecan. Pharmamar says when it designed this phase II study there was no immuno-oncology or Rova-T to consider.
Meanwhile, Abbvie’s Trinity study – Rova-T’s big readout of 2017 – is in the third-line setting, in patients who have already failed topotecan (Event – Abbvie’s long shot at proving Rova-T doubters wrong, July 24, 2017). Tahoe tests Rova-T second line, and is roughly analogous to Pharmamar’s registrational Zepsyre trial, Atlantis.
This is where immuno-oncology, which offers PFS benefits of a mere 1.5-2.5 months, comes in. The risk is that Trinity might not approximate to a real-world setting as its entry criteria limit patients to one prior systemic therapy, which likely means chemo only.
“We allow two systemics, so you can get chemo and IO,” Pascal Besman, Pharmamar’s chief operating officer, told EP Vantage. However, he also accepted that this design quirk meant that Atlantis was not really a second-line trial. “We will file off of the randomised Atlantis if the data supports it.”
A separate issue for Abbvie is whether in Trinity it is recruiting patients expressing DLL3 at a sufficiently high level to drive efficacy. The study recruits subjects with DLL3 at 1% or above, though at Esmo data analyses repeated the view that the benefit in earlier SCLC trials was driven by patients with DLL3 above 50%.
Presentation of early data in additional tumours expressing DLL3 showed a 30% rate of grade 3 or 4 treatment-related adverse events and one drug-related death, though a discussant, Dr Rocio Garcia-Carbonero, called Rova-T “tolerated at tested doses so far”.
Pharmamar’s Zepsyre data showed myelosuppression-related side effects that investigators said were manageable with dose reduction and use of G-CSF. In fairness, in a setting with as few options as relapsed SCLC, regulators might have a relatively high tolerance for adverse events.
|Selected pivotal SCLC studies|
|Rova-T||Trinity||3rd-line, DLL3-high (>1%)||NCT02674568||H2 2017|
|Rova-T||Tahoe||2nd-line, DLL3-high (>75%)||NCT03061812||H2 2019|