AACR 2023 – more hope for Moderna’s neoantigen immunotherapy

December’s toplining of the first ever positive results from a controlled trial of a cancer immunotherapy, Moderna’s mRNA-4157, caused jubilation. The group’s valuation gained $15bn, and the news validated Merck & Co’s earlier $250m bet on the project.

But was the enthusiasm warranted? The answer, after full data from the Keynote-942 trial in adjuvant melanoma were unveiled at AACR today, seems to be: maybe. The results do not raise major questions beyond those aired in December. And one potential issue, underperformance of the comparator arm of Keytruda monotherapy, seems to have been allayed.

Keynote-942’s main limitation appears to have been its small size. The study enrolled just 157 melanoma patients who had had their tumours resected, and was designed to demonstrate the superiority of Keytruda plus mRNA-4157 versus Keytruda alone on the primary endpoint of relapse-free survival (RFS).

In December the companies said this endpoint had been met, with 44% reduction in disease recurrence or death. However, until today nothing was known about the absolute results seen in the two cohorts.

At AACR it was revealed that the RFS rates at 18 months were 78.6% for the immunotherapy combo, versus 62.2% for Keytruda alone. Severe adverse events occurred in 25% versus 18% of patients respectively, and there were no grade 4 events or deaths seen in the mRNA-4157 cohort.

mRNA-4157 is a personalised mRNA therapeutic created on demand and encoding up to 34 neoantigens present in each patient’s tumour. Keytruda is approved for adjuvant melanoma, both for stage III patients (based on the result of the Keynote-054 study) and for less advanced stage IIB/C disease (Keynote-716).

It is Keynote-054 that might hint at Keytruda’s underperformance in Keynote-942. 18-month RFS in the former trial was 71%, so the 62% seen in the new study could be seen as lower. Cross-trial comparisons are imperfect, but if Keytruda’s real-world 18-month RFS benefit is closer to 70% then the 79% of the mRNA-4157 cohort looks less impressive.

That said, there is a further consideration. Keynote-942 included more advanced stage IV melanoma patients, in addition to the stage IIIs to which Keynote-054 was limited. 22 of Keynote-942's 157 subjects were stage IV, a fact that might have contributed to a lesser benefit overall in the study.

Merck told Evaluate Vantage that Keytruda performed consistently with what had previously been observed. Bristol Myers Squibb’s Opdivo is approved in adjuvant treatment of stage IV as well as stage III disease, on the basis of the Checkmate-238 trial, in which 18-month RFS was around 65%.

Before full Keynote-942 data were unveiled Mizuho had suggested that one-year RFS of 75% or more for Keytruda alone, with the mRNA-4157 cohort higher than this, would be a best-case scenario. The RFS result cut at 12 months came out at 77% for control and 83% for Keytruda plus mRNA-4157, meeting Mizuho's home run scenario.

Earlier concerns about the companies’ use of a one-sided p value, and of the hazard ratio’s upper bound above 1.00 (possibly explained away by the small sample size), remain relevant. Such considerations are key to gauging the commercial potential of mRNA-4157 – a very important asset for Moderna in its post-Covid phase.

It is still unclear how the regulatory path for mRNA-4157 might look, but in a statement Moderna said a phase 3 melanoma trial would begin soon, with studies in "lung cancer and beyond" also planned.

Other relevant aspects of Keynote-942 include cutting the data by neoantigen and PD-L1 expression. A separate AACR abstract cut the results by patients’ tumour mutation burden and found that, while Keytruda monotherapy worked better in TMB-high than low populations, there was no such difference for mRNA-4157 plus Keytruda.

Others

Progress of mRNA-4157 is of major interest to biotech watchers, given that the project is the first neoantigen immunotherapeutic of its type to show anything approaching meaningful efficacy.

At AACR 2020 Biontech’s Roche-partnered autogene cevumeran (RO7198457) yielded disappointing data. The partners have moved it into a phase 2 study, also in combination with Keytruda and in melanoma, whose results are expected this year.

The other key player to watch here is Gritstone Bio, whose Granite project is in phase 2/3. Gritstone claims that its technology has a strong T-cell priming effect, aiming to make “cold” tumours “hot”, which is why it is testing Granite in colorectal cancer rather than in a relatively immunogenic setting like melanoma.

The first randomized data from the phase 2 part of Gritstone’s study are due in the fourth quarter.

This is an updated version of a story published earlier.