It would be hard to depart from Asco 2018 in much doubt about the dominant position that Merck & Co has carved out in first-line lung cancer. From adverts for Keytruda plastered over Chicago’s bus stops to the drug’s prime spot at the conference’s high-profile plenary session, evidence abounds that Merck is in control of this space.
Armed with data from two more successful phase III studies, physicians will leave this year’s meeting with even stronger reasons to reach for Keytruda in pretty much any untreated, late-stage lung cancer patient (see tables below). For rivals, competing head-on with Merck just got tougher, and Roche has perhaps already recognised this – it used the conference to emphasise the benefits of Tecentriq plus Avastin in three distinct patient types, where it looks to have the upper hand.
Keynote in tune
First to Merck, though, which on Sunday followed a presentation of highly encouraging results with a Keytruda-chemo combo in squamous disease with data from Keynote-042, Keytruda’s confirmatory monotherapy study across squamous and non-squamous disease.
The drug is already approved as a single agent to treat first-line non-small cell lung cancer in patients who have a PD-L1 expression score of more than 50%. Keynote-042 looked at patients with a score as low as 1%. A significant survival benefit was seen across several slices of the tumour expression data, although as expected those with higher PD-L1 expression responded more strongly.
|Keynote-042 – Keytruda monotherapy proves its place|
|Number of patients||299||300||413||405||637||637|
|OS HR (p value)||0.69 (0.0003)||0.77 (0.002)||0.81 (0.0018)|
|Median survival, months||20||12.2||17.7||13||16.7||12.1|
|Source: Merck press release.|
While the study showed Keytruda monotherapy to work better than chemo across all patients with some level of PD-L1 expression, it seems unlikely that physicians will use the agent alone outside of special cases, such as in patients with very high PD-L1 expression or those who cannot tolerate chemotherapy. Stronger results from trials of Keytruda plus chemo mean the combination will remain the front-line choice in most cases.
“I think until we know better we’re going to be as aggressive as we can” in terms of treatment options, Dr David Graham, of the Levine Cancer Institute, told EP Vantage.
Merck concurred with this view. “Chemo combo should remain the standard of care, and it sets the floor against which everything should be compared, because they are the best results we’ve obtained,” Roy Baynes, Merck’s chief medical officer, told EP Vantage.
The caveats of cross-trial comparisons notwithstanding, a look at the hazard ratios of various front-line trials supports this notion.
As Umer Raffat from Evercore ISI noted, the Keynote-189 results for Keytruda plus chemo are the key to Merck’s dominance of this space, and the ’042 results may be of less significance commercially.
In its entirety, however, Merck’s successful pivotal programme in first-line lung cancer has been of huge commercial importance. The latest data from EvaluatePharma show that the sellside’s consensus for Keytruda sales in 2022 has grown by 20% to $12.1bn this year, and the table below shows just how dominant the drug is expected to become across the PD-(L)1 landscape.
Lung cancer accounts for about half of Keytruda’s forecast sales, though for Opdivo and Tecentriq the tumour type accounts for a much bigger proportion. This is why Bristol-Myers and Roche are trying so hard to remain relevant in this disease, via the various cuts of their front-line studies.
Bristol-Myers presented further data from its controversially redesigned Checkmate-227 study today, from part 1b, showing that Opdivo plus chemo extended PFS over chemo alone. It also highlighted an exploratory endpoint showing substantially improved one-year PFS rates for Opdivo plus Yervoy in patients with high tumour mutation burden, which should help its argument that this biomarker is relevant. The small patients numbers in the analysis make any substantial claims here hard to make, however.
|The PD-(L)1 blockade battle – sales across all indications|
|Product||Company||2022e ($bn)||Change in 2018 ($bn)|
|Keytruda||Merck & Co||12.1||+2.1|
Roche fired its latest salvo at Asco with new data from Impower-150, its front-line trial testing the triple combination of Tecentriq, Avastin and chemo. The data detailed very strong responses in patients who had an EGFR mutation or ALK rearrangement – and had failed on prior targeted therapies – and those with liver metastases. These groups of patients respond poorly to immunotherapy.
There is mechanistic rationale for the triple therapy’s activity here, Roche contends. VEGF is driven downstream by ALK and EGFR and allows these tumours to escape an immune response – so adding the anti-VEGF antibody Avastin to checkpoint blockade unlocks the potential of immuno-oncology in these patients. Those with liver metastases respond because Avastin blocks the high levels of VEGF that are present naturally in the highly vascular organ, which creates a immunosuppressive environment.
“The majority of physicians and scientists don’t think I-O works for these populations. Impower-150 says that is untrue,” Dan Chen, head of cancer immunotherapy development for Roche, told EP Vantage.
Asked whether Roche would seek specific approvals in those subsets, Cindy Perettie, head of oncology product strategy for Roche, said the company would be having that conversation with regulators. “But we think the Impower-150 data set is consistent with a broad, all-comers label,” she said.
Arguably, however, the Impower-150 study does not present a convincing argument as to the benefit of the triple combination in an all-comers, front-line population. Yet a first-line approval is crucial for Roche to have any hope of squaring up to Merck in this market.
What Impower-150 does is define areas that other therapies do not address, Mr Chen said. He pointed to the Impower-132 trial, which tests Tecentriq in combination with various chemo regimens, and which should yield results in the coming months. This study will provide a clearer comparison against Merck’s Keynote-189 data, and help determine Tecentriq’s fortunes in lung cancer.
The subgroups identified in Impower-150 look to be important niches from a clinical perspective, but they are not enough for Roche to become a significant player in this market. For that to happen, a clear and emphatic win must emerge in Impower-132.
|Scrabbling for subsets? Impower-150 analysis|
|Population (n)||Hazard ratio for OS||Tecentriq + Avastin + chemo (arm B)||Avastin + chemo (arm C)|
|Liver mets (94)||0.54||13.2||9.1|
|Notes: ITT=intend to treat; ITT-WT=excludes pts with EGFR/ALK mutations. Source: Roche press release.|