Why did the lung cancer trial exceed expectations?

  • The Chinese phase III OptiTROP-Lung06 trial conducted by Kelun compared sac-TMT plus Keytruda with chemotherapy plus Keytruda as first-line treatment for non-squamous non-small cell lung cancer with PD-L1 expression below 1%.
  • Median progression-free survival was 15 months in the sac-TMT group and 5.7 months in the control group, versus prior expectations of 9 to 12 months. The hazard ratio for disease progression or death was 0.49, also better than the expected figure of below 0.6.
  • Median duration of response was 13.6 months, versus 6.8 months in the control group; the proportions of patients whose tumors shrank by at least 50% were 29% and 17%, respectively. Goldman Sachs believes this is the first phase III validation that an antibody-drug conjugate (ADC) can replace chemotherapy in first-line lung cancer treatment.

Where are the limits of efficacy and tolerability?

  • Overall survival showed a favorable trend, with a preliminary hazard ratio for death of 0.58, but the data remain immature. Short follow-up and the effect of censoring on the data also limit assessment of the durability of efficacy.
  • In the lung cancer trial, the incidence of grade 3 or higher treatment-emergent adverse events was 48% for the sac-TMT combination and 61% for the chemotherapy combination; the former also showed better tolerability in terms of dose reductions and treatment discontinuations.
  • The conference discussant also noted that the frequency of KRAS mutations in the trial warrants attention. Goldman Sachs sees the Chinese results as an important milestone in reducing the risk of Merck’s global first-line lung cancer trial; whether global TroFuse-007 can replicate the results is the next hurdle.

What did the first global phase III success bring?

  • Among patients with endometrial cancer previously treated with platinum-based chemotherapy and immunotherapy, the global TroFuse-005 trial showed median progression-free survival of 7.2 months with sac-TMT and 3.9 months with physician’s choice of chemotherapy; median overall survival was 19.0 months and 12.1 months, respectively.
  • Objective response rates in the two groups were 35.1% and 17.3%, respectively. The incidence of grade 3 or higher treatment-related adverse events was higher in the sac-TMT group, at 54.4% versus 41.4% in the control group, but treatment-related discontinuation rates were 3.1% and 4.9%, respectively.
  • Goldman Sachs finds the consistency between the global phase III results and earlier Chinese phase II data encouraging. The revenue opportunity in endometrial cancer is relatively small, but it could become the first approved indication for sac-TMT.

What does this mean for Merck’s product portfolio?

  • Goldman Sachs believes that, if global lung cancer data support the Chinese trial results, sac-TMT could become a backbone therapy replacing chemotherapy in future first-line treatment. Merck previously said it was considering expanding its development strategy to cover the first-line lung cancer population treated with Keytruda plus chemotherapy.
  • Kelun management said it had submitted a biologics license application in China based on the Lung06 results and was discussing a first-line non-small cell lung cancer indication covering different PD-L1 expression levels with regulators.
  • In Goldman Sachs’ forecasts, sac-TMT contributes more to Merck than intismeran, another cancer immunotherapy. Goldman Sachs has a buy rating on Merck and a 12-month price target of $155.