5-year survival data from CheckMate-067 trial released at ESMO 2019, highlighting the efficacy of immunotherapy in the treatment of malignant melanoma, regardless of BRAF status

In the last decade, immunotherapy has revolutionised the treatment of malignant melanoma. Before 2011, no effective treatment was available for this chemotherapy-resistant cancer, and patients with metastatic disease (stage IV) had an average life expectancy of between 6 -9 months.

The 2011 approval of Yervoy – a then highly novel immunotherapy, drastically improved survival odds for some melanoma patients 1 and kickstarted the immunotherapy revolution. Within five years, two more monotherapies (Keytruda and Opdivo) and a combination therapy (Opdivo plus Yervoy) had received broad-label regulatory approvals for the treatment of metastatic melanoma, adding to the armamentarium of immunotherapies available.

It is only now, however, that the true long-term effect of these therapies is becoming apparent.

Below we review recently reported data from the Phase III CheckMate-067 trial and discuss the importance and potential impact of this data on the treatment landscape of metastatic melanoma.

Immunotherapy significantly prolongs survival for melanoma patients

On Saturday, 5-year survival data from the CheckMate-067 study was presented at the 2019 European Society for Medical Oncology conference in Barcelona.

This Phase III trial evaluated Opdivo monotherapy and Opdivo plus Yervoy combination therapy for the treatment of previously untreated stage III or IV, unresectable, metastatic melanoma, compared to Yervoy monotherapy, which was the standard of care at the time of trial initiation.

Previously published data from this trial highlighted Opdivo monotherapy’s and Opdivo plus Yervoy combination therapy’s superior efficacy over Yervoy 2. This new data further supports these conclusions.

At 5-years, both the Opdivo monotherapy and the Opdivo plus Yervoy combination therapy arms of the trial demonstrated superior overall survival to the Yervoy monotherapy arm, with rates of 44%, 52%, and 26%, respectively.

Response rates, as well as progression free survival rates also highlighted the superiority of both Opdivo containing arms, with the Opdivo plus Yervoy arm demonstrating greatest efficacy in patients with both BRAF-mutation-positive and wild-type disease.

While these results are impressive, they simply support a treatment approach that has previously been reported. However, it is the data from patients who are still alive and currently free from subsequent treatment that have excited melanoma patients and physicians alike.

At 5 years post treatment, the proportion of patients who underwent treatment with Opdivo monotherapy or Opdivo plus Yervoy combination therapy and were alive and free from subsequent therapy was 24% and 36%, respectively, almost double the proportion of the people who had received Yervoy monotherapy (15%) 3.

Implications for malignant melanoma treatment

  • These new data suggest that the previous 5-year survival rate of metastatic melanoma has dramatically increased (from 23% to 36%) for patients that receive first-line immunotherapy.
  • The choice between immunotherapy and targeted-therapy for patients with BRAF mutation-positive disease is becoming clearer.
  • Use of immunotherapy in the earlier settings – adjuvant and neoadjuvant melanoma—may further improve overall survival and long-term remission for melanoma patients.

What will the future hold?

While these results reflect the significant improvements that have been made in the treatment of metastatic melanoma, a definitive “cure” is still a distant hope for the future.

Although we now know that patients who receive and respond to immunotherapy, specifically Opdivo either as monotherapy or in combination with Yervoy, have a better prognosis, there is still a large proportion of patients who do not respond to these treatments.

If a patient has BRAF-mutation-positive disease, targeted therapy such as Tafinlar plus Mekinist or Braftovi plus Mektovi are still an option, but for BRAF-wildtype patients there are no alternative treatments. Work must continue to identify which patients are not likely to respond to immunotherapy, and to find novel treatment approaches for this population.

The issue of toxicity is also a major component in immunotherapy treatment; even though some patients may respond to these therapies, associated toxicities, particularly for the combination approach, can make these treatments impossible to tolerate.

Toxicity will become an increasing limitation as immunotherapy is pushed to the earlier treatment setting for malignant melanoma. Opdivo and Keytruda are now both accepted treatments in the adjuvant setting, and trials investigating Opdivo plus Yervoy in both the adjuvant and neoadjuvant settings have demonstrated promising findings – however, the majority of patients are discontinuing treatment due to toxicity 4.

However, we do expect Opdivo plus Yervoy combination therapy to be the market leading melanoma treatment across our 10-year forecast period. By 2028, this combination is expected to garner patient share of up to 40% in metastatic melanoma and sales of $1.6 billion - 27% of the major market sales for malignant melanoma.

Novel therapies which build on the effectiveness of these immunotherapies may be the key to finding the elusive “cure” for malignant melanoma, but for now, only time will tell how close we really are.

As immunotherapies continue prosper in malignant melanoma, drug developers should explore the following strategic considerations before entering this market:

  • What will limit immunotherapy uptake? Is the market saturated?
  • Could agents with novel mechanisms of action match the efficacy of immunotherapies or should they be used in combination to drive increased efficacy?
  • How are standards of care changing, particularly for distinct populations, i.e., BRAF-mutation positive vs. wild-type, and how will this effect trial design?
  • What are the novel diagnostic/prognostic biomarkers in development for melanoma and how will these alter drug uptake?

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