Mining the Memorial Sloan Kettering database, Dr Warner studied the treatment trajectory of 102 patients who had discontinued anti–PD-1 therapy after having a complete response following a median length of treatment of 9.4 months. The estimated 3-year rate of overall survival from the time of complete response was 82.5%, and more than one-fifth suffered a relapse.2

“What we found is that a higher percentage of patients had progressive disease at some point down the road than we had previously thought, but that doesn’t necessarily mean that continuing anti–PD-1 therapy would have made a difference,” said Dr Warner. “Longer may be better, but we don’t really know because those patients could have stayed on and continued to progress anyway.” She said the findings make an important case for a randomized clinical trial to investigate if staying on anti–PD-1 therapy for the long term prevents the cancer from coming back.

She also looked at whether receiving a second dose had helped relapsed patients and found that only 14% responded to repeated treatment. “Our natural tendency would be to treat them with a second course because they had a good response the first time around, but our data suggest we should try something else before going back to anti–PD-1,” said Dr Warner.  She says it’s unclear if the low rate was because patients’ tumors – and immune responses – had changed over time. “This is a good reason to go into the lab and study tumors from first and second treatments and compare and contrast them,” she said. “It all comes down to understanding why a tumor would come back if it was already successfully treated.”

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In the second ASCO poster, Arissa Young, MD, a resident at Vanderbilt University Medical Center, took to task the previously reported finding in Lancet Oncology that obese metastatic melanoma patients, especially men, responded better to targeted or immune therapy.3 In her research, she decided to look more comprehensively at patients’ body composition and analyzed 290 patients’ pretreatment computed tomography (CT) scans at the L3 vertebra to measure skeletal muscle, visceral fat, and subcutaneous fat tissue.

Dr Young found that in their cohort, having a high BMI was not associated with their response to immune checkpoint inhibitors. Rather, patients with a combination of high fat and high muscle had high response rates and progression-free survival. However, she says this association was not statistically significant and not strong enough to guide patient selection criteria. “I think that overall there were some interesting findings but nothing really dramatic,” she said. “This is why I wouldn’t jump to advising clinicians to incorporate these data into current clinical practice.” She hopes future research will continue to explore the mechanism behind this so-called “obesity paradox,” in which obese people have a higher risk of getting cancer but also respond better to checkpoint inhibitors.

Despite these new insights, the biggest mystery is figuring out why half of patients don’t respond at all to anti–PD-1 therapy. “We’re still trying to understand what’s driving the resistance. The tumors might not be recognized by the immune system, or there might be other molecular features that keep the immune system out of tumors,” said Dr Johnson. He said that he hopes that the use of DNA sequencing to uncover patients’ genetic biomarkers will better predict who might respond to a particular treatment.

For example, his team is working to discover whether patients who test positive for the MHC-II molecule should be given nivolumab plus an experimental immunotherapy drug called relatlimab, while MHC-II–negative patients would be prescribed the traditional regimen of nivolumab plus ipilimumab. “It’s hard to predict what the next successful combination of drugs will be, but there are thousands of clinical trials going on to synergistically stimulate the immune system,” said Dr Johnson. “The last 5 to 10 years have been a time of rapid and incredible progress in melanoma treatment. We remain hopeful it will continue in the next decade to cure an even higher number of patients.” 

References

  1. Atkins MB, Kirkwood JM, Wolchok JD, et al. Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma. J Clin Oncol. 2019;37(no. 15_suppl):9533-9533.
  2. Warner AB, Palmer JS, Shoushtari AN, et al. Responders to anti-PD1 therapy: long-term outcomes and responses to retreatment in melanoma (mel). J Clin Oncol. 2019;37(15_suppl):9513-9513.
  3. McQuade JL, Daniel CR, Hess KR, et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol. 2018;19(3):310-322.
  4. Young A, Quach HT, Davis EJ, et al. Impact of body composition on outcomes from anti-programmed death-1 (PD-1) treatment. J Clin Oncol. 2019;37(15_suppl):9516-9516.