“Next-generation sequencing may help identify who is going to respond to single-agent therapy with low toxicities and who needs a more aggressive combination.”— Douglas B. Johnson, MD, MSCI
“THE CONVERGENCE of two very hot and interesting topics—precision medicine and immuno-oncology”—is being advanced by next-generation sequencing, Douglas B. Johnson, MD, MSCI, made clear at the inaugural OncoSET Symposium: Emerging Approaches to Precision Medicine,” sponsored by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.1 Next-generation sequencing can be useful in identifying biomarkers to predict response to anti–programmed cell death protein 1 (PD-1) and other immune therapies across tumor types and “picking the right therapy for the right patient,” Dr. Johnson said.
As an example illustrating “why we need biomarkers for immune therapy,” Dr. Johnson, Clinical Director, Melanoma, Vanderbilt University Medical Center, Nashville, cited the treatment of melanoma with ipilimumab (Yervoy) and nivolumab (Opdivo) singly or in combination. The combination produced a 58% response vs 43% for nivolumab alone and 19% for ipilimumab alone. Although the combination therapy “clearly makes a dramatic difference for melanoma patients in the higher response rate,” he commented, “this combination therapy also has significantly increased toxicities.” A total of 55% of patients receiving combination therapy had grade 3/4 adverse events vs 16.3% of those receiving nivolumab alone and 27.3% of those receiving ipilimumab alone.2
Next-generation sequencing may potentially help identify “who is going to respond to single-agent therapy with low toxicities and who needs a more aggressive combination,” Dr. Johnson explained. On a broader level, next-generation sequencing may help predict responders for other immune therapies and “prioritize therapy for sites such as non–small cell lung cancer [NSCLC] and bladder cancer, where there are other active therapies.”
Preexisting Immune Response
“THE KEY CONCEPT in immune biomarker discovery, at least for anti–PD-1 responses, and probably for other immune therapies,” Dr. Johnson said, is “preexisting immune response, even before starting therapy.” He cited a study showing patients who responded to therapy “had a ring of CD8 T cells around the tumor before starting treatment.”3
Preexisting response may also be indicated by expression of targets, such as PD-1 and programmed cell death ligand 1 (PD-L1), in the tumor microenvironment. “This would seem to be a no-brainer— you would think you have to have the target for a drug to work,” Dr. Johnson noted. “It turns out this is not the greatest biomarker,” he said, although many studies have shown a loose correlation between the presence of PD-L1 in the tumor microenvironment and response. Looking not just at the microenvironment, but the tumor itself, may indicate whether “there is something more immunogenic about some tumors compared to others,” Dr. Johnson added. This is where next-generation sequencing may be particularly useful.
High Mutational Load
HUMAN CANCERS have a wide spectrum of numbers of mutations, with higher mutational burdens in “carcinogen-induced cancers, such as melanoma, lung cancer, and bladder cancer. Melanoma has perhaps the highest mutational load, but there is dramatic heterogeneity, even within melanoma,” Dr. Johnson reported.
“We didn’t think many of these mutations had much of an impact on the cancer, but it is very clear that tumors with higher mutational burden in lung cancer have a dramatically better outcome than patients with lower mutational burdens. This has also been shown in colon cancer and other cancers with mismatch-repair deficiencies and high mutational burdens,” Dr. Johnson continued.
Total-genome or total-exome sequencing to determine mutational burden “requires a substantial amount of sequencing and analysis” and has other limitations, including expense and turnaround time, Dr. Johnson noted. An alternative would be to use a “more limited platform like FoundationOne, to capture a surrogate burden,” he said. FoundationOne is a hybrid capture-based sequencing platform of 315 genes, 1.25 megabases of DNA.
In a recently published study,4 FoundationOne was used to sequence 62,150 tumors, 4,328 had high mutational burden, and 699 also had high microsatellite instability. “It is interesting that many of the tumor types have high tumor mutation burden but are still microsatellite stable,” Dr. Johnson commented. “I have some reservations about using microsatellite instability testing as the only way of looking for high mutational burden cancers, when many tumor types need a more comprehensive measure.”
Dr. Johnson and his group performed a study to test whether high mutation burden on the FoundationOne platform could predict responses to immunotherapy.5 An initial cohort of 32 patients, those who responded to treatment, “had substantially higher mutational burden than patients who failed to respond,” Dr. Johnson reported. Results were similar in a validation cohort of 33 patients. Response rates were stratified by mutational burden, with the cutoff for high mutational load being 23.1 mutations per megabases. Among those with high mutational load in both cohorts, the overall response rate was 85%, vs < 30% for those with lower levels of mutations. The stratification by mutational burden “is clearly not perfect,” Dr. Johnson acknowledged, as there were some responders in low and particularly in medium mutational burden groups.
Phase II Trial in NSCLC
A PHASE II clinical trial is testing the hypothesis of whether high mutational load will correlate with response to anti–PD-1 across tumor types. Mutational burdens will be determined by FoundationOne or other similar sequencing platforms, according to Dr. Johnson. The trial is starting at Northwestern, Vanderbilt, and several other centers with 47 patients with stage IV or recurrent NSCLC and ≥ 20 mutations/megabase. Patients will receive nivolumab at 240 mg every 2 weeks until disease progression or unacceptable toxicity. ■
DISCLOSURE: Dr. Johnson reported no conflicts of interest.
2. Larkin J, et al: Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373:23-34, 2015.
3. Tumeh PC, et al: PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568-571, 2014.
4. Chalmers ZR, et al: Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 9:34, 2017.
5. Johnson DB, et al: Targeted next generation sequencing identifies markers of response to PD-1 blockade. Cancer Immunol Res 4:959-967, 2016.