NSCLC RESPONDING TO IMMUNOTHERAPY

Immunotherapy with drugs that act on the program death (PD) pathway offers a novel approach to the treatment of non–small cell lung cancer (NSCLC), and a new study provides insights into how these drugs may result in lasting and durable responses in these patients.

The new study, published online on March 12 in Science, suggests that patients with a high mutational burden in their tumors may be most likely to benefit from treatment with a PD-1 inhibitor.

"The study suggests that the genomic landscape of lung cancers shapes the response to anti-PD-1 therapy," corresponding author Timothy Chan, MD, PhD, cancer geneticist in the Human Oncology and Pathogenesis Program and vice chair of radiation oncology at the Memorial Sloan Kettering Cancer Center (MSKCC), in New York City, commented in an institution press release.

The study used pembrolizumab (Keytruda, Merck Sharp & Dohme Corp.), which is in clinical trials in NSCLC as well as other tumor types and is currently approved for use in melanoma. However, another PD inhibitor drug, nivolumab (Opdivo, Bristol-Myers Squibb Company) was very recently approved for use in NSCLC after it showed a survival benefit compared with chemotherapy in patients with advanced disease.

"In contrast to responses seen with chemotherapy and molecular-targeted therapies, in lung cancer, we see that when responses occur with immunotherapy, such as pembrolizumab, it lasts for a long time," commented co–first author Matthew D. Hellmann, MD, thoracic medical oncologist at Memorial Sloan Kettering Cancer Center. Although the response to PD-1 blockade therapy has been truly remarkable, the critical challenge has been to identify those patients most likely to benefit, he told Medscape Medical News.

"We examined the genetics of lung cancers treated with pembrolizumab to see how genetics may impact and predict response," he said, adding, "We were building on the melanoma story."

A few months ago, the same team explained why some patients with melanoma respond to immunotherapy with another checkpoint inhibitor drug, ipilimumab (Yervoy, Bristol-Myers Squibb Company).

"We hypothesized that the immune system can be increasingly exhausted by the extent of DNA damage in tumors. By sequencing tumors from patients with lung cancer treated with pembrolizumab, we were able to show for the first time that PD-1 inhibitors worked best in those tumors that had the most DNA damage," Naiyer A. Rizvi, MD, co–first author and now Price Chair of Clinical Translational Medicine and director of thoracic oncology and immunotherapeutics at Columbia University Medical Center, New York City, told Medscape Medical News.

Identifying the Tumors That Respond Best

The NSCLC study followed a strategy similar to that used in the team's earlier study in melanoma. For the discovery set, researchers undertook whole-exome sequencing of DNA of tumor and normal tissue from 16 patients with NSCLC who were treated with pembrolizumab.

Exome sequencing provides sequences for all protein-coding genes in the DNA.

Tumors were divided into high ("nonsynonymous mutational burden") and low mutational burden groups. Mutational burdens were then correlated with clinical outcomes, such as objective response rate (ORR), durable clinical benefit (DCB) (partial or stable responses lasting for 6 months or more), and progression-free survival (PFS). All clinical outcomes were significantly higher in patients with a high mutation burden (see Table).

In a validation cohort of 18 patients, the researchers showed that clinical responses followed a pattern similar to that seen in the discovery set.

Table

	High Mutational Burden	Low Mutational Burden	P-value
Discovery cohort (n = 16)
DCB	73%	13%	0.04
ORR	63%	0%	0.03
PFS	14.5 months	3.7 months	0.01
Validation cohort (n = 18)
DCB	83%	22%	0.04
PFS	Not reached	3.4 months	0.006
DCB, durable clinical benefit; ORR, objective response rate; PFS, progression-free survival.

In a pooled analysis of all 34 patients, the researchers showed that certain changes (C→A transversions), which are characteristic of smoking-related mutational change, were more frequent in patients showing clinical responses. A previously validated classifier that distinguishes tumors that do or do not harbor a molecular signature of smoking-related mutational change (transversion- high [TH] vs transversion-low [TL]) was also applied.

In their analysis of 34 patients treated with pembrolizumab, the researchers showed that ORR was 56% for patients with TH tumors and 17% in patients with TL tumors, which had a never-smoking signature; DCB was also significantly high for patients with tumors that were imprinted with the molecular signature of smokers (77% vs 22%; P =.004).

"The mutational landscape of responders to pembrolizumab was truly unique. The relationship between nonsynonymous mutation burden and transversion-high tumors with response to pembrolizumab was remarkably reproducible between the discovery and validation sets," Dr Rizvi said.

In previous studies, PD-L1 expression in tumor tissue has been shown to be predictive of response to PD-1 inhibitors, he noted. "However, our analyses have shown that coupling PD-L1 expression with mutation burden is incredibly robust," he added.

The DCB rate was 91% in patients with a high mutational burden and any level of PD-L1 expression; in contrast, patients with a low mutational burden and some level of PD-L1 expression had a DCB of only 10%.

Understanding the Data

Both Dr Rizvi and Dr Hellmann expanded on the findings in interviews with Medscape Medical News. The genetic damage that occurs within tumors can generate tumor-specific antigens that can be recognized by the immune system, Dr Rizvi explained.

Inasmuch as a similar trend was seen in melanomas treated with ipilimumab, the concept that mutation burden is associated with response to immunotherapy may transcend histology and categorizations of cancers based on the site of origin, Dr Hellmann said.

"We hypothesized that in patients with tumors with a high mutational burden, those tumors that look particularly different ― or 'foreign' ― to the immune system are most likely to produce tumor-specific T-cell response," Dr Hellmann told Medscape Medical News.

Indeed, the researchers looked at the landscape of neoantigens, which identifies mutant nonamers that are predicted to be presented on the surface of tumor cells as antigens.

They showed that tumors from patients with DCB had a significantly higher "neoantigen burden," and a higher neoantigen burden was also associated with higher PFS.

In the peripheral blood of one patient who responded to pembrolizumab, the researchers were able to identify a neoantigen-specific T-cell response — which may explain why immunotherapy is working in this patient.

Other Players May Also Contribute to High Mutation Burden

Besides smoking-related changes, the researchers were also able to identify other mutations present in lung cancer that may contribute to a high mutation burden and response to PD-1 inhibition.

Specifically, they noted deleterious mutations in DNA repair and replication genes that have a higher mutation burden response and a higher response to pembrolizuamb, such as POLD1, POLE, and MSH2.

Some of these mutations occur in never-smokers with a high mutational burden, and that may explain why some never-smokers may also respond to therapy with PD-1 inhibitors.

Taking the Research to the Next Level

Both Dr Rizvi and Dr Hellmann shared their thoughts about next steps with Medscape Medical News.

In prospective studies under way at MSKCC and Columbia University Medical Center, NSCLC patients are being treated with PD-1 inhibitors. Tissue samples are prospectively collected for analysis of the genomics and immunophenotype of patients with lung cancers in order to comprehensively assess the predictive correlates of response and resistance.

This approach will be extended to all other potential tumors that respond to therapy with PD-1 inhibitors, such as renal cell carcinoma (RCC), bladder cancer, and head and neck cancer, the researchers noted.

The analysis in RCC is particularly intriguing, because RCC is a cancer that does not typically carry a high mutational burden, Dr Hellmann told Medscape Medical News.

These studies will provide insights into the interplay between genomics and immunobiology to help fully understand the predictors and mediators of response to PD-1 blockade, he added.

Several authors on the article report a pending patent related to determinants of cancer response to immunotherapy; some report personal fees, grant support, and/or nonfinancial support from industry.

Science. Published online March 12, 2015. Abstract