Medical World News: Clinical Updates

Tumor Mutational Burden Predicts Who Will Respond to Immunotherapy

The advent of immunotherapy has significantly shifted the treatment paradigm and prognosis for multiple advanced-stage cancers. In cancers like metastatic melanoma and non—small cell lung cancer (NSCLC), the treatment class has greatly improved survival rates.

However, not all patients respond to the treatments, highlighting the need for predictive biomarkers to determine who will benefit. Early reports and small cohorts suggest that high tumor mutational burden (TMB) is associated with improved clinical response, and now the results of a large study¹ confirm the hypothesis.

“Given the potential toxicities of immunotherapy and the highly variable response to immune checkpoint inhibitors, as well as the significant economic cost of these agents, there is an urgent need for biomarkers that can predict immunotherapy response,” the researchers of the study explained.

Looking at data from more than 1000 patients with stage IV or metastatic disease for which immune checkpoint inhibitors are approved, including NSCLC, melanoma, renal cell carcinoma, bladder cancer, and head and neck cancer, researchers found that higher somatic TMB is associated with improved overall survival.

Patients were treated with atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), or tremelimumab. TMB was calculated by normalizing the number of somatic nonsynonymous mutations to the total of megabases sequenced, and noting that mutational load varied across tumor types, the researchers defined TMB within each cancer type.

The authors found that, across all cancers, more mutations translated into improved overall survival. The authors noted that the association remained even when removing NSCLC and melanoma from the analysis.

“Although the effect for some individual cancers did not reach statis- tical significance, possibly because of smaller sample size, the numerical trend of better overall survival was observed in nearly all cancer types, with glioma the clearest exception,” the authors wrote. These findings mirror real-world evidence, which has shown gliomas to be immunosuppressive and remain difficult to treat.²

Of note, what constituted as high TMB varied greatly by cancer type, which suggests there is likely not a viable universal number that could define high tumor mutational burden and predict response to immune checkpoint inhibitors across all cancers. Although breast cancers and renal cell carcinomas only need 6 mutations per 1 million DNA to predictably respond well to immune checkpoint inhibitors, melanomas need 30.7 and colorectal cancers need 52.2.

According to the researchers, this can likely be explained by distinct tumor microenvironments as well as other factors that have been shown to independently predict response, including clonality, immune infiltration, and immune cell exclusion.

REFERENCES:

1. Samstein R, Lee C, Shoushtari A, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types [published online January 14, 2019]. Nature. doi: 10.1038/s41588-018- 0312-8.
2. Dangi-Garimella S. Identifying rational immunotherapy combinations for glioblastoma: a progress report. The American Journal of Managed Care^® website. ajmc.com/conferences/asco-2018/identifying-rational-immunotherapy-combinations-for-glioblastoma-a-progress-report. Published June 2, 2018. Accessed January 19, 2019.

Once-Weekly Carfilzomib Improves PFS, OS in High-Risk Patients With MM Over Twice-Weekly Dose

Patients with multiple myeloma who have high-risk cytogenetic abnormalities typically have shorter progression-free survival (PFS) and overall survival (OS) compared with standard-risk patients, but carfilzomib (Kyprolis) has been shown to improve survival in high-risk patients.

A study presented at the 60th American Society of Hematology Annual Meeting & Exposition investigated the role of carfilzomib, a second-generation protease inhibitor, in high-risk patients with newly diagnosed multiple myeloma (NDMM) based on an analysis of 2 phase 1/2 studies. Patients were transplant ineligible and received nine 28-day induction cycles of carfilzomib, either 70 mg/m² once weekly or 36 mg/m² twice weekly, plus once-weekly 300 mg/m2 cyclophosphamide and 40-mg dexamethasone.

A total of 121 NDMM patients were enrolled in the 2 studies, and cytogenic data were available for 94 patients. Overall, 37 patients (31%) had high-risk chromosomal abnormalities: 18% had del(17p), 10% t(4;14), and 3% t(14;16).

After the induction phase, results were similar between the standard- and high-risk groups, with overall response rates of 86% and 92%, respectively, and near complete responses of 39% and 41%.

However, after a median follow-up of 39 months, the median PFS was not reached in standard-risk patients but was 27.8 months in high-risk patients (HR, 0.76; P = .38). High-risk patients treated with once-weekly carfilzomib saw a greater PFS benefit, with a median PFS of 39.6 months, compared with a median PFS of 24.2 months for high-risk patients treated with twice-weekly carfilzomib.

In standard-risk patients, the median OS was not reached during the follow-up period and was 47.5 months in high-risk patients. Again, patients taking the once-weekly dose saw improved outcomes. The median OS for high-risk patients taking the once-weekly dose was 47.5 months compared with 44.1 months in high-risk patients receiving the twice-weekly dose.

“As compared to twice-weekly carfilzomib at 36 mg/m², once-weekly carfilzomib, at the dose of 70 mg/m², confirmed to be effective in high-risk patients,” the authors concluded. “These data support the use of carfilzomib for the treatment of high-risk NDMM patients.”

REFERENCE:

Cervical Cancer Screening Rates "Unacceptably Low," Researchers Find

Mina R, Larocca A, Petrucci MT, et al. Long-term carfilzomib for high-risk patients with newly-diagnosed multiple myeloma: a pooled analysis of two phase 1/2 studies. Presented at 60th American Society of Hematology Annual Meeting & Exposition; December 2, 2018. San Diego, CA. Abstract 3240. ash.confex.com/ash/2018/ webprogram/Paper112075.html.January marked Cervical Health Awareness Month, during which healthcare stakeholders emphasized the importance of screening for the disease, which has reduced the incidence of cervical cancer death by more than 60% since its introduction in the 1950s. However, the percentage of women who get screened for cervical cancer may be far lower than national data suggest, according to Mayo Clinic researchers.

As of 2012, cancer screening guidelines recommend Papanicolaou (Pap) testing every 3 years for women aged 21 to 65 years or Pap—human papilloma virus (HPV) testing every 5 years for women aged 30 to 65 years.

Publishing their study results in Journal of Women’s Health,¹ researchers obtained data from the Rochester Epidemiology Project for women 16 years and older living in Olmstead, Minnesota, from 2005 to 2016 and found that screening rates for all eligible women were well below the Healthy People 2020 goals. The findings contradict self-reported data from the 2015 National Health Interview Study, in which 81% of women reported compliance.

In 2016, less than two-thirds (64.6%) of the 274,178 women aged 30 to 65 years were up to date with cervical cancer screening, most of whom (60.8%) were screened with a Pap—HPV cotest within 5 years. Among women aged 21 to 29 years, more than half (53.8%) were adherent to screening, with the majority screened with Pap tests (47.3%).

“Total Pap and Pap—HPV cotest screening rates in 2016 for adolescent girls and women aged 16 to less than 21 years and more than 65 years were appropriately low, 2.1% and 8.8%, respectively, and were consistent with recommendations against screening women in those age groups,” the researchers noted.

Looking across the study period, there were significant declines in Pap test rates in all age groups but significant increases in Pap—HPV cotesting. Pap testing rates decreased from 62.8% in 2005 to 47.3% in 2016 among women aged 21 to 29 years and from 67.5% to just 3.9% among women aged 30 to 65 years. However, during the same time period, cotesting rates varied for women aged 21 to 29 years, but remained under 10%. Among women aged 30 to 65 years, there was a significant increase in cotesting between 2007 and 2016, jumping from 10% to 60.8%, which suggests increasing adoption of 2012 screening recommendations.

The researchers also observed troubling disparities across racial/ethnic groups. “African American women were 50% less likely to be up-to-date on cervical cancer screening than white women in 2016,” said Kathy MacLaughlin, MD, family medicine specialist, Mayo Clinic, and the study’s lead author, in a statement.² “Asian women were nearly 30% less likely than white women to be current on screening. These racial disparities are especially concerning.”

According to MacLaughlin, clinicians must start thinking outside the box on ways to best reach these women to ensure they are receiving these life-saving screening tests.

REFERENCES:

1. MacLaughlin K, Jacobson R, Breitkopf C, et al. Trends over time in Pap and Pap—HPV cotesting for cervical cancer screening [published online January 7, 2019]. J Womens Health. doi: 10.1089/jwh.2018.7380.
2. Mayo researchers find ‘unacceptable low’ cervical cancer screening rates [press release]. Rochester, MN: Mayo Clinic; January 3, 2019. newswise.com/articles/view/705993/. Accessed January 10, 2019.