The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

/pdf/mismatch-repair-deficiency-predicts-response-of-solid-tumors-2mgnsq9rdf.pdf

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.

https://escholarship.org/content/qt7gf847t7/qt7gf847t7.pdf?t=qaejdd

Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.

Summary Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care. For many of the most common cancers in low-income and middle-income countries, radiotherapy is essential for effective treatment. In high-income countries, radiotherapy is used in more than half of all cases of cancer to cure localised disease, palliate symptoms, and control disease in incurable cancers. Yet, in planning and building treatment capacity for cancer, radiotherapy is frequently the last resource to be considered. Consequently, worldwide access to radiotherapy is unacceptably low. We present a new body of evidence that quantifies the worldwide coverage of radiotherapy services by country. We show the shortfall in access to radiotherapy by country and globally for 2015–35 based on current and projected need, and show substantial health and economic benefits to investing in radiotherapy. The cost of scaling up radiotherapy in the nominal model in 2015–35 is US$26·6 billion in low-income countries, $62·6 billion in lower-middle-income countries, and $94·8 billion in upper-middle-income countries, which amounts to $184·0 billion across all low-income and middle-income countries. In the efficiency model the costs were lower: $14·1 billion in low-income, $33·3 billion in lower-middle-income, and $49·4 billion in upper-middle-income countries—a total of $96·8 billion. Scale-up of radiotherapy capacity in 2015–35 from current levels could lead to saving of 26·9 million life-years in low-income and middle-income countries over the lifetime of the patients who received treatment. The economic benefits of investment in radiotherapy are very substantial. Using the nominal cost model could produce a net benefit of $278·1 billion in 2015–35 ($265·2 million in low-income countries, $38·5 billion in lower-middle-income countries, and $239·3 billion in upper-middle-income countries). Investment in the efficiency model would produce in the same period an even greater total benefit of $365·4 billion ($12·8 billion in low-income countries, $67·7 billion in lower-middle-income countries, and $284·7 billion in upper-middle-income countries). The returns, by the human-capital approach, are projected to be less with the nominal cost model, amounting to $16·9 billion in 2015–35 (–$14·9 billion in low-income countries; –$18·7 billion in lower-middle-income countries, and $50·5 billion in upper-middle-income countries). The returns with the efficiency model were projected to be greater, however, amounting to $104·2 billion (–$2·4 billion in low-income countries, $10·7 billion in lower-middle-income countries, and $95·9 billion in upper-middle-income countries). Our results provide compelling evidence that investment in radiotherapy not only enables treatment of large numbers of cancer cases to save lives, but also brings positive economic benefits.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(15)00222-3.pdf

Expanding global access to radiotherapy

http://static.guim.co.uk/ni/1432986420413/Ann-Oncol-2015.pdf

A standardised, generic, validated approach to stratify the magnitude of clinical benefit that can be anticipated from anti-cancer therapies: the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS)

Global colorectal cancer burden in 2020 and projections to 2040

The price of patented cancer drugs in the USA rises steadily after their launch, according to a study by Noa Gordon (Rabin Medical Centre, Petah Tikva, Israel) and colleagues. The researchers calculated the monthly, annual, and cumulative changes in the cost of 24 patented injectable cancer medications that obtained US Food and Drug Administration (FDA) approval between 1996 and 2012. Overall, the mean cumulative cost increase of all 24 drugs was 36·5% (95% CI 24·7–48·3) over the total follow-up of 12 years (mean 8 years [range 3 to 12]). After adjustment for inflation, the average drug price increase over the study period was 18% (range –16 to 59). During the 12 years, the percentage change in the cumulative inflationadjusted monthly cost of the monoclonal antibodies rituximab and trastuzumab was 49% and 44%, respectively. Despite an annual general inflation rate growth of 1·09% and health-related inflation rate of 1·15% during the 12 years, the cost of the 24 cancer medications increased by an annual average of 3·73%. These price increases occurred independently of the introduction of competitors in the market, the addition of off-label indications, or new supplemental FDA approvals. Mariana Socal (Johns Hopkins University, Baltimore, MD, USA) explained, “The patent protection enables the price increases and prevents these increases from being mitigated by generic competitors entering the market”. Socal added that manufacturers often find means of extending patents that are nearing expiration by patenting new drug formulations, devices for application, or drug combinations. “Once they have obtained patent protection, pharmaceutical companies can start marketing and influence providers’ decisions.” Co-author Daniel Goldstein (Rabin Medical Centre) believes that the rising costs are partly attributable to insufficient regulation. “The other factor is that Medicare has to provide FDA-approved drugs, but it is not permitted to negotiate with the manufacturers on cost”, he explained. He added that FDA Commissioner Scott Gottlieb has attempted to address some of the issues around drug pricing, although his focus so far has largely been on generic drugs and their entry into the market. “It will be interesting to see if he decides to do anything related to patented drugs and their price changes”, concluded Goldstein.

Rising cancer drug costs in the USA

A new study has reaffi rmed the value of fl exible sigmoidoscopy screening for colorectal cancer. The trial randomly assigned roughly 100 000 individuals aged 50–64 years taken directly from the Norwegian Population Register. 78 220 individuals were included in the control group, and the remaining 20 572 were assigned to screening; either to fl exible sigmoidoscopy or, in equal numbers, to fl exible sigmoidoscopy in combination with once-only immunological faecal occult blood test (FIT). 12 955 (63%) of 20 572 patients adhered to screening, and after a median follow-up of 10·9 years, mortality from colorectal cancer was significantly lower in the screening group as a whole than in the control group (hazard ratio [HR] 0·73, 95% CI 0·56–0·94; p=0·02), as was overall disease incidence (HR 0·80, 0·7–0·92; p=0·001). Moreover, eff ectiveness did not diff er between fl exible sigmoidoscopy alone and its use in combination with FIT. The results are in keeping with previous large-scale clinical trials of fl exible sigmoidoscopy, one of which showed a decrease in colorectal cancer mortality of 43% among those screened. So the efficacy of flexible sigmoidoscopy seems to be established. “The problem is we don’t have head-to-head comparisons between the diff erent screening tests”, explained lead author Oyvind Holme (Sorlandet Hospital, Kristiansand, Norway). England is rolling out flexible sigmoidoscopy for men and women aged 55 years, in addition to its operational guaiac faecal occult blood test (FOBT) screening programme for those aged 60–74 years. “There is lots of evidence that FOBT works, but it does not reduce mortality very much and there is no evidence that it reduces incidence”, points out Wendy Atkin (Imperial College London, UK). She believes the crucial question is how fl exible sigmoidoscopy compares with FIT. “The UK will probably end up replacing FOBT with FIT”, she commented. FIT is more sensitive and specifi c. “It is a very simple test but it has to be done every 2 years, and we don’t know how it works over multiple runs.” Holme suggests that countries introducing national colorectal cancer screening programmes should do so as randomised trials comparing two of the screening methods. “They should use this opportunity to evaluate the tests”, he concluded.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(14)70394-8.pdf

Talha Khan Burki

Papers

Rising cancer drug costs in the USA

Flexible sigmoidoscopy screening for colorectal cancer.

Darolutamide for non-metastatic, castration-resistant prostate cancer

Pomalidomide for symptomatic Kaposi's sarcoma

BRICS nations tackle non-communicable diseases