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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. The genomes of cancers deficient in mismatch repair (MMR) contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with MMR deficiency were sensitive to immune checkpoint blockade with anti-PD-1 antibodies. We have expanded this study to now evaluate efficacy of PD-1 blockade in patients with advanced MMR-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 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 MMR-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

Therapy with immune checkpoint inhibitors has uncovered a subset of tumors that are highly responsive to an endogenous adaptive immune response. When the interaction between the checkpoint ligands and their cognate receptors on the effector cells is blocked, a potent and durable anti-tumor response can be observed and on occasion this response can be accompanied by severe autoimmunity (–). These findings support the notion that many cancer patients contain in their immune system the capacity to react selectively to their tumors, ostensibly through recognition of tumor-specific antigens.The molecular determinants that define this subset of tumors is still unclear, however several markers, including PD-L1 expression, RNA expression signatures, mutational burden and lymphocytic infiltrates have been evaluated in specific tumor types (–). Though such markers appear to be helpful in predicting response in specific tumor types, none of them have been evaluated prospectively as a pan-tumor biomarker. Another potential determinant of response is mutation-associated neoantigens (MANAs) that are encoded by cancers (–).

As previously described, mismatch-repair deficient cancers are predicted to have a very large number of MANAs that might be recognized by the immune system (–). This prediction led us to conduct a small phase II study, focused on eleven patients with colorectal cancers, in which it was demonstrated that PD-1 blockade was an effective treatment for many patients with these tumors. Since the initiation of that trial, other studies have shown that the number of mutations in MMR-proficient cancers correlates with the response to PD-1 blockade, providing further support for a relationship between mutation burden and treatment response.The genomes of mismatch repair-deficient tumors all harbor hundreds to thousands of somatic mutations, regardless of their cell of origin. We therefore sought to investigate the effects of PD-1 blockade (using the anti-PD-1 antibody pembrolizumab) in mismatch-repair tumors independent of the tissue of origin. In the current study, we prospectively evaluated the efficacy of PD-1 blockade in a range of different subtypes of mismatch repair-deficient cancers ( number, NCT01876511).Eighty-six consecutive patients were enrolled between September 2013 and September 2016.

The data cutoff was December 19, 2016. All patients received at least one prior therapy and had evidence of progressive disease prior to enrollment. Twelve different cancer types were enrolled in the study. All enrolled patients had evidence of mismatch repair-deficiency as assessed by either polymerase chain reaction or immunohistochemistry. For most cases, germline sequencing of MSH2, MSH6, PMS2 and MLH1 was performed to determine if the mismatch repair-deficiencies were associated with a germline change in one of these genes (i.e., whether the patients had Lynch Syndrome). Germline sequence changes diagnostic of Lynch syndrome were noted in 32 cases (48%), with MSH2 being the most commonly mutated gene.

In seven additional cases where germ line testing was not performed, the patient reported a family history consistent with a diagnosis of Lynch syndrome. Patient survival and clinical response to Pembrolizumab across 12 different tumor types with mismatch repair deficiency( A) Tumor types across 86 patients. ( B) Waterfall plot of all radiographic responses across 12 different tumor types at 20 weeks. Tumor responses were measured at regular intervals and values show the best fractional change of the sum of longest diameters (SLD) from the baseline measurements of each measurable tumor. ( C) Confirmed radiographic objective responses at 20 weeks in blue compared to the best radiographic responses in the same patients in red. The mean time to the best radiographic response was 28 weeks. ( D) Swimmer plot showing survival for each patient with mismatch repair deficient tumors, indicating death, progression and time off therapy.

( E) Kaplan-Meier estimates of progression-free survival and ( F) overall patient survival.The adverse events to treatment were manageable, and similar to those found in other clinical studies employing pembrolizumab, as shown in. While 74% of patients experienced an adverse effect, most were low grade. Endocrine disorders, mostly hypothyroidism, occurred in 21% of patients and was easily managed with thyroid hormone replacement.Seventy-eight patients had disease that could be evaluated by Response Evaluation Criteria In Solid Tumors (RECIST). Objective radiographic responses were noted in 53% of patients (46 of 86 patients; 95% CI, 42–64%), with 21% (n = 18) achieving a complete radiographic response. Disease control (measured as partial response + complete response + stable disease) was achieved in 66 (77%) of the 86 patients (95% CI, 66–85%).

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Radiographic responses could be separated into two classes. First, in twelve cases, scans at 20 weeks showed stable disease, which eventually converted to an objective response (measured as tumor size reduction in response to therapy, according to RECIST criteria). Second, in eleven additional cases, we observed an initial partial response or stable disease at the 20-week scan that later converted to complete responses while treatment was continued. The average time to any response was 21 weeks and the average time to complete response was 42 weeks.

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Adobe lightroom crack mac. Of note, the objective response rate was similar between colorectal cancer versus other cancer subtypes. Specifically, objective responses were observed in 52% (95% CI 36 to 68%) of patients with colorectal cancers and 54% (95% CI 39 to 69%) of the patients with cancers originating in other organs. There was also no significant difference in the objective response rate between Lynch and non-Lynch syndrome-associated tumors; 46% (95% CI of 30 to 63%) versus 59% (95% CI of 41 to 76%), respectively (p = 0.27). Summary of therapeutic response to pembrolizumab (anti-PD-1) treatmentRadiographic responses, progression-free survival (PFS) and overall survival (OS) estimates were measured using the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guidelines. Patients were considered not evaluable if they did not undergo a 12-week scan due to clinical progression.

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The rate of disease control was defined as the percentage of patients who had a complete response, partial response, or stable disease for 12 weeks or more. NR, not reached. Neither median progression-free survival (PFS) nor median overall survival (OS) has yet been reached (median follow-up time of 12.5 months; ) and the study is ongoing. However the estimates of PFS at 1- and 2-years were 64% and 53%, respectively. The estimates of OS at 1- and 2-years were 76% and 64%, respectively, which is markedly higher than expected based on the advanced state of disease in this cohort. The PFS and OS was not significantly different in patients with colorectal cancers as compared to those with other cancer types. Neither PFS (HR 1.2; 95% CI of 0.582 to 2.512, p = 0.61) or OS (HR 1.71; 95% CI of 0.697 to 4.196; p = 0.24) were influenced by tumors associated with Lynch Syndrome.Eleven patients achieved a complete response and were taken off therapy after two years of treatment.

No evidence of cancer recurrence has been observed in those patients with a median time off therapy of 8.3 months. Seven other patients had residual disease by imaging, but pembrolizumab was discontinued after reaching the 2-year milestone or because of intolerance to therapy. To date, the average time off therapy for this group was 7.6 months.

As of the data cutoff, none of these patients has shown evidence of progression since discontinuation of pembrolizumab.Twenty patients with measurable radiographic disease underwent percutaneous biopsies between 1 month and 5 months after the initiation of therapy. Twelve of these biopsies demonstrated no evidence of tumor cells and were shown to have varying degrees of inflammation, fibrosis and mucin, consistent with an ongoing immune response. The other eight cases showed residual tumor cells. The absence of cancer cells in post-treatment biopsies was a strong predictor of progression free survival (HR for PFS was 0.189, 95% CI 0.046 to 0.767, p = 0.012) with median PFS of 25.9 months versus 2.9 months for biopsies with evidence of residual tumor. While there was no significant difference in OS between patients whose biopsies were positive or negative for tumor cells, median OS has not yet been reached in patients with negative biopsies.Primary clinical resistance to initial therapy with pembrolizumab (as measured by progressive radiographic disease on the first study scan) was noted in twelve (14%) patients. We determined the exomic sequences of tumor and matched normal DNA from three of these patients and compared them to the exomes of 15 primary tumors from patients that had achieved objective responses to the therapy.

The three therapy-insensitive tumors harbored an average of 1,413 non-synonymous mutations, not significantly different from the number in patients with objective responses (1,644 non-synonymous mutations; p = 0.67, Student’s t test). The gene ( B2 M) encoding β2-microglobulin, a protein required for antigen presentation , was not mutated in any of the primary tumors from the resistant group.Only five cases of acquired resistance were noted, where patients developed progressive disease after an initial objective response to pembrolizumab. Three of these cases were atypical in that the tumors emerged in occult sites such as the brain (two cases) or bone (one case). All three cases were treated with local therapy (radiation or surgery) and patients survived and continued treatment with pembrolizumab. However, in accordance with study design, these three patients are listed in.