Tumors with mismatch repair deficiency (MMRD) or tumors with high tumor mutational burden (TMB) respond better to therapy with checkpoint inhibitors than tumors without these properties.
Fernanda Herrera, University Hospital Lausanne (Switzerland), summarized important studies on tumor treatment with immunotherapeutics in a highlight session at the ESMO Congress 2019 in Barcelona.
A mismatch repair deficiency (MMRD), as in Lynch syndrome (alternatively called hereditary non-polyposis colorectal cancer or HNPCC), or a sporadic MMRD develop as spontaneous mutations can no longer be recognized and repaired. Insertions, deletions, and altered microsatellites accumulate in the newly replicated DNA. Microsatellite instability (MSI) is characterized by the appearance of new alleles within short repetitive DNA sequences (microsatellites). Immune checkpoints are strongly expressed in MMRD tumors, which are highly inflamed. However, not all MMRD tumors have high TMB.
The hypothesis of Diaz and colleagues was that treatment of MMRD tumors with PD1 inhibitors can induce a potent antitumor immune response not only in colorectal cancer but also in other tumors with MMR deficiency1. This was based on findings that patients with MMRD colorectal cancer responded significantly better to treatment with a PD1 inhibitor than patients with colorectal cancer without MMRD. They analyzed the pooled data from the KEYNOTE 158 and KEYNOTE 164 Phase 2 studies, in which 28 tumor types were monitored for at least another 18 months. Included were 124 patients with MSI-H colorectal cancer and 233 patients with non-colorectal MSI-H tumors, such as endometrial carcinoma (n = 49), gastric carcinoma (n = 24), cholangiocarcinoma (n = 22) or pancreatic carcinoma (n = 22). The patients were median 59 years old, 98% had received at least one pre-therapy and all were treated with standard-dose pembrolizumab.
The primary endpoint (the objective response rate) was 34% in the total population, 8% achieved a complete response. The median duration of response has not yet been reached (range 2.9 to 31.3+ months). This resulted in an overall median survival of 27.8 months with a 2-year survival rate of 52%. Median progression-free survival (PFS) was 4 months, but the curve flattened out and after 2 years 31% of patients were still without progression. The benefit was seen in almost all tumor types, but pancreatic carcinomas and glioblastomas did not respond well to pembrolizumab therapy.
Pembrolizumab thus develops a high antitumor activity with a sustained response in patients with MSI-H tumors regardless of tumor type.
TMB is a predictor of the efficacy of checkpoint inhibitors. Marabelle and colleagues investigated the association of TMB with the outcome of patients in the KEYNOTE-158 study2. The KEYNOTE-158 study is a phase 2 basket trial investigating the efficacy and tolerability of pembrolizumab in various tumor types such as small cell lung cancer (SCLC), mesothelioma, anal, biliary, cervical, endometrial, thyroid or vulvar cancer. They received pembrolizumab for 35 cycles or until progression or intolerance.
99 patients (13.2%) had a high TMB in tissue. They were tracked at a median of 11.7 months. 652 patients (86.8%) did not have a high TMB, they were observed for a median of 13.1 months. High TMB was defined as ≥ 10 mutations/Mb. In the group with high TMB, 65.7% were PD-L1 positive and 14.1% showed high MSI-H. Patients with high TMB responded better to pembrolizumab therapy with 28.3% than patients with low TMB (6.5%). The median duration of response has not yet been reached for both groups.
The authors concluded that TMB is a good biomarker for the effect of pembrolizumab in different tumor types.
The optimal duration and timing of treatment with checkpoint inhibitors are not yet known. In some patients, the response persists despite a therapy halt. So far, there is only limited data available on the efficacy of re-treatment with a checkpoint inhibitor after a pause, when the disease progresses again. Sheth and colleagues3 investigated the efficacy of PD-L1 inhibitor durvalumab retreatment in 1,022 patients with advanced solid tumors. They had been treated with durvalumab for up to one year in the Phase 1/2 study NCT01693562. Patients who responded to the treatment stopped them after 1 year and could be treated again with durvalumab if they progressed.
Of the 1,022 patients, 168 stopped durvalumab treatment after 1 year because there was no progression recurrence. Of these, 71 patients were treated again with the PD-L1 inhibitor at progression. In the median, the patients had not been treated for 8.9 months. 11.4% achieved a partial response, 60% a stabilization of disease. Of the 8 patients with partial response during retreatment, 5 (63%) had initially shown a complete/partial response.
The authors concluded that retreatment is a promising strategy. The benefit of the treatment is not tumor or histology-specific. However, the data still has to be validated prospectively. The optimal duration of PD-(L1)-treatment remains unknown.
PARP inhibition in BRCA-mutated tumors leads to the accumulation of DNA damage and genome instability, which ultimately triggers cell death. According to preclinical data in BRCA1-deficient mice, PARP inhibition increases PD-L1 expression, increases T cell infiltration in tumors, and triggers an antitumor immune response via a STING pathway. This suggests combining the PARP inhibitor olaparib with the PD-L1 inhibitor durvalumab. At the ESMO Congress, Domchek and colleagues presented initial data from the MEDIOLA study of patients with BRCA-mutated HER2-negative metastatic breast cancer who had undergone partial chemotherapy4. They received olaparib and durvalumab until progression. Primary endpoints were disease control rate (DCR) at 12 weeks and safety. Of the 30 patients, 43% were hormone-receptor-positive and 57% were triple-negative. 30% had not been chemotherapeutically pretreated.
Treatment was generally well-tolerated. There were no new previously unknown adverse effects of these therapies.
The objective response rate was 63.3%. The greatest effect with an objective response rate of 70% was seen in the group with 0 to 1 pre-therapy. The median response was 9.2 months. The median PFS was 8.2 months, the median OS 21.5 months.
The combination of durvalumab and olaparib in this study showed promising long-term activity and tolerability in patients with metastatic breast cancer and BRCA germline mutation.
1. Diaz AL, et al. Pembrolizumab in microsatellite instability high cancers: Updated analysis of the phase II KEYNOTE-164 and KEYNOTE-158 studies. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 11740.
2. Marabelle A, et al. Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 11920.
3. sheth S, et al. durvalumab activity in previously treated patients who stopped durvalumab without disease progression. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 11750.
4. Domchek S, et al. Phase II study of olaparib and durvalumab (MEDIOLA): Updated results in patients with germline BRCA-mutated metastatic breast cancer. ESMO 2019 Annual Meeting, 27 September to 1 October 2019, Barcelona, 11910.
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