AUGUST 2022
This month's featured editor is Dr. Matthew Hellmann, Deputy Editor for the Case Reports section.
“Pembrolizumab plus chemotherapy in advanced triple-negative breast cancer”
by Javier Cortes
et alNEJM (2022)
The previously published results of the protocol-specified second interim analysis of the phase III, randomized, double-blind, international trial KEYNOTE-355 demonstrated that the addition of pembrolizumab to chemotherapy significantly prolonged progression-free survival in patients with triple-negative breast cancer (TNBC) whose tumors express PD-L1. Javier Cortes and colleagues describe the final analysis of KEYNOTE-355, in which pembrolizumab plus chemotherapy treatment led to statistically significant and clinically meaningful improvement in overall survival (OS) for patients with TNBC with a PD-L1 combined positive score (CPS) of 10 or greater. Median OS in the CPS 10 or greater subgroup with pembrolizumab plus chemotherapy treatment was 23.0 months versus 16.1 with chemotherapy alone (hazard ratio 0.73, 95% confidence interval 0.55 to 0.95, p = 0.0185). No significant between-group difference was observed with the addition of pembrolizumab to chemotherapy in the patients whose tumors had PD-L1 CPS of 1 or more. In exploratory analyses, the magnitude of OS benefit with pembrolizumab plus chemotherapy versus chemotherapy alone was not greater with a higher CPS score cutpoint of 20. Similarly, there was no difference in treatment effect between the group with tumors with CPS of 1 to 9 and the group with tumors with CPS of less than 1. Immune-related adverse events occurred in 26.5% of the patients treated with pembrolizumab plus chemotherapy group and 6.4% of those receiving chemotherapy alone, with the most common being hypothyroidism and hyperthyroidism. No deaths due to immune-related adverse events occurred.
Why this matters: The final analysis of KEYNOTE-355 conclusively demonstrates that pembrolizumab plus chemotherapy prolongs survival in TNBC, confirming this regimen as the standard of care for first-line treatment for patients with tumors with PD-L1 CPS greater than 10.
“Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer”
by Patrick M. Forde
et alNEJM (2022)
Roughly 30–50% of patients who undergo curative surgery for resectable non-small cell lung cancer (NSCLC) have disease recurrence leading to mortality. In the first efficacy results from the international, open-label, randomized, phase III trial CheckMate 816, Patrick M. Forde and colleagues report significantly prolonged event-free survival (EFS) and a higher rate of pathologic complete response (pCR) with three cycles of neoadjuvant nivolumab plus chemotherapy versus chemotherapy alone in patients with stage IB to IIIA resectable NSCLC. Rationale for neoadjuvant nivolumab include the well-established role for anti-PD-1 in the management of metastatic NSCLC as well as the opportunity to generate an enhanced immune response with the in situ tumor present prior to surgery. A total of 358 patients were assigned to receive either neoadjuvant nivolumab plus chemotherapy or chemotherapy alone and 176 in each arm underwent treatment. No significant differences emerged in the rates of delayed surgery or surgical complications between the arms, and a trend toward shorter surgeries and more minimally invasive surgeries was seen in the nivolumab group. The 1-year EFS rates were 76.1% and 63.4% for the nivolumab plus chemotherapy and chemotherapy alone groups, respectively. At 2 years, the EFS rates were 63.8% and 45.3% and the benefit was maintained after adjustment for optional adjuvant therapy, disease progression, disease recurrence, or death. In exploratory analyses, patients with stage IIIA disease and patients with PD-L1 expression ≥1% had the greatest magnitude of EFS benefit. The pCR rate was 24.0% for nivolumab plus chemotherapy and 2.2% for chemotherapy alone. In exploratory analyses, patients with pCR had longer EFs. Median OS was not reached in either arm. Among the 89 patients for whom circulating tumor DNA analysis was possible, clearance was observed in 56% of patients in the nivolumab plus chemotherapy arm and 35% of patients in the chemotherapy alone arm—clearance of circulating tumor DNA was associated with improved EFS. Safety was consistent with previous reports and the incidence of immune related adverse events was low.
Why this matters: CheckMate 816 establishes neoadjuvant nivolumab plus chemotherapy as a new standard of care for resectable NSCLC. Future correlative studies are needed to validate the role of pCR and ctDNA analyses as surrogate markers for long-term survival.
“An autoimmune stem-like CD8 T cell population drives type 1 diabetes”
by Sofia V. Gearty
et al Nature (2021)
CD8+ T cells specific for insulin-producing beta cells are known to be responsible for the pathophysiology of type 1 diabetes mellitus, however, the origins and molecular programs sustaining these alloreactive cells has long remained a mystery. By following the fate of endogenous beta cell-specific CD8+ T cell populations over the entire disease course in the non-obese diabetic mouse model, Sofia V. Gearty and colleagues identify a stem-like progenitor population in the pancreatic draining lymph node that gives rise to the self-reactive effectors that destroy insulin-producing cells. A population of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific CD8+ T cells were detectable in the pancreas and pancreatic draining lymph node before diabetes emerged in the mice, as early as 5 weeks of age, and the frequency increased with time to a peak of roughly 0.3% and 20% of the total population in each site by 15–20 weeks, at which time disease emerged in most of the animals. In the pancreatic draining lymph node, 80% of the IGRP-specific CD8+ T cells expressed the memory, longevity, and self-renewal transcription factor TCF1 at high levels. A similar phenotypic split of 80% TCF1hi and 20% TCF1lo was also seen for insulin B-chain specific T cells in the pancreatic draining lymph node. The TCF1hi cells expressed numerous Wnt target genes regulating self-renewal and stemness and were highly clonally diverse whereas the TCF1lo cells had a transcriptional signature characteristic of terminal differentiation and effector function. Notably, the TCF1lo population in the pancreas were transcriptionally distinct from the lymph node-resident TCF1lo cells, indicating further differentiation. Lymph node-derived TCF1hi cells induced diabetes in immunodeficient hosts in adoptive and serial transfers as well as established stable populations of both self-renewing and effector cells, even at very low numbers of transplanted cells. Pharmacologic blockade of lymph node egress protected mice from developing diabetes, emphasizing the importance of the pancreatic draining lymph node niche for maintaining the stem-like population.
Why this matters: The identification of a lymph node-resident stem-like T cell population that gives rise to self-reactive effectors not only lays the groundwork for novel treatments for type 1 diabetes, but also may offer insights into immunobiology of anti-cancer immunity as well as the pathophysiology of immune-related adverse events.
“Therapeutic KRASG12C inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers”
by Edurne Mugarza
et alSci Adv (2022)
Mutations in KRAS are among the most common drivers of cancer, but the protein was long considered to be undruggable. The first targeted therapy inhibiting oncogenic KRAS with a G12C mutation, sotarasib, was approved by the United States Food and Drug Administration in the non-small cell lung cancer setting in 2021 and although response rates are high, resistance emerges rapidly. To assist in the development of rationale combination approaches involving immunotherapy, Edurne Mugarza et al provide a detailed characterization of the effects of KRAS G12C inhibition on the lung tumor immune microenvironment. In human and murine lung cancer cell lines, inhibition of KRAS G12C was associated with an upregulation of canonical interferon-related genes in a MEK-dependent but JAK- and STAT-independent manner. KRAS G12C inhibition led to decreased MYC transcripts and knockdown of MYC in KRAS G12C mutant cell lines recapitulated the upregulation of interferon-related genes in the absence of inhibition. Tumor cell-intrinsic responses to interferon gamma were also enhanced at the transcript and protein level by KRAS G12C inhibition. In vivo, KRAS G12C inhibition led to upregulation of genes involved in interferon, IL-2, and IL-6 signaling, allograft rejection, and complement and inflammatory responses in the aggressive and highly immunogenic 3LL delta NRAS model. A significant reduction in suppressive myeloid cells with a concomitant increase in infiltrating cytotoxic effector cells and dendritic cells was also seen. In immunogenic tumor models, combination KRAS G12C inhibition and anti-PD-1 prolonged survival. Notably, no additive effects of anti-PD-1 and KRAS G12C inhibition were seen in immunologically cold or interferon non-responsive tumor models.
Why this matters: Combinations involving KRAS G12C inhibition and anti-PD-1 are under ongoing investigation and initial results from early trials were recently presented at the 2022 World Conference on Lung Cancer. These findings suggest that toxicity of the combination may be meaningful.