Tom Feys MBA, MSc

Radiotherapy in the lung cancer immuno-oncology era

ABSTRACT

Radiotherapy not only allows us to selectively target the tumour, it also interacts with the tumor microenvironment and consequently the host’s immune system. Theoretically this can lead to an in situ vaccination and trigger so-called abscopal responses, away from the irradiated site. Unfortunately, these are rarely seen the clinic. Over the past years, both preclinical and clinical studies demonstrated synergistic effects of radiation in combination with several types of immunotherapy. However, the optimal dose and fractionation of radiation therapy as well as the optimal combination and sequence of radiotherapy and immunotherapy still needs to be determined.

Chimeric antigen receptor T-cells: is the success in haematological malignancies translatable to solid tumours?

SUMMARY

Chimeric antigen receptor (CAR) T-cell therapy is a new cancer immunotherapy targeting specific cell surface antigens. This type of adoptive cell immunotherapy has been a breakthrough in the treatment of aggressive B-cell lymphoma and B-cell precursor acute lymphoblastic leukaemia (ALL) and is currently being studied in other cancer types, including multiple myeloma and chronic lymphocytic leukaemia. With the unprecedented success of CAR T cells in haematological malignancies, a growing number of (pre)clinical studies are focusing on translating this treatment to solid tumours. However, response rates to CAR T-cell therapy have so far been much less favourable in non-haematologic malignancies, mainly due to a paucity of unique tumour target antigens, limited CAR T-cell trafficking to tumour sites, tumour heterogeneity, antigen loss, the presence of an immune suppressive tumour microenvironment and recognition of normal cells expressing the targeted antigen. A broad range of strategies is currently being explored to overcome these hurdles. For example, TCR-CAR-T hybrids have been developed that can also target intracellular antigens which broadens the potential scope of the CAR-T cell strategy. This article reviews completed and ongoing CAR T-cell trials in solid tumours and discusses the strategies to improve the efficacy of this treatment modality in solid tumours, including accelerated production flows. CAR-T’s might very well be the upcoming major advance in cancer treatment.

Immunotherapy for locally advanced unresectable non-small cell lung cancer

The progress that has been made in the last decades in the treatment of stage IV non-small cell lung cancer (NSCLC) has overall not been translated in the curative setting of stage I to III disease. In fact, the list of failed clinical trials aimed at improving the cure rates in this setting is long. The recent successes with immune checkpoint inhibition in stage IV NSCLC formed the basis to also study these agents in the curative setting. The first clinical trials to yield results in this setting evaluate immune checkpoint inhibition as consolidation treatment following chemoradiotherapy in locally advanced, unresectable NSCLC. The PACIFIC trial demonstrated that consolidation therapy with PD-L1 inhibitor durvalumab significantly prolongs both the progression-free (PFS) and overall survival (OS) compared to placebo in patients with disease control after chemoradiotherapy for stage III unresectable NSCLC. These findings have recently led to the EMA indication of durvalumab as a treatment of locally advanced, unresectable NSCLC patients whose tumors express PD-L1 on ≥1% of tumor cells and whose disease has not progressed following platinum-based chemoradiation therapy. In addition to this, recent phase II data show that consolidation pembrolizumab following concurrent chemoradiotherapy substantially prolongs the time to metastasis or death in patients with inoperable stage III NSCLC. Finally, the phase II ETOP NICOLAS trial demonstrated that the addition of nivolumab to concurrent chemoradiotherapy is safe and tolerable in stage III NSCLC with promising efficacy signals. Together all these data support the further exploration of immune checkpoint inhibition in the curative NSCLC setting. Several trials are currently ongoing, including studies on the potential of adjuvant immune checkpoint inhibition in stage II and IIIA disease and trials in the pre-operative setting.

Highlights in breast cancer

During ESMO 2018 an entire presidential session was dedicated to breast cancer. In addition to exciting immuno-oncology data in the treatment of triple negative breast cancer (TNBC), this session featured the presentation of the overall survival (OS) data of the phase III PALOMA-3 trial, evaluating the alpha-specific PI3K-inhibitor alpelisib in PI3KCA-mutant advanced breast cancer, and results of a clinical trial demonstrating improved outcomes when adding a histone deacetylase (HDAC) inhibitor to exemestane in hormone-receptor positive advanced breast cancer. In early breast cancer it was further demonstrated that non-compliance with adjuvant endocrine treatment is an under-appreciated and under-reported problem. In addition, the HOBOE-2 adds to the evidence that adjuvant bisphosphonates also improve the disease-free survival (DFS) in premenopausal luminal breast cancer patients who have received ovarian function suppression combined with an aromatase inhibitor. Finally, a subgroup analysis of the ShortHER trial suggests that for low- and intermediate risk cancer HER2-positive early breast cancer, 9 weeks of trastuzumab might be non-inferior to the standard 1-year treatment duration. However, the interpretation of this trial is challenging and as such, one year of trastuzumab should remain the standard for now.

Highlights in melanoma

The introduction of immune checkpoint inhibitors and the combined use of BRAF and MEK inhibitors dramatically changed the treatment landscape of advanced melanoma over the last decade. The success of these agents in the advanced setting formed the basis to also evaluate these drugs in less advanced disease stages. During ESMO 2018 updates were given on the adjuvant use of dabrafenib and trametinib in resected stage III melanoma patients. In addition to this, results were presented on the use of immune checkpoint inhibitors in the neo-adjuvant setting. In the advanced melanoma setting, the most important data came from the four-year survival update of the CheckMate 067 trial and the presentation of the Keynote-022 study, in which the immune checkpoint inhibitor pembrolizumab was used in combination with dabrafenib and trametinib in the first-line treatment of BRAF-mutation positive advanced melanoma.

Highlights in melanoma

The melanoma highlights from ASCO 2018 include data on the surgical management of sentinel lymph node (SLN) positive melanoma, updated results from the Checkmate 238 study evaluating adjuvant nivolumab or ipilimumab for resected stage III and IV melanoma, the overall survival (OS) data of the COLUMBUS trial assessing the combination of the BRAF inhibitor encorafenib with the MEK inhibitor binimetinib in the treatment of unresectable BRAF-mutant melanoma and two studies evaluating immunotherapy for unresectable Merkel cell carcinoma. For a more complete overview of melanoma data presented at ASCO 2018 please refer to the official congress website (www.am.asco.org).

Immunotherapy for locally advanced unresectable non-small cell lung cancer

The progress that has been made in the last decades in the treatment of stage IV non-small cell lung cancer (NSCLC) has overall not been translated in the curative setting of stage I to III disease. In fact, the list of failed clinical trials aimed at improving the cure rates in this setting is long. The recent successes with immune checkpoint inhibition in stage IV NSCLC formed the basis to also study these agents in the curative setting. The first clinical trials to yield results in this setting evaluate immune checkpoint inhibition as consolidation treatment following chemoradiotherapy in locally advanced, unresectable NSCLC. The PACIFIC trial demonstrated that consolidation therapy with PD-L1 inhibitor durvalumab significantly prolongs both the progression-free (PFS) and overall survival (OS) compared to placebo in patients with disease control after chemoradiotherapy for stage III unresectable NSCLC. These findings have recently led to the EMA indication of durvalumab as a treatment of locally advanced, unresectable NSCLC patients whose tumors express PD-L1 on ≥1% of tumor cells and whose disease has not progressed following platinum-based chemoradiation therapy. In addition to this, recent phase II data show that consolidation pembrolizumab following concurrent chemoradiotherapy substantially prolongs the time to metastasis or death in patients with inoperable stage III NSCLC. Finally, the phase II ETOP NICOLAS trial demonstrated that the addition of nivolumab to concurrent chemoradiotherapy is safe and tolerable in stage III NSCLC with promising efficacy signals. Together all these data support the further exploration of immune checkpoint inhibition in the curative NSCLC setting. Several trials are currently ongoing, including studies on the potential of adjuvant immune checkpoint inhibition in stage II and IIIA disease and trials in the pre-operative setting.