How to Bring Innovation to Patients Diagnosed with Rare Cancers?

Disappointing results from two clinical trials on rare malignancies, presented at the ESMO Virtual Congress 2020, reinvigorate the urgent need to re-think how research in this domain is conducted. “The molecular landscape and potentially actionable driver frequencies should be assessed, and relevant biomarkers should be found to predict benefit before randomised trials are initiated,” says Prof. Aldo Scarpa from the University of Verona, Italy. Although the incidence of individual rare malignancies is relatively low, they represent nearly a quarter of all cancers when considered as a collective. “With better patient selection, treatments for rare diseases could also be made more cost effective. However, research in the field is lagging behind due in part to the difficulty in organising large-scale trials.”

Negative results were reported from the phase II STIMULI trial (Abstract LBA84), with no improvement in progression-free survival (PFS) with consolidation immunotherapy (nivolumab plus ipilimumab then nivolumab monotherapy) versus observation in patients with limited-stage small-cell lung cancer (LS-SCLC), which the authors speculated may be due to the short period on active treatment. Median PFS was 10.7 months in the consolidation immunotherapy arm and 14.5 months in the observation arm. All 153 patients – half the intended sample size, as trial enrolment closed prematurely because of slow accrual – had received prior standard chemotherapy and thoracic radiotherapy with prophylactic cranial irradiation. Median overall survival (OS) was not reached with consolidation immunotherapy and was 31.6 months with observation. Of note, the median time to treatment discontinuation was only 1.7 months with consolidation immunotherapy. Grade ≥3 adverse events (AEs) were experienced by 62% patients in the consolidation immunotherapy arm and 25% in the observation arm, with 4 and 1 fatal AEs, respectively.

Another phase II trial reported premature enrolment closure due to slow accrual, this time in progressive advanced medullary thyroid cancer (Abstract 1919P). In the per-protocol population, median PFS was 7.0 months with the triple angiogenesis inhibitor of VEGF, FGF and PDGF receptors, nintedanib, and 3.9 months with placebo in 31 patients who had progressed after 1–2 lines of tyrosine kinase inhibitor treatment. Respective median OS was 12.3 and 16.4 months. The authors reported no major safety concerns, but stated that the low power of the trial prevented conclusions being made on efficacy. In a phase II trial including patients with anaplastic thyroid cancer (ATC; n=71), accrual occurred earlier than expected, but there was no significant difference in OS when paclitaxel plus intensity-modulated radiation therapy was compared with pazopanib or placebo (Abstract 1914MO).

Scarpa thinks that methodological limitations may have affected the outcomes of the trials. “Applying the classical randomised trial design used with prevalent cancers is not always suitable with rare diseases. Unsuccessful accrual can reduce the power of trials and, even when adequate accrual was achieved in the ATC trial, it may be difficult to detect any benefits.” In addition, the high levels of toxicity seen in the STIMULI trial indicate that feasibility and tolerability may need to be first evaluated in earlier phases.

Innovative trial designs are needed, says Scarpa. “Bayesian (probabilistic) statistics, flexible (adaptive) trial designs and the use of surrogate endpoints in the context of non-randomised trials might be useful,” he notes. “Using innovative approaches to study rare cancers, such as using basket or umbrella trials and master protocols, has the advantage of potentially investigating multiple agents in multiple subgroups at the same time.”

Another option for studying rare cancers with known molecular characterisation is by retrospective review of databases, which could help identify patterns of disease presentation and offer insights into how best to manage rare cancers. A retrospective study from Singapore investigated the tumour characteristics and molecular profiles of adolescent and young adult (AYA) patients (aged 16–39 years) with lung cancer using electronic health records data (Abstract 1383P). AYA patients, compared with an older study cohort, were more likely to be female (58.2% versus 47.0%), have a higher ALK mutation rate (27.8% versus 4.0%) and a lower EGFR mutation rate (27.8% versus 53.0%). Most young patients presented with advanced disease that had an aggressive course. In addition to rare cancers, Scarpa thinks special consideration should be given to rarer variants, such as those related to the stage of disease (e.g. LS-SCLC) or age of onset (e.g. AYA), regarding how they are defined, studied and managed.

Abstracts and sessions details

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