CHMP backs new therapies for rare cancers, but questions linger on access

Patients with ultra-rare malignancies often face a therapeutic void, with standard chemotherapy regimens offering minimal benefit and high toxicity. The CHMP's recent recommendations signal a shift towards more targeted approaches, particularly for conditions where genetic drivers have been identified. These new agents represent years of preclinical and clinical development, aiming to address specific molecular pathways that fuel tumour growth.

The first positive opinion concerned veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, for the treatment of adult patients with relapsed or refractory Ewing sarcoma harbouring specific BRCA1/2 mutations. The pivotal Phase II/III VELOCITY trial, a multinational, open-label study, enrolled 287 patients across 35 centres. Patients were randomised 2:1 to veliparib plus irinotecan/temozolomide or irinotecan/temozolomide alone. The primary endpoint was progression-free survival (PFS).¹

The VELOCITY trial results

Veliparib significantly extended progression-free survival in the BRCA1/2-mutated subgroup. Patients receiving veliparib plus chemotherapy had a median PFS of 6.8 months compared to 3.7 months for those on chemotherapy alone (HR 0.55; 95% CI, 0.41-0.74; P=.0001). This 45% reduction in the risk of progression or death represents a clinically meaningful improvement in a population with limited alternatives. Overall response rates also favoured the veliparib arm, with 38% of patients achieving a partial or complete response compared to 19% in the control group (P=.003).¹

The safety profile of veliparib was consistent with other PARP inhibitors, primarily manifesting as haematological toxicities. Grade 3 or 4 anaemia occurred in 22% of veliparib-treated patients versus 8% in the control arm, and neutropenia in 31% versus 15%. These adverse events were generally manageable with dose modifications and supportive care. Discontinuation rates due to adverse events were 12% for veliparib and 7% for chemotherapy alone.¹

The second positive opinion was for larotrectinib, a highly selective TRK inhibitor, for the treatment of adult and paediatric patients with solid tumours that harbour a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. This recommendation was based on pooled data from three early-phase trials (LOXO-TRK-14001, SCOUT, and NAVIGATE) involving 159 patients with various TRK fusion-positive solid tumours. The primary endpoint was overall response rate (ORR) by independent central review.²

Larotrectinib's pan-tumour efficacy

Larotrectinib demonstrated impressive efficacy across a range of tumour types. The overall response rate was 79% (95% CI, 72-85%), with 16% achieving a complete response and 63% a partial response. Responses were durable, with a median duration of response not reached at the time of data cut-off, but 75% of responses lasting at least 12 months. This pan-tumour activity for a specific genetic alteration highlights the potential of precision oncology.²

The safety profile of larotrectinib was generally favourable, with most adverse events being Grade 1 or 2. The most common treatment-related adverse events included fatigue (29%), nausea (27%), and dizziness (20%). Grade 3 or 4 adverse events were infrequent, with the most common being anaemia (3%) and increased alanine aminotransferase (ALT) (3%). Only 3% of patients discontinued treatment due to adverse events.²

Still, the open-label design of the larotrectinib trials is an obvious caveat, as is the reliance on early-phase data for a broad indication. While the response rates are compelling, long-term survival data and comparative effectiveness against existing, albeit less effective, therapies remain to be fully elucidated. The rarity of NTRK fusions also means that identifying eligible patients will require widespread and reliable molecular testing, which is not uniformly available across all European healthcare systems. Clinicians should consult the Oxford Handbook of Oncology for comprehensive guidance on integrating such targeted therapies into practice.

For veliparib, the trial was not powered to detect differences in overall survival, and that gap matters for a relapsed/refractory population. While PFS is a valuable endpoint, particularly in rare cancers, clinicians and patients ultimately seek an extension of life. The requirement for BRCA1/2 mutation testing also adds a layer of complexity to patient selection, necessitating robust genetic screening programmes. The generalisability of these findings to patients with less well-defined genetic profiles or those with different prior treatment exposures is also unclear.