FWIW, this dude has a really great take down of the trial on the med net.
Stanislav (Stas) Lazarev, MD
Assistant Professor
Icahn School of Medicine at Mount Sinai
Answered on August 1 2024
Updated answer on August 7 2024
Update: On August 6, 2024, the FDA approved Vorasidenib for IDH-mutant low-grade gliomas based on findings from the INDIGO trial. This decision highlights the FDA's incompetence and lack of scientific integrity, clearly demonstrating that the agency prioritizes pharmaceutical companies' interests over patients' well-being.
It is concerning that we are considering Vorasidenib in LGG without any credible data that it results in a clinically meaningful benefit for our patients. The fact that it was added to NCCN is deeply troubling.
The
INDIGO trial was a phase 3 RCT evaluating the efficacy of Vorasidenib, an IDH inhibitor, in patients with LGG harboring IDH mutations. Specifically, the patient population that was included in this study were patients who actually had gross macroscopic disease, either a residual tumor after the initial surgery or a recurrent disease. Per protocol, gross disease was mandated to involve at least 1 target lesion measuring =>1 cm. In this investigation, the patients were randomized to receive either Vorasidenib or a placebo. Notably, the Vorasidenib arm patients were mandated to receive the drug in continuous 28-day cycles, essentially, indefinitely, or until the time of radiographic progression.
One of the most striking concerns with the INDIGO trial is its departure from the standard of care in the control arm. The standard for high-risk LGG, previously listed as a category 1 recommendation in early versions of the NCCN CNS section, is RT + chemotherapy, not observation. Adult high-risk LGGs are defined as age =>40, or subtotal resection (i.e. gross disease). So, by definition, the presence of gross disease is considered high-risk LGG.
Patients on the INDIGO trial, with gross disease measuring at least 1 cm,
had high-risk LGG. Therefore, randomizing them to placebo was not appropriate. We have phase 3 data demonstrating that patients with high-risk LGG who do not receive adjuvant chemoRT have markedly inferior outcomes (
RTOG 9802 (Buckner et al., PMID 27050206): median OS of patients who did not receive chemoradiotherapy on RTOG 9802 (and were only treated with adjuvant RT; not even observed (!!) was
5.5 years shorter than those who did (7.8 vs 13.3 years, p=0.003). One may argue that in the high-risk LGG, there might be a subset of patients (asymptomatic, indolent tumors) who may be observed. However, the same RTOG 9802 had a low-risk arm (<40 and GTR), and in that cohort,
71% progressed with a median PFS of 6.9 years, and 10-year and 15-year OS were only 77% and 65% (
Iwamoto et al., Neuro-Oncology 2022 (SNO Conference). If the rationale for observing patients with gross disease in INDIGO is based on the presence of 'favorable biology' tumors, this argument is not supported by data. I am not sure a 77% 10-year and 65% 15-year survival for a young 30-year patient (median age on RTOG 9802 low-risk arm) is a particularly impressive outcome.
Another major flaw of INDIGO was that patients in the placebo arm received a placebo until progression, and then, when they progressed, they were still deprived of the standard of care chemoRT. Instead, they were crossed over to receive Vorasidenib. In the INDIGO trial, 31.9% of patients (INDIGO study table S2) were crossed over. Allowing crossover on INDIGO was not appropriate. The efficacy of Vorasidenib has never been established – why did the investigators allow cross-over? If the efficacy of a drug has not been established in later lines of therapy and is being tested in the first line, crossover should not be permitted. In this scenario, there is a reasonable chance that the drug is completely ineffective or, worse, harmful.
Importantly, Vorasidenib has an incredibly poor response rate, with
ORR consisting
only 10.7% (INDIGO Appendix, Table S2). Using current RANO criteria, where partial response is defined as =>50% decrease in radiographic tumor findings compared to pretreatment MRI,
Vorasidenib had an abysmal 1.2% ORR, because 9.5% of patients had minor response. With a response rate of only 10.7% and
NO difference when it comes to stable disease (82.7% on Vorasidenib) vs 88.3% on Placebo, how exactly Vorasidenib improves PFS is unclear. Finally, the
probability of patients progressing on INDIGO at 2 years was a staggering 49.3% (page 10 of INDGO Appendix). Why are we even considering treatment of an intervention with such an abysmal local control rate compared to the standard of care chemoRT?
The entire premise of INDIGO—that radiation induces neurocognitive dysfunction - is questionable. As of 2024, there are no robust data indicating that local RT with 50-54 Gy using modern techniques such as IMRT/VMAT, tighter margins, excellent image guidance, and improved radiation therapy dosimetry software, leads to clinically significant neurocognitive deficits. Symptomatic QoL-altering radiation necrosis with doses <54 Gy is exceedingly rare as well, likely <1%. Additionally, if 50% of patients in INDIGO progress within 2 years of starting the treatment, where is the evidence that delaying RT by 2 years provides any clinical benefit to the patient?
Next, the trial's endpoints raise concerns about their clinical relevance. The primary endpoint is image-guided PFS. While surrogate endpoints like PFS can expedite drug approval, their correlation with patient-centered outcomes such as overall survival (OS) and quality of life (QoL) remains uncertain, particularly in chronic and indolent diseases like LGGs. One may argue that unless a novel intervention improves OS or QoL, it should not be approved. The study’s secondary endpoint was time to the next intervention.
Why is there a goal in cancer therapy to keep patients on an indefinite cancer treatment?
Vorasidenib's staggering cost in excess of $10,000 per month (
Vorasidenib) raises additional questions, considering patients receive the drug continuously until disease progression. This financial burden, combined with the trial's design flaws and potential conflicts of interest (the majority of authors having financial ties to the drug manufacturer), raises serious ethical concerns and independence of the study's findings.
The FDA's expedited review and inclusion of Vorasidenib in treatment guidelines, specifically NCCN, based on the INDIGO trial findings are highly premature, in my opinion. This highlights broader concerns regarding regulatory oversight and the influence of pharmaceutical interests on treatment recommendations, potentially compromising patient care and oncological outcomes.
Finally, if a novel intervention like Vorasidenib is truly transformational, it should not be difficult to prove its superiority over SOC. Otherwise, we should acknowledge that we might be giving patients a treatment that may be no better, or potentially even worse, than SOC.
