We recently returned from the European Society for Medical Oncology (ESMO) meeting where conference news highlighted the increased movement of targeted therapies and immunotherapies into adjuvant and early-stage cancer settings, plus plenty of positive data from a variety of combination therapy trials in breast cancer, including triple-negative breast cancer.
(Neo)Adjuvant Treatment Gets a Boost
The past decade has witnessed exciting advances in treatment options for many tumor types, from new targeted therapies to novel immunotherapies. While early explorations and research emphasis was in patients with later-stage disease who had already failed at least one treatment, we are now starting to see data emerge on the use of such drugs in adjuvant settings or for the treatment of earlier-stage cancers. A number of reports at ESMO were encouraging.
One of the presentations that excited many conference attendees was the long-term follow-up data from Novartis’ COMBI-AD trial with Tafinlar (dabrafenib) and Mekinist (trametinib) as adjuvant therapy in resected Stage III BRAF-mutated melanoma. The first trial of this combination in an adjuvant setting, following previous positive results in unresectable or metastatic melanoma associated with BRAF V600E or V600K mutations, investigators reported a durable four-year relapse-free survival rate of 54% for those who received the combination following surgery versus a 38% rate for patients who received placebo.
Melanoma has a high cure rate when diagnosed and treated early. However, patients with stage III disease who have lymph node involvement remain at a high risk of relapse following surgery. These study results suggest that the use of adjuvant dabrafenib and trametinib in patients with the BRAF V600 mutation (about 50% of those with advanced melanomas) greatly reduces the risk of relapse compared to watching and waiting.
While BRAF mutations represent only a subset of melanoma patients and no other biomarkers yet exist to select patients most likely to gain from the treatment, analysis suggested that a high tumor mutational burden plus high levels of interferon-gamma might predict a greater benefit. At the same time, subgroup analysis from the COMBI-AD study suggests the benefit of the adjuvant therapy is similar regardless of the patient’s baseline disease state, metastatic load, or tumor ulceration status.
Also of interest were Phase 2 results from a small 14-patient study from Bristol-Myers Squibb pairing Opdivo (nivolumab) and low-dose Yervoy (ipilimumab) as neo-adjuvant treatment of early stage Mismatch Repair (MMR)-deficient colon cancer. The investigators reported a 100% “major pathological response,” with patients experiencing a complete or near-complete response to the treatment within four weeks — significantly more dramatic than that which had been previously reported for the combination in metastatic MMR-deficient colorectal cancer (CRC). Moreover, the patients tolerated the combination treatment well. Experts believe that if such adjuvant immunotherapy can improve tumor shrinkage prior to surgery or reduce post-surgical relapse in such early-stage CRC patients, it could have a broad impact on the treatment of this type of disease, due to the high incidence of colorectal cancers.
Focus on Breast Cancer
Breast cancer was also a big focus of ESMO, with data reported from a large number of trials. Exciting to some was the positive immunotherapy trial for triple-negative breast cancer (TNBC), the Impassion130 trial of Roche’s Tecentriq (atezolizumab) plus Celgene’s chemotherapeutic, Abraxane (nab-paclitaxel). Approximately 900 patients were randomized in the Phase 3 trial to receive either Tecentriq plus Abraxane or Abraxane plus placebo. The combination therapy showed a 2.5 month improvement in progression-free survival, but a 10 month overall survival benefit in patients with PD-L1 positive breast cancer — not unusual in immunotherapy trials where a response often increases over time. The results of the trial showed for the first time that immunotherapy can work in the hard-to-treat TNBC patient population, given selection of the right patients.
We found two other combination studies reported at ESMO noteworthy. The first, Pfizer’s Phase 3 PALOMA-3 trial combining Ibrance (palbociclib), their CKD 4/6 inhibitor, with fulvestrant in second line HR+ / HER2- breast cancer reported survival data for the first time. The combination therapy provided an overall survival benefit of 6.5 months over fulvestrant alone – an outcome that was less than statistically significant, although Pfizer said the trial was not designed to show significance against that endpoint. Instead, the primary endpoint of the trial was median progression-free survival, where Pfizer reported that the combination therapy offered 11.2 months of PFS versus the 4.6 months of PFS with fulvestrant plus placebo.
The SOLAR-1 trial from Novartis reported Phase 3 results in patients with endocrine-resistant advanced or metastatic breast cancer showing BYL719 (alpelisib), the company’s alpha-specific PI3K inhibitor, plus fulvestrant reduced the risk of death or disease progression by 35% over fulvestrant plus placebo. Progression-free survival was nearly doubled in some patients, with median PFS reaching 11 months compared to 5.7 months for fulvestrant alone.