Implementation of imatinib, trastuzumab and vemurafenib to clinical practice has opened a new era of genomic-driven medicine in oncology. Imatinib in chronic myeloid leukaemia (CML) prolongs overall survival (OS) of the treated patients to the level of OS reached by the general population. Trastuzumab in HER2-expressing breast cancer allows for a 35–50% reduction of mortality in the adjuvant setting and a 20% reduction of mortality of metastatic patients. Vemurafenib in BRAF-mutated melanoma patients extends survival but unfortunately most patients have progression after several months of response. These 3 drugs were taken as exemplary milestones in precision oncology because they have paved new roads but also because they have shown us some important limitations of targeted drugs. Imatinib is extremely effective in CML where the target – bcr-abl kinase – is a real driver oncogene and CML cells are oncogene-addicted; if bcr-abl kinase is switched off by imatinib, the CML cells are not able to survive. However, in contrast to CML, solid tumours with the same genetic aberration are much less sensitive to imatinib because other known and unknown genetic alterations are driving their growth together or independently of bcr-abl kinase. Trastuzumab is highly effective in HER2-expressing breast cancer, moderately affective (lower response rates and response duration in patients) in HER2-expressing gastric cancer patients and marginally or not effective in different HER2-expressing solid tumours. Vemurafenib has demonstrated high activity in BRAF-mutated melanoma patients but fast and inevitable progression of disease is observed in all responders after a relatively short period of time.
Precision oncology assumes that individual comprehensive molecular profiling of the patient’s tumour sample is able to define a draggable target or even multiple targets which enable one to tailor treatment better than that based on current clinical experience and the histopathology report. In the US but also in other countries, including Poland, molecular profiling is marketed directly to patients despite lack or very vague evidence of benefit of such an approach so far. Only one randomised clinical trial (SHIVA) has been published and a few large clinical series of patients have been evaluated. Table 1 shows clinical studies that have evaluated molecular profiling of patients.
Updated results of studies highlighted above and some other series were reported at the ASCO Annual Conference 2017 which was held in Chicago at the beginning of June.
Olivier Tredan and coworkers presented results of the ProfiLER Study at ASCO 2017. ProfiLER (NCT01774409) is a molecular profiling clinical trial exploring cancer cell genomic alterations in patients with advanced disease to guide treatment. Patients with confirmed diagnosis of advanced cancers are eligible for ProfiLER. DNA is extracted from either archival or fresh collected tumour samples and is analyzed by targeted exon sequencing of 60 cancer related genes and whole genome array comparative genomic hybridization (CGH). A multidisciplinary molecular board analyses genomic data and recommends molecular targeted therapies (MTT) when actionable alterations are found. As of January 2017, 2490 patients (55% female, median age 59, range 1–90) had consented; 1826 (73.3%) tumours were analysed, 301 (12%) are ongoing (not done in 363 patients (14.6%) due to technical issues). Tumour types were colorectal (10.3%), gynaecological (9.5%), breast (8.8%), head and neck (7.1%) carcinomas, sarcomas (7.1%) and brain tumours (6.5%). 940/1826 patients (51.5%) had at least 1 actionable mutation (AM): 579 patients with only one AM, while 358 with 2 or more AM (up to 6). Mutations (including substitutions and small indels), amplifications and homozygous deletions (HD) were observed respectively in 55.3%, 42.1% and 25.5% of tumour samples. The most common AMs were on KRAS (n = 156; 8.5%), PIK3CA (n = 150; 8.2%), CDKN2A HD (n = 174; 9.5%), PTEN HD (n = 49, 2.7%), CCND1 (n = 97; 5.3%), FGFR1 (n = 56; 3.1%), MDM2 (n = 53; 2.9%), HER2 (n = 42; 2.3%) and HER1 (n = 41; 2.2%). MTT were recommended in 644 patients. Among them, 101 initiated a recommended MTT. MTT received were mTOR inhibitors (39%), anti-angiogenic TKI (21%), EGFR TKI (9.8%), and cell cycle inhibitors (6.9%). Best responses were complete response (CR; n = 2, 2.3%), partial response (PR; n = 13, 15.1%), stable disease (SD; n = 29, 33.7%), progressive disease (PD; n = 42, 48.8%), with a median of progression-free survival (PFS) of 2.8 months (95% IC: 2.2–3.5). 24% are alive progression free at 6 months.
Sylvian Dureau and colleagues presented results of the SHIVA trial with survival analysis during ASCO 2017. The SHIVA trial was a proof-of-concept, multicentric randomized phase II trial comparing molecularly targeted therapy among 11 drugs based on tumour molecular profiling versus conventional therapy in patients with any type of cancer that is refractory to standard of care (NCT01771458). The study was conducted at eight academic sites in France. Only patients who had a druggable molecular alteration (DMA) identified on a mandatory tumour sample from a metastatic site using targeted sequencing, CGH and IHC were randomized. Cross-over was allowed at disease progression. The trial did not show any difference for its primary endpoint (PFS) [Le Tourneau et al., Lancet Oncol 2015]. At ASCO 2017 the OS of randomized and non-randomized patients was reported. OS was estimated in the 4 following groups: 1) randomized patients, 2) patients for whom a DMA was identified but who were not subsequently randomized because they did not meet the randomization criteria (PS of 0 or 1, adequate organ function), 3) non-randomized patients because of the absence of DMA, and 4) non-randomized patients because no genomic analyses were performed. Since 70% of patients randomized to the standard arm eventually crossed over to the targeted therapy arm, all randomized patients were analyzed in group 1. The groups were compared in terms of patient characteristics using Student’s t-test and the 2 test. OS was estimated using the Kaplan-Meier method. Among 741 patients included in SHIVA follow-up data were available for 680 out of the 733 patients. 197, 78, 222 and 183 patients belonged to groups 1 to 4, respectively. Median OS of the whole cohort was 7.9 months (95% CI: 7.0–9.1). As compared to non-randomized patients due to the absence of identified DMA, non-randomized patients with a DMA had a significantly worse prognosis: HR = 2.3 (95% CI: 1.7–3.0; p > 0.0001) whereas randomized patients had a non-significant trend toward a better prognosis: HR = 0.85 (95% CI: 0.7–1.1; p = 0.18). A statistically significant difference in OS was only observed in patients with a DMA who were not randomized. However, the analysis does not show a prognostic value of the DMA on OS. Figure 1 shows SHIVA’s primary endpoint – PFS.
Apostolia Tsimberidou and colleagues at ASCO 2017 presented an analysis of treatment results of 637 patients in the IMPACT trial – an MD Anderson precision medicine study. Patients with advanced, refractory cancer who had tumour genomic analyses were treated with matched targeted therapy (MTT) when available. Overall, 1,179 (82.1%) of 1,436 patients had ≥ 1 alteration (median age, 59.7 years; men, 41.2%); 637 had ≥ 1 actionable aberration and were treated with MTT (n = 390) or non-MTT (n = 247). Patients treated with MTT had higher rates of CR and PR (11% vs. 5%; p = 0.0099), longer failure-free survival (FFS) (3.4 vs. 2.9 months; p = 0.0015), and longer overall survival (OS) (8.4 vs. 7.3 months; p = 0.041) than unmatched patients. Two-month landmark analyses showed that, for MTT patients, FFS for responders vs. non-responders was 7.6 vs. 4.3 months (p < 0.0001) and OS was 23.4 vs. 8.5 months (p < 0.0001); for non-MTT patients (responders vs. non-responders), FFS was 6.6 vs. 4.1 months (p = 0.0005) and OS was 15.2 vs. 7.5 months (p = 0.43). Patients with both PI3K and MAPK pathway alterations matched to PI3K/Akt/mTOR axis inhibitors alone showed outcomes comparable to unmatched patients.
The author declares no conflict of interest.
References
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Address for correspondence
Sergiusz Nawrocki MD, PhD
Oncology and Radiotherapy Chair
Medical University of Silesia
Ceglana 35
40-514 Katowice, Poland
e-mail: sergiusz.nawrocki@me.com
