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PIK3CA mutations occur in approximately 40% of patients with hormone receptor–positive breast cancer. A PI3K inhibitor, alpelisib, combined with fulvestrant led to a median progression-free survival of 11 months, as compared with 5.7 months with placebo plus fulvestrant. Hyperglycemia, rash, and diarrhea were more common with alpelisib.

In patients with advanced HR-positive, HER2-negative breast cancer, the addition of the cyclin-dependent kinase inhibitor ribociclib to letrozole was associated with a significantly higher rate of progression-free survival than placebo. Up to 75% of breast cancers express the estrogen receptor or progesterone receptor (hormone-receptor [HR]–positive). 1 , 2 Endocrine therapy is the standard of care for postmenopausal women with advanced breast cancer that is HR-positive and human epidermal growth factor receptor 2 (HER2)–negative, with aromatase inhibitors being the preferred first-line treatment option. 3 , 4 However, in the majority of patients, resistance to currently available options eventually develops, which requires the administration of sequential therapy with alternative endocrine regimens. 4 – 8 Thus, the identification of effective treatment options that prolong or restore sensitivity to endocrine therapies is important. Cyclin-dependent kinases 4 and 6 (CDK4/6) in . . .

Background Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2− breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. Methods In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. Results We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2− breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2− breast cancer models. Conclusions These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2− breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.

In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380. Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of −7·1 (SD 7·0) mV (p<0·0001), and in the second, with a change of −3·7 (SD 7·3) mV (p=0·032). We recorded a response in total chloride transport (defined as a change in nasal PD of −5 mV or more) in 16 of the 23 patients in the first cycle's treatment phase (p<0·0001) and in eight of the 21 patients in the second cycle (p<0·0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle's treatment phase (p=0·0003) and for nine of 21 in the second cycle (p=0·02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded. In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction. PTC Therapeutics, Cystic Fibrosis Foundation Therapeutics.

The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described.

Nonsense mutations inactivate gene function and are the underlying cause of a large percentage of the individual cases of many genetic disorders. PTC124 is an orally bioavailable compound that promotes readthrough of premature translation termination codons, suggesting that it may have the potential to treat genetic diseases caused by nonsense mutations. Using a mouse model for cystic fibrosis (CF), we show that s.c. injection or oral administration of PTC124 to Cftr-/- mice expressing a human CFTR-G542X transgene suppressed the G542X nonsense mutation and restored a significant amount of human (h)CFTR protein and function. Translational readthrough of the premature stop codon was demonstrated in this mouse model in two ways. First, immunofluorescence staining showed that PTC124 treatment resulted in the appearance of hCFTR protein at the apical surface of intestinal glands in Cftr-/- hCFTR-G542X mice. In addition, functional assays demonstrated that PTC124 treatment restored 24-29% of the average cAMP-stimulated transepithelial chloride currents observed in wild-type mice. These results indicate that PTC124 can effectively suppress the hCFTR-G542X nonsense mutation in vivo. In light of its oral bioavailability, safety toxicology profile in animal studies, and efficacy with other nonsense alleles, PTC124 has the potential to be an important therapeutic agent for the treatment of inherited diseases caused by nonsense mutations.

In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor (HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer. This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18–59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients. Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigator's assessment, median progression-free survival was 23·8 months (95% CI 19·2–not reached) in the ribociclib group compared with 13·0 months (11·0–16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44–0·69; p<0·0001). Grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (203 [61%] of 335 patients in the ribociclib group and 12 [4%] of 337 in the placebo group) and leucopenia (48 [14%] and four [1%]). Serious adverse events occurred in 60 (18%) of 335 patients in the ribociclib group and 39 (12%) of 337 in the placebo group, of which 15 (4%) and six (2%), respectively, were attributed to the study regimen. 12 (4%) of 335 patients in the ribociclib group and ten (3%) of 337 in the placebo group discontinued treatment because of adverse events. No treatment-related deaths occurred. 11 deaths occurred (five [1%] in the ribociclib group and six [2%] in the placebo group) during or within 30 days after treatment, most of which were due to progression of the underlying breast cancer (three [1%] and six [2%]). The remaining two deaths in the ribociclib group were due to an intracranial haemorrhage in an anticoagulated patient, and a pre-existing wound haemorrhage in another patient. Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients. Novartis.

Phosphatidylinositol 3-kinase (PI3K) pathway activation in squamous cell carcinoma of the head and neck contributes to treatment resistance and disease progression. Buparlisib, a pan-PI3K inhibitor, has shown preclinical antitumour activity and objective responses in patients with epithelial malignancies. We assessed whether the addition of buparlisib to paclitaxel improves clinical outcomes compared with paclitaxel and placebo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. In this multicentre, randomised, double-blind, placebo-controlled phase 2 study (BERIL-1), we recruited patients aged 18 years and older with histologically or cytologically confirmed recurrent and metastatic squamous cell carcinoma of the head and neck after disease progression on or after one previous platinum-based chemotherapy regimen in the metastatic setting. Eligible patients were enrolled from 58 centres across 18 countries and randomly assigned (1:1) to receive second-line oral buparlisib (100 mg once daily) or placebo, plus intravenous paclitaxel (80 mg/m2 on days 1, 8, 15, and 22) in 28 day treatment cycles. Randomisation was done via a central patient screening and randomisation system with an interactive (voice and web) response system and stratification by number of previous lines of therapy in the recurrent and metastatic setting and study site. Patients and investigators (including local radiologists) were masked to treatment assignment from randomisation until the final overall survival analysis. The primary endpoint was progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in all randomly assigned patients. Efficacy analyses were done on the intention-to-treat population, whereas safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01852292, and is ongoing but no longer enrolling patients. Between Nov 5, 2013, and May 5, 2015, 158 patients were enrolled and randomly assigned to receive either buparlisib plus paclitaxel (n=79) or placebo plus paclitaxel (n=79). Median progression-free survival was 4·6 months (95% CI 3·5–5·3) in the buparlisib group and 3·5 months (2·2–3·7) in the placebo group (hazard ratio 0·65 [95% CI 0·45–0·95], nominal one-sided p=0·011). Grade 3–4 adverse events were reported in 62 (82%) of 76 patients in the buparlisib group and 56 (72%) of 78 patients in the placebo group. The most common grade 3–4 adverse events (occurring in ≥10% of patients in the buparlisib group vs the placebo group) were hyperglycaemia (17 [22%] of 76 vs two [3%] of 78), anaemia (14 [18%] vs nine [12%]), neutropenia (13 [17%] vs four [5%]), and fatigue (six [8%] vs eight [10%]). Serious adverse events (regardless of relation to study treatment) were reported for 43 (57%) of 76 patients in the buparlisib group and 37 (47%) of 78 in the placebo group. On-treatment deaths occurred in 15 (20%) of 76 patients in the buparlisib group and 17 (22%) of 78 patients in the placebo group; most were caused by disease progression and none were judged to be related to study treatment. On the basis of the improved clinical efficacy with a manageable safety profile, the results of this randomised phase 2 study suggest that buparlisib in combination with paclitaxel could be an effective second-line treatment for patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck. Further phase 3 studies are warranted to confirm this phase 2 finding. Novartis Pharmaceuticals Corporation.

Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein. To evaluate ataluren activity, safety, and pharmacokinetics in children with nonsense mutation CF. Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients took ataluren three times per day (morning, midday, and evening) with randomization to the order of receiving a lower dose (4, 4, and 8 mg/kg) and a higher dose (10, 10, and 20 mg/kg) in the two cycles. The study enrolled 30 patients (16 male and 14 female, ages 6 through 18 yr) with a nonsense mutation in at least one allele of the CFTR gene, a classical CF phenotype, and abnormal baseline nasal epithelial chloride transport. Ataluren induced a nasal chloride transport response (at least a -5-mV improvement) or hyperpolarization (value more electrically negative than -5 mV) in 50% and 47% of patients, respectively, with more hyperpolarizations at the higher dose. Improvements were seen in seven of nine nonsense mutation genotypes represented. Ataluren significantly increased the proportion of nasal epithelial cells expressing apical full-length CFTR protein. Adverse events and laboratory abnormalities were infrequent and usually mild. Ataluren pharmacokinetics were similar to those in adults. In children with nonsense mutation CF, ataluren can induce functional CFTR production and is well tolerated.

PTC124: a no-nonsense drug Many inherited diseases result from premature termination during translation of a messenger RNA into protein; one such disease is muscular dystrophy. Welch et al . now report that a small molecule, PTC124, enables the translation machinery to bypass sites that cause premature termination, but still terminate normally at the end of the mRNA. In human and mouse cells, this drug restores normal translation of the gene that is mutated in muscular dystrophy, and it restores muscle function in the mdx mouse model for the human disease. This work offers the hope that similar drugs might be used to target nonsense mutations and restore protein function in a wide variety of diseases. PTC124 is now undergoing clinical trials in muscular dystrophy and cystic fibrosis patients. A small molecule, PTC124, enables the translation machinery for mRNA into proteins to bypass sites that cause premature termination, but still terminate normally at the end of the mRNA. In human and mouse cells, this drug restores normal translation of the gene that is mutated in muscular dystrophy, and restores muscle function in mdx mice that model the human disease. Nonsense mutations promote premature translational termination and cause anywhere from 5–70% of the individual cases of most inherited diseases 1 . Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease 2 , 3 . To address the need for a drug capable of suppressing premature termination, we identified PTC124—a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2–8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.