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Oncology Pipeline Full, and Not Just with Immunotherapies

August 2015 Vol 8, Special Issue: Payers' Perspectives in Oncology - Emerging Therapies

The oncology pipeline remains robust, especially as the industry embraces the promise of immune checkpoint inhibitors. Although immunotherapies were arguably the hottest topic at ASCO 2015, clinicians will also soon have more targeted therapies at their disposal, including drugs with novel mechanisms of action. The following descriptions include some of the most promising agents currently in development, based on studies presented at the meeting.

PD-1/PD-1 Ligand 1 Inhibitors

The PD-1/PD-1 ligand 1 (PD-L1) checkpoint inhibitors are being evaluated in numerous tumor types. Early trials were presented for a host of emerging agents in the anti–PD-1/PD-L1 class, including atezolizumab (MPDL­3280A), avelumab (MSB0010718C), MEDI0680, MEDI0639, MEDI6469, and MEDI4736.

Atezolizumab, an anti–PD-L1 agent, was evaluated in several early-phase studies. In a phase 2 randomized study in advanced non–small-cell lung cancer (NSCLC), 287 patients received atezo­lizumab or docetaxel as a second-line or third-line treatment. Atezolizumab reduced overall mortality by 22%, producing a median overall survival (OS) of 11.4 months versus 9.5 months with docetaxel. In patients expressing PD-L1, the differences were far greater, with the median OS not reached in the highest PD-L1 expressers. In another study, atezolizumab given with chemotherapy shrank tumors in 67% of patients. Three phase 3 studies of atezolizumab in combination with chemotherapy in NSCLC have been initiated.

Bladder cancer may also respond to atezolizumab, based on a study of 92 patients with metastatic disease in whom atezolizumab produced a 60% objective response rate (ORR). The responses were highest in PD-L1 expressers. Immune-related adverse events were observed in only 5% of patients; 40% of patients had a grade 3 or 4 adverse event.
The anti–PD-L1 agent avelumab was also shown to be effective in several tumor types. In the largest reported data set of patients with recurrent ovarian cancer who received the anti–PD-L1 therapy (N = 75), 11% of the patients responded and 55% achieved disease control. Phase 3 clinical development is planned.

Breast Cancer

The phase 3 ExteNET trial evaluated 1 year of treatment with the tyrosine kinase inhibitor neratinib after chemotherapy plus trastuzumab in patients with early HER2-positive breast cancer. ExteNET met its primary end point, improving the invasive disease-free survival rate at 2 years from 91.6% with placebo to 93.9% with neratinib (hazard ratio [HR], 0.67; P = .046).

The positive results, however, were not met with total enthusiasm by all, because some listeners felt that the drug’s toxicity outweighed the benefit. Grade 3 diarrhea was a problem for 39.9% of patients, but intensive prophylaxis with loperamide reduced its frequency later in the study.

Gastrointestinal Cancers

TAS-102, an oral agent that combines trifluridine and tipiracil hydrochloride, improved OS in patients with refractory colorectal cancer in the phase 3 RECOURSE study. The investigators presented a subanalysis of patients aged ≥65 years, showing the median OS to be 7.0 months in the TAS-102 group versus 4.6 months with placebo (HR, 0.62; P = .002), with only a mild increase in toxicity. The risk for progression was reduced by 59% in the experimental arm (P <.001).

A novel agent that facilitates the delivery of chemotherapy into pancreatic tumors proved effective in a phase 2 study of patients with previously untreated metastatic disease. The drug, PEGylated recombinant human hyaluronidase (PEGPH20), which aims to deplete hyaluronan in tumors, was associated with a doubling in progression-free survival (PFS) when combined with gemcitabine plus nab-paclitaxel in a study of 135 patients with previously untreated advanced pancreatic cancer and high hyaluronan expression. The median PFS was 9.2 months in the PEGPH20 arm versus 4.3 months with gemcitabine plus nab-paclitaxel alone. The triplet also doubled the ORR and the duration of response, and showed a trend toward improved OS (12 months vs 9 months; HR, 0.62). A global phase 3 randomized trial in patients with pancreatic cancer and high hyaluronan expression will start in 2016.

Central Nervous System

The phase 2 ReACT study evaluated the addition of an immunotherapeutic molecule, rindopepimut, to bevacizu­mab in recurrent glioblastoma, and met its primary end point. Rindopepimut is composed of an EGFRvIII peptide conjugated to the keyhole limpet hemocyanin protein and is administered via intradermal injection; it targets the EGFRvIII variant known to be associated with poor prognosis in glioblastoma. The 6-month PFS rate was 28% with rindopepimut versus 15% with bevacizumab alone. A phase 3 registration study has completed accrual.

Also in relapsed or refractory glioblastoma, the pan-PI3 kinase inhibitor buparlisib combined with bevacizumab produced an ORR of 32%, a median PFS of 5.3 months, and a median OS of 10.8 months.

Multiple Myeloma

For the treatment of multiple myeloma, 2 monoclonal antibodies turned heads at ASCO 2015. Both drugs have received breakthrough status from the US Food and Drug Administration (FDA).

In the phase 3 ELOQUENT-2 trial (N = 646), elotuzumab, given with lenalidomide and dexamethasone, extended PFS by a median of 5 months compared with lenalidomide plus dexamethasone alone in patients with a median of 2 previous therapies (see article, page 17). In the phase 2 Sirius MMY2002 trial (N = 106), single-agent daratumumab showed robust activity in heavily pretreated patients with refractory disease who had exhausted other therapeutic options, of whom 29% responded.


The phase 3 PERSIST-1 trial in myelofibrosis showed the JAK inhibitor pacritinib to be significantly more effective than best alternative therapy. A significant reduction in spleen volume was observed at 24 weeks in 25.0% of the pacritinib arm versus in 5.9% of the control arm (P = .001). Of note was pacritinib’s activity in the subset of patients with very low platelet counts (<50,000/µL), 33.3% of whom responded to pacritinib versus 0% to best alternative treatment (P = .037). This thrombocytopenic subset of patients typically has shorter survival times and an increased risk for leukemic transformation, and these patients lack an FDA-approved treatment option.

Ovarian Cancer

Trebananib, an antiangiogenic peptide, when combined with weekly pac­litaxel, extended PFS in patients with recurrent ovarian cancer and ascites by 2.2 months (P = .011) compared with paclitaxel alone in a phase 3 study of 919 women. There was no significant advantage to adding trebananib in the overall intent-to-treat population.

The Wee1 kinase inhibitor AZD1775, added to paclitaxel and carboplatin, was associated with a significant increase in PFS when compared with paclitaxel plus carboplatin, as well as acceptable tolerability, in a biomarker-­directed phase 2 study of 121 women with ovarian cancer and confirmed TP53 mutations. The PFS improved from a median of 34.86 weeks to 42.86 weeks, using Response Evaluation Criteria in Solid Tumors (HR, 0.55; P = .030), with the addition of AZD1775 to paclitaxel plus carboplatin.

The oral poly (ADP-ribose) polymerase inhibitor rucaparib was well-tolerated, and demonstrated a 74% ORR in an open-label phase 2 study of 40 patients with heavily pretreated platinum-sensitive relapsed ovarian cancer with a BRCA mutation.

Lung Cancer

Nedaplatin, a second-generation platinum compound, combined with docetaxel improved the median OS in a phase 3 study of 355 patients with advanced squamous-cell lung cancer compared with cisplatin and docetaxel. The median OS was 13.6 months with nedaplatin plus docetaxel compared with 11.4 months for cisplatin plus docetaxel (HR, 0.81; P = .037). The OS rates at 1 year were 55.9% with nedaplatin and 43.5% with cisplatin plus docetaxel, and 27.1% and 18.1%, respectively, at 2 years.

Alectinib, a highly selective oral anaplastic lymphoma kinase (ALK) inhibitor with activity in the central nervous system (CNS), was associated with an ORR of 57.1%, a complete response (CR) of 20.0%, and a disease control rate of 85.7% in 35 patients with ALK-positive NSCLC with measurable CNS metastases in a single-arm global phase 2 study. In 85 patients with any CNS metastasis, the ORR was 42.9%, the CR was 27.4%, and the disease control rate was 83.3%. The median duration of CNS response was 10.3 months.

In an open-label phase 2 study in ALK-positive NSCLC (N = 48), the CNS disease control rate was 87.5% and the CNS CR was 18.8% when patients with baseline measurable and nonmeasurable CNS disease were included in the analysis.

A bevacizumab biosimilar candidate, called BCD-021, demonstrated noninferiority to branded bevacizumab on the end point of ORR in a phase 3 trial of 138 patients with advanced nonsquamous NSCLC. The rates of CR, partial response, stable disease, and progression were also similar. The safety and tolerability characteristics were similar, and the immunogenic potential of the biosimilar was low.

In a multicenter phase 2 study of 140 patients with ALK-positive NSCLC pretreated with ≥1 platinum doublet, ceritinib demonstrated an ORR of 38.6%, a median duration of response of 9.7 months, and a median PFS of 5.7 months. In the subset of 100 patients with brain metastases, the ORR was 33.0%, the median duration of response was 9.2 months, and the median PFS was 5.4 months.

Bladder Cancer

An inhibitor of heat shock protein 27, apatorsen improved OS and PFS when added to gemcitabine and cisplatin in patients with advanced bladder cancer. In a phase 2 study of 179 patients, the HR for OS was 0.898, and for PFS was 0.927 with apatorsen plus gemcitabine and cisplatin compared with gemcitabine and cisplatin plus placebo. Patients with poor prognosis who received apatorsen had a greater reduction in the risk for death (HR, 0.717) than patients with good prognosis (HR, 1.44).

Olaratumab, a human antiplatelet-derived growth factor α monoclonal antibody, added to doxorubicin improved OS in patients with advanced soft-tissue sarcoma. In the phase 1b/2 study of 133 patients with unresectable or metastatic soft-tissue sarcoma, the median PFS was 6.6 months with olaratumab plus doxorubicin versus 4.1 months in the doxorubicin-alone arm (HR, 0.672). An interim OS analysis also favored the combination (25 months vs 14.7 months, respectively; HR, 0.44).

In a phase 2 study of 53 evaluable patients with metastatic and nonresectable soft-tissue sarcomas, the median PFS was 3.4 months and the median OS was 9.2 months with tivozanib, a potent and selective inhibitor of VEGF receptors 1, 2, and 3 tyrosine kinases. The PFS at 4 months was 34.6%.

Kidney Cancer

Lenvatinib, a highly potent tyrosine kinase inhibitor of VEGF receptors and fibroblast growth factor receptors, improved PFS over everolimus alone when given as monotherapy or in combination with everolimus in patients with metastatic renal-cell carcinoma in a randomized phase 2 trial.

Supportive Care

Anamorelin increased lean body mass, body weight, total body mass, and fat mass, and restored energy balance, in an analysis of 2 phase 3 studies (N = 979) of patients with advanced NSCLC and cachexia. The patients also experienced significant improvement in the symptoms related to their anorexia or cachexia.

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Last modified: August 30, 2021