Industry Trend Analysis - Immuno-Oncology Will Remain Key Cancer Pipeline Focus In 2018 - DEC 2017

BMI View: Immuno-oncology will remain a hot topic through 2018 . The market will see expansion past PD-1 inhibitors, with new drug classes nearing approval . Leading oncology players will continue to reinforce their positions with long-term data, while small biotechs will present as opportunities for partnerships and acquisition prospects.

Data released at the 2017 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain covered new indications for established drugs, reinforcing data for already approved indications, combination immunotherapies and new compounds. Some of the top oncology companies, such as Roche, Pfizer, Merck & Co and Bristol-Myers Squibb presented data, plus small biotechs also had a presence. PD-1 inhibitors were a recurring theme, as this market is becoming crowded, and presenting positive results is a key method of improving uptake. Novel immuno-oncology products also had a presence, but despite this interest targeted therapies will remain the backbone of the cancer treatment market, with immuno-oncology taking market share from chemotherapies.

Immuno-Oncology Will Not Challenge Targeted Therapies Leading Status
Oncology Sector Breakdown (%)
Other includes chemo, supportive and hormonal therapies. Source: Novartis, BMI

Maintaining Presence Through Reinforced Data

Big pharma will continue to reinforce data for established drugs in order to remain competitive as new drugs from small biotechs are increasing their competitive edge. Positive data for any product in a portfolio, especially long-term outcomes and new indications, can provide a boost to revenues. Long-term outcomes data will aid in optimising brand value, and protect legacy products as new compounds are expedited through development. With competition increasing from small molecules and immuno-oncology, data will be crucial in driving treatment utilisation.

Roche And Pfizer Aim For ALK Inhibitor Expansion

Both Roche and Pfizer presented results for their respective ALK-inhibitors with the aim of expanding the reach of these growth drivers. Roche had particularly positive results, while Pfizer reported unfavourable data.

Roche announced results from the global Phase III ALUR study showing that Alecensa (alectinib) significantly reduced the risk of disease worsening or death (progression-free survival [PFS]) by 85% compared to chemotherapy in patients with ALK-positive advanced non-small cell lung cancer (NSCLC), who had progressed following treatment with platinum-based chemotherapy and crizotinib (hazard ratio [HR]=0.15, 95% CI: 0.08-0.29, p<0.001). Median PFS reported by the investigators, the primary endpoint of the study, was 9.6 months in patients who received Alecensa (95% CI: 6.9-12.2) compared with 1.4 months (95% CI: 1.3-1.6) in those who received chemotherapy. Median PFS assessed by an independent review committee (IRC), a secondary endpoint, was 7.1 months for patients who received Alecensa versus 1.6 months for patients who received chemotherapy (HR=0.32, 95% CI: 0.17-0.59; p<0.001).

Pfizer showcased final overall survival (OS) data from the PROFILE 1014 trial examining Xalkori (crizotinib) in previously untreated patients with ALK-positive advanced NSCLC. After a median follow-up of 46 months, the median OS for patients randomised to Xalkori was not reached (95% CI: 45.8 months, not reached) and was 47.5 months for patients randomised to chemotherapy (95% CI: 32.2 months, not reached). Results indicated a numerical improvement in OS for patients treated with first-line Xalkori compared with chemotherapy, although this difference did not quite achieve statistical significance (HR=0.760 [95% CI: 0.548, 1.053]; p=0.0978). The majority (84%) of patients initially randomised to chemotherapy received Xalkori after they progressed and this likely affected the OS results.

PD-1 Inhibitor Competition Continues

With new competitors gaining approvals, and competition between the main PD-1 players increasing, new data will aid in establishing market share. Merck and BMS lead the field with numerous trial results presented in new and established indications.

BMS announced three-year OS data from CheckMate -017 and CheckMate -057, two pivotal Phase III randomised studies evaluating Opdivo (nivolumab) versus docetaxel in patients with previously treated metastatic NSCLC. In CheckMate -017, a trial in previously treated squamous NSCLC, 16% of patients treated with Opdivo were alive at three years (21/135) versus 6% of those treated with docetaxel (8/137; HR=0.62; 95% CI: 0.48 to 0.80). In CheckMate -057, a trial in previously treated non-squamous NSCLC, 18% of patients treated with Opdivo were alive at three years (49/292) versus 9% of those treated with docetaxel (26/290; HR=0.73; 95% CI: 0.62 to 0.88). Similar to prior reports, an OS benefit was observed across histologies, and three-year survivors included patients whose tumours expressed PD-L1 and those that did not.

BMS also reported that treatment with Opdivo 3mg/kg resulted in a significant improvement in recurrence-free survival (RFS) compared to Yervoy (ipilimumab) 10mg/kg in patients with Stage IIIb/c or Stage IV melanoma following complete surgical resection. At this planned interim analysis, Opdivo met its primary endpoint, showing a statistically significant improvement of 35% in RFS (HR=0.65; 97.56% CI: 0.51 to 0.83; p<0.0001) compared to Yervoy. The 18-month RFS rates for the Opdivo and Yervoy groups, respectively, were 66.4% (95% CI: 61.8 to 70.6) and 52.7% (95% CI: 47.8 to 57.4). Median RFS had not yet been reached for either group at the time of this analysis.

Merck announced updated results from the Phase III KEYNOTE-045 trial evaluating Keytruda (pembrolizumab) in patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy. Updated data showed that with median follow-up of 22.5 months, Keytruda continues to demonstrate an OS benefit over investigator's choice of paclitaxel, docetaxel or vinflunine as a second-line therapy, post-platinum failure, regardless of PD-L1 expression (HR=0.70 [95% CI, 0.57-0.86], p=0.0003).

Results of the Phase III KEYNOTE-040 trial investigating Keytruda compared to standard treatment (methotrexate, docetaxel or cetuximab) in patients with recurrent or metastatic head and neck squamous cell carcinoma (SCCHN) with disease progression on or after platinum-containing chemotherapy were also presented. The study did not meet its pre-specified primary endpoint of OS. The findings included updated survival data showing a 19% reduction in the risk of death over standard treatment in the intent-to-treat population (HR=0.81 [95% CI, 0.66-0.99]; one-sided p=0.0204), with pre-specified p-value required for statistical significance of 0.0175, and a median OS of 8.4 months with Keytruda (95% CI, 6.5-9.4) compared to 7.1 months with standard treatment (95% CI, 5.9-8.1).

AstraZeneca also strengthened its PD-1 inhibitor data, showcasing the full PFS data from a planned interim analysis of the investigational Phase III PACIFIC trial. Results showed that Imfinzi (durvalumab) demonstrated a statistically significant and clinically meaningful improvement in PFS compared to current standard-of-care with active surveillance in patients with locally-advanced (Stage III), unresectable NSCLC who had not progressed following standard platinum-based chemotherapy concurrent with radiation therapy (CRT).

PD-1 Combinations To Drive Growth

PD-1 inhibitors remain at hot topic at cancer conferences, and combinations are the next phase of development in this landscape. Combination therapies with PD-1 inhibitors will offer a significant advantage over current monotherapies. Keytruda is leading the development of combinations, with approximately 270 trials involving Keytruda with another compound.

Combination therapies give a two-pronged attack on a tumour thereby blocking many pathways in which a tumour can survive. While monotherapies are always the first to be approved due to the relative simplicity of trials, combination therapies allow companies to build up a library of additional useful interactions to further add value to their therapeutics and prolong the life of a franchise. Combinations have become standard treatment and deal making will continue as a limited number of companies will have all the appropriate agents to target key pathways at their disposal in-house.

BMS announced results from the Phase III CheckMate -214 trial evaluating Opdivo plus Yervoy versus sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC), including data on key subgroups. With a minimum follow-up of 17.5 months, Opdivo in combination with Yervoy reduced the risk of death by 37% (HR=0.63; 99.8% CI: 0.44 to 0.89; p<0.0001) compared with sunitinib, the current standard of care, in an interim analysis of OS in intermediate- and poor-risk patients, the co-primary endpoint. The median OS had not yet been reached for the combination and was 26 months for sunitinib (95% CI: 22.1 to NA).

Incyte released updated data from the ongoing Phase I/II ECHO-202 trial (KEYNOTE-037) evaluating epacadostat, Incyte's selective IDO1 enzyme inhibitor, in combination with Keytruda in patients with advanced melanoma. Among all patients with advanced melanoma, including treatment-naive and treatment-experienced, data showed an overall response rate (ORR) of 56% (n=35/63) in patients treated with the combination of epacadostat and Keytruda; median PFS was 12.4 months, with PFS rates of 65% at six months, 52% at 12 months, and 49% at 18 months.

Eisai highlighted interim results from the advanced RCC cohort of Study 111, a Phase Ib/II study investigating lenvatinib in combination with Keytruda in patients with selected solid tumours. In this cohort of both treatment-naive and previously treated patients with metastatic clear cell RCC (n=30), the confirmed ORR at week 24, the primary endpoint of the study, was 63% (95% CI: 44-80) based on investigator-assessed immune-related RECIST, all of which were partial responses (PR; n=19), and disease control rate (DCR; complete response [CR] + PR + stable disease [SD]), a secondary endpoint, was 96% (including 33% SD [n=10]).

Merck highlighted updated results from Cohort G of the Phase II KEYNOTE-021 trial investigating Keytruda in combination with pemetrexed and carboplatin (pem/carbo) in patients with previously untreated advanced non-squamous NSCLC, with or without PD-L1 expression. With an additional five months of follow-up, significant improvements observed in prior analyses were maintained, including improvements in ORR and PFS for Keytruda+pem/carbo compared to pem/carbo alone. With a median of 18.7 months of follow-up, more than half of patients in the Keytruda combination arm responded to treatment compared to approximately one-third in the pem/carbo arm (ORR of 56.7% vs 31.7% [95% CI, 7.2-40.9], p=0.0029). The risk of progression or death continued to be reduced by nearly half with Keytruda+pem/carbo compared to pem/carbo alone (HR=0.54 [95% CI, 0.33-0.88, p=0.0067]). In addition, despite the crossover design, a trend in improvement in OS continues to be seen for Keytruda+pem/carbo compared to pem/carbo alone (HR=0.59 [95% CI, 0.34-1.05, p=0.03]).

New data from Ionis Pharmaceuticals' clinical programme for IONIS-STAT3-2.5Rx (AZD9150) were presented at ESMO 2017. The presentation included clinical and safety results from the Phase Ib/II study evaluating the activity of IONIS-STAT3-2.5Rx in combination with Imfinzi in patients with advanced solid tumours and recurrent metastatic head and neck cancer. In the study, the combination treatment resulted in encouraging anti-tumour activity with a safety and tolerability profile supportive of continued development. In the study, combination therapy with IONIS-STAT3-2.5Rx and Imfinzi in 28 PD-L1 treatment-naive patients with refractory and metastatic (R/M)-SCCHN resulted in encouraging antitumour activity and deep responses to treatment. The treatment combination demonstrated a 29% (8/28) ORR with four PRs and four CRs, of which one was a CR in target lesions only. An additional eight patients on the treatment combination had SD at 12 weeks, resulting in an overall disease control rate of 57% (16/28). Importantly, a CR was seen in a patient with R/M-SCCHN that was refractory to previous PD-L1 treatment.

In addition, an interim analysis of Immune Design's ongoing, randomised Phase II trial showed that NY-ESO-1+ soft tissue sarcoma (STS) patients receiving the combination of CMB305, a prime-boost vaccine, and Genentech (Roche)'s checkpoint inhibitor, Tecentriq (atezolizumab), experienced greater clinical benefit and immune response than those receiving atezolizumab alone.

Small Space Left In The PD-1 Market

The PD-1 inhibitor market is now crowded with five approved therapies vying for market share: Merck & Co's Keytruda, BMS' Opdivo, Roche's Tecentriq, AstraZeneca's Imfinzi and Pfizer/ Merck KGaA's Bavencio (avelumab). A large proportion of big pharma has a stake in the PD-1 market. Despite this crowding, there are new PD-1 inhibitors progressing through clinical trials, and while these will not be able to reach the heights of the first-to-market, they will be able to add to a well-rounded immuno-oncology portfolio. With PD-1 inhibitor combinations gaining traction, a big company lacking a PD-1 product will aim to partner or acquire in order to keep combinations in house, and be able to offer deals to incentivise use. Small biotechs presented data at ESMO highlighting their clinical stage PD-1 offerings and how these are differentiated from the market leaders.

Curis presented preliminary data from the initial 34 patients with cancer treated in the dose escalation stage of the Phase I trial of CA-170 conducted in the US, South Korea and Spain. As a result of the initial safety data and preliminary evidence of clinical benefit observed in the trial, Curis's collaborator and discoverer of CA-170, Aurigene Discovery Technologies announced plans to initiate a Phase II trial of CA-170 to be conducted at sites in India. CA-170 is an oral small molecule targeting the immune checkpoints PDL1 and VISTA. Data presented at ESMO 2017 represent the initial 34 patients treated to date in the dose escalation Phase I trial. In total, 30 patients were naive to prior immunotherapy treatment, while four patients had experienced prior treatment with approved anti-checkpoint antibodies. Evidence of immune modulation, including an increase in activated CD8+ T-cells, was observed in patient blood and tumour biopsy samples examined following treatment. Of the 21 patients evaluable for disease assessment, 13 patients experienced disease stabilisation. Four immunotherapy treatment-naive patients treated with CA-170 experienced shrinkage of their tumours. Six patients remained on drug treatment beyond three months, including all four patients with tumour shrinkages.

BeiGene presented preliminary data from multiple disease-specific subgroups in the ongoing Phase Ia/Ib trial of its investigational anti-PD-1 antibody BGB-A317 in advanced solid tumours at ESMO. The three posters contained preliminary data from patients with gastric cancer (GC) and oesophageal cancer, SCCHN and ovarian cancer (OC). The preliminary Phase I data suggest that BGB-A317 was generally well tolerated and exhibited preliminary evidence of anti-tumour activity in advanced patients with each of these tumour types.

Differentiated Immuno-Oncology Segments Emerging

While the primary focus has been on PD-1 inhibitors in the immuno-oncology market, there is a broader market potential with many different classes of immuno-oncology therapeutics. These are starting to progress through clinical development, and we will see expansion in the area occur rapidly throughout 2018.

IRX Therapeutics presented results from a Phase IIa trial of IRX-2, the company's lead drug candidate, in SCCHN at the ESMO Congress. In a subset study of seven patients, it was demonstrated that IRX-2 upregulates immune checkpoint markers, including PDL1 and CTLA4 expression, suggesting that the effects of IRX-2 treatment may be enhanced by combination therapy with checkpoint inhibitors. The trial also demonstrated that IRX-2 promotes expression of chemokine pathway genes (CCLs, CCRs, CXCLs and CXCRs), which are chemoattractants whose expression may result in increased lymphocyte infiltration.

Inovio Pharmaceuticals showcased an interim data analysis that demonstrated its INO-5150 cancer immunotherapy product generated antigen-specific CD8+ killer T-cell responses measured in peripheral blood from subjects with biochemically recurrent prostate cancer. The immunology results demonstrate that INO-5150 treatment as a monotherapy generated prostate specific antigen (PSA) and prostate specific membrane antigen (PSMA) specific T-cell responses in peripheral blood in 60% (35/58) of the subjects. Moreover, patients with specific CD8+ T-cell responses experienced dampening in the rise of PSA and significant increases in PSA Doubling Times (PSADT).