Old and new therapies

Cancer remains one of the world’s top healthcare challenges, but over the years our ability to treat the disease has dramatically improved. In fact, there is a sense that a new generation of therapies – and particularly those harnessing the power of the immune system – could dramatically extend expected survival and even effect long-term cures in patients.

We are still in the earliest stages of this treatment shift, but there’s no question that we are experiencing a bonanza in new cancer therapies. Between November 2016 and October 2017, the FDA approved 31 new therapies for more than 16 types of tumour, including the first cell-based therapies, the first tumour-agnostic drugs and 13 new targeted medicines that block the growth and spread of cancer by interfering with specific molecular targets. Such is the pace of progress that patients can now be hopeful of getting a clinical response even in early-stage trials.

There’s little doubt immunotherapy is leading the charge at the moment, headed by checkpoint inhibitors that target receptors that inhibit the patient’s own immune response, as well as T-cell-based therapies and oncolytic viruses that attack malignant cells directly, and cancer vaccines that try to kickstart an intrinsic immune reaction to the tumour.

Checkpoint inhibitors – old and new

The first wave of checkpoint inhibitors targeting PD-(L)1 and CTLA-4, from Bristol-Myers Squibb, Merck & Co, Roche, AstraZeneca and Merck KGaA/Pfizer, have had transformative results in some diseases such as melanoma, non-small cell lung cancer and bladder cancer – among others. The first anti-PD1 antibody was approved four years ago to treat melanoma and this class of therapeutics has now been approved to treat at least ten different cancers.

Non-small cell lung cancer (NSCLC) is a prime example of the impact the new PD-(L)1 drugs can have. Last year, the FDA approved Merck’s Keytruda (pembrolizumab) as a first-line agent alongside chemotherapy for metastatic NSCLC on data showing the chance of cancer progression was cut in half. And AZ’s Imfinzi (durvalumab) meanwhile has shown its worth as a maintenance therapy to stop recurrence of earlier-stage, locally-advanced NSCLC.

It’s not all been plain sailing, with BMS’ Opdivo (nivolumab) and Roche’s Tecentriq not doing as well as hoped in frontline NSCLC, revealing there are differences between checkpoint inhibitors – or at least between trial design. Moreover, around a third of patients do not respond to current immunotherapies, some develop resistance and, in most cases, we don’t have the biomarkers available to identify those that will benefit from treatment.

They are also associated with a range of immune-related adverse effects involving the skin, gastrointestinal system, lungs, endocrine system and respiratory system.

Researchers are now trying to identify biomarker-based subgroups and drug combinations to try to improve therapeutic outcomes for patients. Combining PD-(L)1 and CTLA-4 inhibitors – which work on different signalling pathways but both activate T-cells – has improved efficacy in some cancers like melanoma, but disappointed elsewhere.

For instance, AZ’s MYSTIC of Imfinzi and CTLA4 drug tremelimumab in lung cancer wasn’t able to impact progression-free survival and – while the company is still hoping to show next year that the duo can extend overall survival when used together – hopes are receding that it will provide the synergy once anticipated.

The field is marching on rapidly. Studies of checkpoint inhibitors are now taking place in less common forms of cancer with greater unmet needs, such as gastric cancer, acute myelocytic leukaemia and ovarian cancer, and some tumours such as pancreatic and prostate cancers have proved resistant to current immunotherapies.

There’s also a progressive effort to move the first generation upstream in treatment to first-line and adjuvant therapy, such as the ongoing ALCHEMIST trial, which is exploring whether giving Opdivo after standard treatment of early-stage lung cancer can reduce recurrences and help patients live longer by killing tumour cells remaining after surgery and standard chemotherapy.

Meanwhile, despite the mixed results for checkpoint inhibitor combinations to date, there’s no let-up in the pursuit of new cocktail recipes. Roche has already chalked up the first successes pairing Tecentriq (atezolizumab) with its veteran anticancer antibody Avastin (bevacizumab) in first-line NSCLC and kidney cancer, with additional trials of the duo in play. The drugmaker thinks Avastin may enhance Tecentriq’s activity by inhibiting local immunosuppression and boosting T-cell responses.

There’s also a host of drugs targeting new immuno-oncology targets coming through the pipeline with data due in the coming months – too many to include them all in this article – but, as recent experience with Incyte and Nektar Therapeutics has shown, not all new drugs and combinations will succeed.

Nektar Therapeutics’ CD122 agonist NKTR-214 posted mixed results in mid-stage trials alongside Opdivo in solid tumours at the American Society of Clinical Oncology (ASCO) meeting this year that disappointed some observers, although partner BMS was encouraged enough to press on with a pivotal trials programme. Meanwhile, Incyte’s Merck & Co partnered IDO inhibitor epacadostat bombed when paired with Keytruda in a melanoma trial and, while Incyte insists IDO isn’t a dead target just yet, BMS and NewLink have also dropped their IDO programmes.

It’s a whole new therapeutic vista of course, so setbacks are only to be expected, and there are plenty of other new targets in the biopharma industry’s sights. Among these is BMS’ LAG-3 inhibitor relatlimab, which targets a protein that boosts T-cell activity against tumours and also inhibits other T-cells that can suppress an immune response. The antibody is being tested alongside Opdivo in melanoma patients who stop responding to PD-(L)1 drugs alone and showed promising results in a phase I/II trial presented at ASCO last year, and a larger, 1,000-patient study across multiple cancers is due to report in 2020.

Other emerging checkpoint targets include the CSF1R receptor, with candidates from Syndax/AstraZeneca, Amgen, Five Prime and Deciphera making their way through early-stage trials, and CD73 inhibitors from Arcus (AB680) and Innate Pharma (IPH53) – both of which work by blocking immunosuppressive mechanisms in the tumour microenvironment.

There are also new agents coming through that stimulate activators of T-cells. They include Pfizer’s OX40 agonist PF-04518600, in early-stage testing in combination with the company’s Bavencio (avelumab) and targeted cancer drug Inlyta (axitinib) as well as chemotherapy, CD137-targeting drugs from the likes of Crescendo Biologics and Pfizer, and Celldex’ CD27-targeting antibody varlilumab which is in phase II testing for various solid tumour types. There are various companies working on toll-like receptor agonists that stimulate antigen-presenting cells, such as Idera’s TLR9-targeted drug IMO-2125 which boosted the activity of BMS’ CTLA4 drug Yervoy (ipilimumab) in an early-stage trial.

Following after the first generation of mainly antibody-based immuno-oncology drugs are a host of small-molecule drugs. Among the plethora in the pipeline, Aurigene and BMS are looking at PD-1 inhibitors that can be dosed orally, Novartis, iTeos and Aduro are developing STING agonists that can ramp-up innate immune responses, and Cancer Research UK is repurposing an AZ chemokine CCR4 receptor drug (AZD2098) originally developed for asthma in kidney cancer.

Cell-based therapies

It’s no surprise that adoptive cell immunotherapy was named the 2018 Advance of the Year by the American Society of Clinical Oncology (ASCO), shortly after two chimeric antigen receptor T-cell (CAR-T) therapies from Novartis and Gilead gained regulatory approval in 2017 for acute lymphoblastic leukaemia (ALL) and diffuse large B-cell lymphoma (DLBCL) after showing remarkable results in clinical trials.

The CAR-Ts have transformed the treatment of childhood ALL – an otherwise incurable blood cancer – and have been shown to work in hard-to-treat lymphomas in adults and drive multiple myeloma into remission. Celgene and Juno hope to crash the party soon with JCAR017, armed with positive data in diffuse large B-cell lymphoma (DLBCL).

The challenges ahead are to improve the safety of the procedure, develop easier-to-administer, off-the-shelf therapies that don’t require a patient’s cells to be harvested, and to extend the benefits seen in blood cancers to solid tumours.

Precision cancer treatment

The shift towards immunotherapies has been accompanied by another key trend – targeting cancer not on the basis of where it appears in the body, but purely on the molecular defects that are driving its growth, in contrast to targeted therapies that tie the biomarker to a particular tumour type.

The approvals of Keytruda and Opdivo for solid tumours with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) motifs are key examples, and it’s a trend that’s also extending to targeted cancer drugs, with Loxo Oncology and Bayer’s larotrectinib filed for TRK gene fusion tumours and due for an FDA verdict in November.

There are big advantages to this approach, including the spend of clinical development, a favourable regulatory environment, biomarker-based patient selection, and parallel development in adult and paediatric patients. But there are downsides too. It’s worth noting that Roche’s BRAF-targeting drug Zelboraf (vemurafenib) for melanoma has seen mixed results in other tumours, suggesting that ‘histologic context’ – ie the effects of where a tumour is located – can still have an impact on clinical efficacy.

Additional work is going to stratify tumours according to these molecular signatures, and a recent study from California’s Buck Institute for Research on Ageing has analysed 33 cancer types and reclassified them into 28 molecular clusters in the hope that more effective and targeted cancer treatments can be developed.

Oncolytic viruses

An oncolytic virus is a virus that preferentially infects and kills cancer cells, and to date a handful of therapies – Amgen’s Imlygic (talimogene laherparepvec) in the US and EU and others in China and Eastern Europe – have reached the market. While use of Imlygic has been limited, its approval in 2015 was a milestone in cancer immunotherapy, particularly as data showed the drug – which is injected directly into melanoma tumours – also seems to have an effect on metastases. It’s also been shown to have improved efficacy when given alongside Keytruda.

Other oncolytic viruses are coming through the pipeline, including SillaJen/Transgene’s Pexa-Vec for liver cancer and other solid tumours with trial results due between now and the end of the year, Targovax’ mesothelioma candidate ONCOS-102 with data due in 2019 and M032, an investigator-developed candidate in trials for glioblastoma. Another virus – Viralytics’ Cavatak – showed promise in a phase I trial as a combination with Keytruda in melanoma, piquing Merck’s interest and prompting a $394m takeover deal earlier this year. Cavatak is now in three trials in melanoma, bladder cancer and NSCLC that are due to generate results in 2018/2019.

Meanwhile, AbbVie and Johnson & Johnson have both struck deals this year with biotechs in this field – Turnstone Biologics and BeneVir Biopharm respectively – suggesting the oncolytic virus sector is heating up.

Vaccines

While the first therapeutic cancer vaccines have reached the market, eg Dendreon’s Provenge and Antigenics’ Oncophage, commercially they haven’t yet made much impact and the pipeline has been marked more by failures than successes, with a string of candidates (including Aduro’s GVAX, CancerVax’ Canvaxin, and Genitope’s MyVax) missing the mark in late-stage testing.

Progress is however being made. Neoantigen vaccines – a new form of personalised immunotherapy in which antigens that are found in diseased tissues but not normally in healthy patients are used to develop targeted vaccines – are starting to show promise in early-stage testing. Candidates from Neon Therapeutics, Aduro and BioNTech have passed early-stage testing and are now being studied along with checkpoint inhibitors to see if they can deliver a double-whammy to tumours.

Researchers are also investigating whether preventive vaccines could be deployed in people with high-risk cancer mutations, such as the HeritX consortium in BRCA-related breast and ovarian cancers, but this still in the very earliest stages.

To sum up, because of the ageing and growing population, there will be more new patients with cancer every year, and for every life saved, there are many more waiting for the next breakthrough for themselves or their loved ones.

Immunotherapy is gradually spreading across the spectrum in cancer, but the challenge now is to design more rational and appropriate synergistic combinations, and to develop effective biomarkers that can identify those patients most likely to benefit from treatment.