Cancer Advance of the Year: IMMUNOTHERAPY 2.0! Expanded Use and Appropriate Patient Selection

The American Society of Clinical Oncology (ASCO) named Immunotherapy 2.0 its advance of the year. Understanding immune control of cancer took scientists 100 years ( the journey beginning with Coley’s Toxins). Blocking immune checkpoints is a particularly successful approach. These specialized proteins brake immunity, enabling appropriate activity while preventing autoimmune disease and excessive inflammation from unnecessary activation.

Checkpoint inhibition, also called blockade or regulation, prevents cancer from braking immunity, allowing attacks on malignant cells. Since major effectiveness was discovered in 2011 in malignant melanoma skin cancer treatment , research has accelerated dramatically. Last year, 5 newly FDA-approved inhibitors entered lung, head-and-neck, bladder, kidney and Hodgkin lymphoma treatment. In 2016, patient-selection knowledge also advanced.

Progress with Immune Checkpoint Inhibitors

Immunotherapy prolongs life in advanced melanoma. Cases have increased markedly worldwide over 30 years. In America in 2016, about 76,380 adults were diagnosed. United States statistics rank melanoma 7th in men and 5th in women.

Although only %1 of skin cancers, melanoma causes a substantial share of skin cancer deaths. Most patients can be cured surgically. However, in metastatic melanoma only %17 survive 5 years.

Immunotherapies quickly changed the outlook. Results led experts to discuss achieving treatment success through immunotherapy.

FDA-approved ipilimumab (Yervoy) was the first treatment prolonging advanced melanoma survival; it blocks cytotoxic T-lymphocyte protein-4 [CTLA-4]. At the end of 2014, the FDA approved pembrolizumab (Keytruda) and nivolumab (Opdivo). Both proved more effective and less harmful than ipilimumab.

A large trial also showed that adjuvant immunotherapy in surgically removable stage III melanoma could help prolong survival . Despite successful surgery, approximately % 60 of these patients experience recurrence within 4 years.

Another major discovery was prolonged survival with PD-1 inhibitors nivolumab and pembrolizumab in advanced lung cancer. Lung cancer, in 2012 with 1.8 million new diagnoses, was the world’s commonest cancer. It causes 3 deaths per minute.

NSCLC accounts for most cases (% 85). In 2015, adding PD-1 inhibitors pembrolizumab and nivolumab to advanced NSCLC treatment extended mean life expectancy beyond 20 months.

In 2016, researchers compared pembrolizumab with standard docetaxel after prior advanced NSCLC treatment. Median survival was 10.4 versus 8.5 months. With higher PD-L1 (positive cells for PD-L1 at least % 50), survival was longer (14.9 v 8.2 months). Side effects were fewer (% 16 vs % 35). Immunotherapy offers longer life and is often easier to tolerate than chemotherapy.

These findings establish pembrolizumab as a new standard option for previously treated advanced NSCLC. The study also emphasizes PD-L1 as a biomarker testing to select beneficiaries.

Another large trial found pembrolizumab more effective than chemotherapy in metastatic NSCLC with high PD-L1 as initial treatment and it received FDA approval; however, a similar trial of the other PD-1 inhibitor nivolumab did not show superiority. These findings will change initial treatment and require PD-L1 testing in every newly diagnosed patient. Those with high PD-L1 will probably receive immunotherapy instead of chemotherapy.

Another checkpoint inhibitor, atezolizumab, received FDA approval in 2016 for previously treated metastatic NSCLC. It was previously approved for bladder cancer treatment and is a PD-L1 inhibitor. Atezolizumab is also the first PD-L1 checkpoint inhibitor FDA-approved for any use.

Immunotherapy has played an important role in early bladder cancer through FDA approval of Bacillus Calmette-Gu’erin (BCG), a live bacterium related to bovine tuberculosis. BCG has been a tuberculosis vaccine for over a century. Its bladder-cancer mechanism is incompletely understood, but researchers think it activates immunity against malignant cells. Atezolizumab approval opened further checkpoint research.

Immunotherapies have also proved effective against cancers difficult to treat when recurrent or spread, requiring an advanced specialist team approach: head and neck cancer treatment . More than 600.000 people worldwide are diagnosed annually.

New-generation immunotherapies offer longer and better lives. We believe the first wave is only a beginning. To improve success, remember fewer than half of treated patients benefit and solutions to resistance are needed (immunotherapy resistance). A study presented in February 2017 at the Genitourinary Cancers Symposium showed antibiotics reduce immunotherapy in kidney cancer patients effectiveness. Antibiotics damage intestinal flora (microbiota = beneficial bacteria). Their reduced immunotherapy effectiveness supports earlier findings that immunity interacts strongly with intestinal flora. This supports the findings of earlier research. In certain cancers, tumor subsets carrying numerous genetic mutations may be more sensitive to current immunotherapy options (microsatellite instability). Alongside selecting beneficiaries, researchers test immunotherapy combinations with each other, radiotherapy and chemotherapy to broaden effects. These efforts have brought the next stage: Immunotherapy 2.0!