How treatment developed
1977
A Nobel Prize for the hormones of the hypothalamus
Andrew Schally and Roger Guillemin share the 1977 Nobel Prize in Physiology or Medicine, with Rosalyn Yalow, for work on the hormones made by the hypothalamus. Schally had isolated and synthesised several of these peptide hormones. After 1978 he turned his laboratory to using analogues of them against hormone dependent cancers, including prostate cancer.
April 1985
The first GnRH analogue is approved for advanced prostate cancer
The US Food and Drug Administration approves Lupron (leuprolide acetate), a synthetic analogue of gonadotropin releasing hormone, for palliative treatment of advanced prostate cancer. It is a daily injection that lowers testosterone, offered as an alternative to surgical removal of the testes or oestrogen treatment. A review of cancer formulations lists triptorelin as authorised in 1986, and long acting depot leuprolide and goserelin in 1989, with goserelin for both prostate and breast cancer.
21 October 1988
Octreotide is approved for the symptoms of neuroendocrine tumours
Octreotide, a lab made version of somatostatin, the hormone that restrains several others, is first approved in the United States to treat severe diarrhoea and flushing caused by carcinoid tumours and VIPomas. Somatostatin itself had been isolated and its structure reported in 1973. The approval was for symptom control, not for slowing the tumours.
2009 and 2013
Somatostatin analogues are shown to slow tumour growth
The PROMID trial of 85 people with midgut neuroendocrine tumours, published in 2009, finds that long acting octreotide lengthens the time before the tumour grows, from 6.0 to 14.3 months. In 2013 the larger CLARINET trial of 204 people with non functioning tumours of the gut and pancreas reports the same effect for lanreotide, with a hazard ratio of 0.47. After two years 62% of people on lanreotide had not progressed or died, against 22% on placebo.
18 December 2020
Not a peptide: an oral GnRH blocker joins the injections
The FDA approves relugolix, the first oral GnRH receptor antagonist, for adults with advanced prostate cancer. In the HERO trial of 934 men, randomised two to one against leuprolide injections every three months, 96.7% of men on relugolix kept testosterone at castrate levels, below 50 ng/dL, from day 29 through 48 weeks. The company reported 88.8% for leuprolide. Relugolix is a small molecule, so it sits outside peptide research, but it competes directly with the peptide injections above.
What conventional treatment has not solved
Most of the peptide based treatments that have reached patients slow a cancer rather than remove it. The trials behind them mostly measured how long people lived before their disease grew, and in several of the largest the survival result was either not statistically significant or hard to read because people in the comparison group were allowed to switch to the new drug. The peptide vaccines that looked promising in early trials did not extend survival in phase 3. Several of the newest approaches, the alpha emitting radioligands, have so far reported response rates in single arm studies or topline statements without full numbers.
The peptide research, by what it was trying to do
Radioligands: molecules that carry radiation to the tumour
12 January 2017 and 26 January 2018
NETTER-1: the first phase 3 trial of a peptide radioligand
The NETTER-1 trial, published in the New England Journal of Medicine, randomised 229 people with advanced midgut neuroendocrine tumours that had grown despite somatostatin analogue treatment. Lutetium 177 dotatate, a somatostatin analogue carrying radioactive lutetium, given with long acting octreotide, was compared with high dose octreotide alone. At month 20 an estimated 65.2% of people on the radioligand had not progressed, against 10.8% on high dose octreotide. Tumours responded in 18% against 3%.
The FDA approved lutetium 177 dotatate, brand name Lutathera, for gut and pancreatic neuroendocrine tumours on 26 January 2018. The final survival analysis, published in The Lancet in 2021, found a median of 48.0 months against 36.3 months, a hazard ratio of 0.84 that was not statistically significant.
29 August 2018
NICE recommends Lutathera for the NHS, with conditions
The National Institute for Health and Care Excellence recommends lutetium 177 oxodotreotide for unresectable or metastatic, progressive, well differentiated neuroendocrine tumours of the gut and pancreas that carry somatostatin receptors, but only if the company provides it under its commercial arrangement. For gut tumours the committee found it did not meet NICE's end of life criteria, because life expectancy is 5 to 6 years, but recommended it because treatment options are limited.
June 2021 and 23 March 2022
Not strictly a peptide: VISION and the first PSMA radioligand approval
The VISION trial of 831 men with PSMA positive metastatic castration resistant prostate cancer who had already had hormone pathway drugs and chemotherapy found that adding lutetium 177 vipivotide tetraxetan, now sold as Pluvicto, to standard care cut the risk of progression or death, with a hazard ratio of 0.40, and reduced the risk of death by nearly 40%. Grade 3 or worse side effects occurred in 52.7% against 38%. The FDA approved it on 23 March 2022 with a PSMA imaging kit. Its targeting molecule is a small molecule rather than a peptide, but it follows the model the peptide radioligands set.
Trying to teach the immune system with peptides
December 2013 and September 2014
Tecemotide: a lung cancer vaccine misses its goal
Tecemotide, a vaccine built around a peptide from the MUC1 protein, was tested in the START phase 3 trial of 1,239 people with unresectable stage III lung cancer after chemoradiotherapy. Median survival was 25.6 months on tecemotide against 22.3 months on placebo, a hazard ratio of 0.88 that was not statistically significant. A subgroup who had concurrent chemoradiotherapy did better, 30.8 months against 20.6, which led to further trials. In September 2014, after a Japanese study also showed no effect, Merck stopped development of tecemotide as a single treatment in stage III lung cancer and discontinued its other company sponsored trials in the disease.
27 June 2016
NeuVax: a breast cancer vaccine is stopped for futility
On 27 June 2016 the independent data monitoring committee of the phase 3 PRESENT trial of nelipepimut S (NeuVax), a HER2 derived peptide given with GM-CSF to women with early stage, node positive breast cancer, recommended stopping it for futility. The planned interim analysis was triggered after 70 disease free survival events, with 71 reviewed. The trial had enrolled 758 patients and was designed to run to 141 events. The sponsor, Galena Biopharma, said its own investigation confirmed the recommendation and found no sign of treatment arms being reversed, and closed the trial.
2009 and April 2010
Thymosin alpha 1: activity signals, no confirmed survival benefit
Thymosin alpha 1, a peptide made by the thymus gland, has been tested as an immune booster in several cancers. In a randomised phase 2 trial of 25 people with liver cancer, published in 2009, adding it to chemoembolisation raised the response rate from 45.5% to 57.1% and median survival from 57.0 to 110.3 weeks, but neither difference was statistically significant. In a 488 patient randomised study in metastatic melanoma, published in the Journal of Clinical Oncology in 2010, combinations with dacarbazine produced more tumour responses than the control, 10 and 12 against 4, which met the trial's primary goal. Progression free survival was longer with a hazard ratio of 0.80, but the difference did not reach statistical significance (p = 0.06). The authors concluded that it had activity and justified further evaluation.
19 February 2016 and 22 January 2021
Not a peptide: anamorelin adds muscle, not strength
Anamorelin acts on the receptor for ghrelin, a peptide hormone made in the stomach, though the drug itself is a small molecule. In the ROMANA 1 and 2 phase 3 trials, in 979 people with advanced lung cancer and cachexia, it increased lean body mass over 12 weeks, by a median of 0.99 kg against a loss of 0.47 kg in ROMANA 1, and 0.65 kg against a loss of 0.98 kg in ROMANA 2. It did not improve handgrip strength, the second main goal. Japan approved it for cancer cachexia in lung, stomach, pancreatic and colorectal cancer on 22 January 2021.