Lung cancer is treated according to driver mutation and the discovery of new mutations may equate to new drug discoveries in lung cancer. Currently about 20% of lung cancers have the KRAS positive mutation and this group has had no viable treatment options. Some promising drug developments:
BMS’s Opdivo where the past two years have seen great advances in lung cancer with the new immunotherapy drugs, which appear to work regardless of KRAS mutation status. It was approved in non-squamous NSCLC that has stopped responding to chemotherapy after reporting median overall survival in PD-L1 expressors of around 18 months (versus 9 months in the chemotherapy arm). At 18 months an estimated 39% of patients were alive compared to 23% for Docetaxel. The doubling of survival was regardless of the level of PD-L1 expression. In non-expressors the survival was similar to chemotherapy, but safety was better with the Nivolumab arm. Non-squamous are around 70% of lung cancers.
BMS's Opdivo for squamous NSCLC was approved even earlier in March of 2015. In September 2015 BMS reported 28% of patients were alive at 18 months, compared to 13% on the chemotherapy (Docetaxel) arm in second-line squamous NSCLC. The superior overall survival appears to extend to patients with KRAS mutant status, a group making up more than around 20% of patients, who have a poor prognosis due to resistance. Therefore this is a very welcomed treatment option for this subgroup. Squamous represents over about 25% of lung cancers.
Array’s Selutinib is in early stages of development and may help for KRAS mutations, although the survival benefits are incremental.
Biothera’s Imprime PGG is based on advances in lung cancer from a deeper understanding of molecular characteristics of cancer cells. Therefore we have seen that in order for immunotherapy to work optimally, we may need cancer cells to express the PDL1 molecule. Combination treatments are achieving excellent results in very early trials to address this PDL1 negative group. In other cancer indications Biothera think they may be able to spark PDL1 expression. They achieved median overall survival of 16.1 months versus 11.6 months in 10 patients in phase 2 front-line NSCLC trials of their drug with Avastin.
Bergen Bio’s BGB324 in combination with chemotherapy is in NSCLC trials. In preclinical models they achieved durable tumour clearance in combination with anti-CTLA4 and anti PD1 therapies that were not achieved when these immunotherapies were used alone. They target cancer stem cells by blocking the epithelial to mesenchemyal (EMT) transition. Cells go back and forth between these states and this contributes to drug resistance and metastasis (see stem cells).
Astrazeneca’s MEDI and 9291 combination; on 2nd June 2015, showed an 85% response rate versus 65% in 9291 alone (Astrazeneca says it has data on 9291). This early Phase 1b trial of NSCLC EGFR T790M data is only for seven T790M-positive patients, but the response rates are promising. Astrazeneca said early data indicates the molecules are well tolerated in combination at their Phase 3 doses, providing early promise of a potential new standard of care in EGFR mutations and T790m positive NSCLC. EGFR mutations are approximately 25% of lung cancers.
The targeted therapy 9291 is also in trials as a single agent and Astrazeneca say it is on track to be the fastest drug launch ever.
Astrazeneca’s MEDI and Treme immunotherapy combinations; showed a good 38% response rate in the PDL1-negative subgroup versus monotherapy response rate of only around 6% in this subgroup. This was a phase 1 trial in only 13 patients who were PDL1-negative, yet the difference is remarkable as this subgroup has so far been slow to respond. There are also trials with this MEDI+Treme combo in second/third-line gastric cancer, second-line pancreatic cancer, first-line bladder cancer and second-line squamous cell carcinoma of the head and neck (SCCHN).
Merck’s Keytruda has been approved for PDL1 positive NSCLC’s, both squamous and non-squamous. It achieved a 41% reponse rate in PDL1 expressors. In 2015 we saw evidence that the more mutations a tumour has, the more likely it is to respond well to immunotherapy, at least that is what we saw in colorectal tumours treated with the immunotherapy drug Keytruda (see colorectal cancer).