The FUTURE in Metastatic LUNG CANCER

If you shake the branches of a tree, sometime the hidden fruit drops down. And so it is with Metastatic Lung Cancer. From here to there at the speed of molecular inhibition/excitation we have come a long way baby!.

Long heralded as an open and shut case of short-term limited survival lung cancer is now exposing its roots for targeted attacks and the survival is improving. We can take down this tree!

The treatment for metastatic lung cancer has long been combination chemotherapy with a doublet regimen and the benefits are displayed below:

Metric	Prior to 1990s	1990 – 2000
Overall Response	15%	25%
Median Survival	6 months	8-10 months
1-year Survival	15-20%	30%
2-year Survival	Less than 5%	10-15%
Time to Progression	2 months	4 months

The new molecular targeting agents are changing the present and the future. Survival in those with genomic-target-able regions is being enhanced substantially. See below:

Metric	2000s	Present
Overall Response	35%	35-65%
Median Survival	12-14 months	15-24 months
1-year Survival	40-50%	50-60%
2-year Survival	20%	25-505
Time to Progression	6 months	7-12 months

Among the various forms of Non-Small Cell Lung Cancer, Adenocarcinoma seems to have opened itself to therapeutic intervention. The population of patients with NSCLC can now be stratified into those with target-laden actionable groups and others where knowledge is still wanting. None of these new targets however result in curative outcomes, only prolonged survival at the present time but that might change in the future. In the Squamous Cell type NSCLC various molecular targets have been determined, but at present they are not actionable. These include the following kinases and receptors: MAPK, PI3K, FGFR, EGFR, TOR. Recently however a drug called Opdivo was approved by the FDA yielding 3 months extra survival in late stage Squamous cell lung cancer. Small step but that is how paths emerge.

In Adenocarcinoma sub-type however there are target-able switches:

Mutation	Frequency
KRAS	22%
EGFR	17%
EML4-ALK	7-8%
BRAF	Less than 2%

The IPASS trial was the first to show the advantage of actionable targets with improved Progression-Free Survival (PFS). Since then we have come a long way and the information is cascading as voluminous cataract. The IPASS trial showed a 71.2% Response Rate (RR) and a 3.4 month improvement in median PFS (n=261). The OPTIMAL trial with erlotinib showed an 83% RR and a 8.5 month PFS improvement (n=154). Other confirmatory trials also showed similar benefits, yet none showed an actual increase in Overall Survival, indicating temporary phenomena.

Further teasing the data revealed that almost 60% of the EGFR target developed a mutation called the T790M. A CO-1686 selective inhibitor of the EGFR T790M resulted in further improvement of the PFS by >12 months and the CO-1686 inhibitor passed through the Blood Brain Barrier exhibiting Central Nervous System responses! With current 1-year survival rates more than doubled from 15-20% to 40-50% and the 2-year survivals from less than 5% to almost 20%, this is indeed a success story that does not get the press it deserves.

Another target on the Adenocarcinoma NSCLC  is the EML4-ALK mutation in 3-8% of the NSCLC population . In a study of 141 patients 13% were positive for the mutation. An agent named Crizotinib resulted in a 60% RR. (n = 261). Resistance was further chipped away with newer agents such as Ceritinib and AP 21163 (preliminary unpublished data from ASCO). Additionally a minor mutation called ROS-1 (in 1% of NSCLC) has a targetable interface that has resulted in improved outcomes in that very specific patient population. Median Survival has also improved from 6 months to 12-15+ months. All indications appear to suggest a paradigm shift occurring with the advent of targetable sites on the NSCLC cell lines.

The future in NSCLC is primed for further enhancements given that we have molecular targets; KRAS, BRAF, PIK3CA, Her 2, MET amplification, MEK-1, NRAS, AKT. Using molecular target inhibitors in doublets concurrently or in sequence might be one future to behold. Other mechanisms using HSP-90, mTOR inhibitors might also play a part downstream. All options are open. We are no longer relegated to the chemicals only. A combination of the chemicals and molecular targeting might be another approach. Recently the FDA approved Nivolumab (Opdivo) a PD-1 inhibitor for Squamous Cell NSCLC. PD-1 negatively regulates T cell responses and inhibiting that regulatory behavior allows for a more robust immune directed response against the cancer.

If one lets the imagination wander a bit, as in a thought experiment for instance, you might find a whole array of gold nano discs and nano wires circulating in the blood stream looking for a match against one of the targets and upon contact send a message to a "Tricorder"about the existence of the disease in its infancy and voila a slew of antibodies are released against the targets. The cancer wouldn't know what hit it. Of course we might even pick up the first inkling of the disease before targets are needed, like the adenomas in colon and remove them to prevent cancer. Ah the possibilities are endless, as is our desire to cure as is the imagination running wild and free.

Like all futures they are always different than what we imagine, because there are 7+ billion minds out there vying for chance to subdue this disease and from that diversity, where ever these paths lead us, will be a better place for us all.

GO ON DREAM! IMAGINE! then INNOVATE!

Have Fun doing it!

References:

Geftinib or carboplatin-placlitaxel in pulmonary adenocarcinoma. Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, Sunpaweravong P, Han B, Margono B, Ichinose Y, et al. N Engl J Med361(10):947-957, 2009

Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study.Lancet Oncol. 2011 Aug ;12(8):735-42.

Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. Shaw AT, Kim DW, Nakagawa K, Seto T, Crinó L, Ahn MJ, De Pas T, Besse B, Solomon BJ, Blackhall F, Wu YL, Thomas M, O’Byrne KJ, Moro-Sibilot D, Camidge DR, Mok T, Hirsh V, Riely GJ, Iyer S, Tassell V, Polli A, Wilner KD, Jänne PA:  N Engl J Med 2013, 368(25):2385-2394

Crizotinib in ROS1-rearranged non-small-cell lung cancer. Shaw AT, Ou SH, Bang YJ, Camidge DR, Solomon BJ, Salgia R, Riely GJ, Varella-Garcia M, Shapiro GI, Costa DB, et al.N Engl J Med. 2014 Nov 20; 371(21):1963-71. Epub 2014 Sep 27.