TARGETING LUNG CANCER

Lung cancer is the second most common cancer in both women and men, eclipsed only by breast cancer in women and prostate cancer in men. ACS estimates 221,200 cases in 2015 with 158,040 related cancer deaths. It accounts for 13% of all cancer occurrences and 27% of all deaths related to cancer. Early diagnosis and treatment meets with cures although only 15% of the NSCLC are diagnosed early.

NSCLC treatment has mostly revolved around, surgery, radiation therapy and chemotherapy for the longest time. The marginal successes have had little impact on overall survival. Today the era of Molecular medicine hopes to change that paradigm.

Non Small Cell Lung Cancers are grouped into Adenocarcinoma (50%), Squamous Cell (30%) and Others (20%). Each subset carries its own characteristics of genetic mutations, although overlap is commonly seen amongst the groups.

Common known Mutations in Adenocarcinoma: 

1. Epidermal Growth Factor Receptor (EGFR) is the most common one and is present in 50% of the Asian patients and 10% in the non-Asians.
2. KRAS mutations in 25% of cases are less common among smokers and absent in Asians.
3. ALK and EML4 fusion is present in 2-7% of the NSCLC (mostly adenocarcinoma) non-smoker patients.

Targeted Inhibitors designed to target these molecular structures include:

1.              Erlotinib and Geftinb are most effective in cases with exon 19 deletion, exon 21 L858R, and exon 18 G719X. The Pan-Asia study showed a 9.6 months survival in gefitinib-treated patients, versus a 41% ORR with a median duration of response of 5.5 months for the carboplatin/paclitaxel chemotherapy group. (Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010 Jun 24. 362 (25):2380-8). However resistance is noted after one year of therapy with these Kinase Inhibitors. A specific mutation noted at the exon 20 T790M is found in the resistant cell lines. these mutations have been targeted effectively with another Inhibitor Afatinib with modest success. In the LUX-Lung Trial, results showed the Afatinib group’s progression-free survival (PFS) was 11.1 months compared with 6.9 months for those treated with pemetrexed/cisplatin chemotherapy regimen. (Sequist LV, Yang JC, Yamamoto N, O'Byrne K, Hirsh V, Mok T, et al. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. J Clin Oncol. 2013 Jul 1)
2.          However Cetuximab a monoclonal antibody to EGFR noted to have activity in NSCLC (adenocarcinoma) without the EGFR mutation, later a post hoc analysis revealed that the EGFR mutation status conferred a better response rate.
3.          For patients with ALK mutations Crizotinib and Ceritinib have modest efficacy. Trilas showed response rates of approximately 50% to 60% with crizotinib. Response duration was 42-48 weeks. (Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010 Oct 28. 363(18):1693-703). (Shaw AT, Kim DW, Mehra R, Tan DS, Felip E, Chow LQ, et al. Ceritinib in ALK-rearranged non-small-cell lung cancer. N Engl J Med. 2014 Mar 27. 370(13):1189-97).

In (Squamous Cell Cancer or SCC) NSCLC The demonstrated impact of molecular targeting is less clear since the targets have as yet to be clearly defined. in about 5% of SCC cases the EGFR, KRAS and ALK mutations are noted presumably from the mixture of cell types (adenocarcinoma + Squamous Cell) these patients after a Cisplatin based chemotherapy regimen show a 18% response rate to the small molecule targeted inhibitors such as Erlotinib, Afatinib. SCC is a well known entity that occurs secondary to dysplastic changes in smokers and other environmental toxins. These dysplastic cells have variable damage to the genetic structure early on. Further oxidative stresses to these dysplastic cell lines increases the genetic mutation burden and leads to cancer.

The following targets have shown success in SCC:

1.        Monoclonal Antibody PD-1 (Nivolumab) and (Pembrolizumab or MK-3475 an Anti PD-1) an immune checkpoint blockade in unselected SCC cases lead to a 16-23% response rate and disease control rates of up to 50%, especially with the PD-L1 over-expressers. Smokers seem to benefit from the anti PD-1 and PD-L1 checkpoint blockades. Anti PD-L1 agents currently in Phase i/II trials with encouraging early results include MPDL3280A (atezolizumab) showing a 25% improvement over Docetaxol in a head to head comparison.
2.        Anti CTLA-4 (Iplimumab) that restores downstream immune activation against the cancer has had limited success in SCC with Phase I/II trials in progress against advanced NSCLC SCC patients.

We have come a long way in securing newer targets to attack against Lung Cancer. The success will ultimately depend on the durability of the response in improving overall survival hopefully with improvement in the Quality of life as well. Combinations of molecular targeted therapy with Immune checkpoint blockade as well as Restoring Immune surveillance in limited disease lung cancer can be personalized to the patient in the future.

There are many other paths that have yet to be travelled...

Only the curious have, if they live, a tale worth telling at all - Alistair Reid