Molecular Discoveries Pave Way for Rapid Advances in Lung Cancer

Giorgio V. Scagliotti, MD

In less than a decade, lung cancer has evolved from a disease state with relatively few treatment options to tumor types whose molecular characteristics have become increasingly well defined.

Giorgio V. Scagliotti, MD, has played a prominent role in researching and developing therapies to attack molecular targets. He is a professor and chair of Medical Oncology at the University of Torino in Italy, and director of the Thoracic Oncology Division at the San Luigi Gonzaga University Hospital in Turin.

At the 13th International Lung Cancer Congress, Scagliotti discussed progress in identifying the driver mutations in lung cancer, noting that researchers have been able to characterize those mutations for approximately 50% of lung tumor types. In NSCLC, there are two FDA-approved therapies with definitive targets: erlotinib (Tarceva) for tumors that harbor EGFR mutations and crizotinib (Xalkori) for ALK-translocated tumors.

“We have made much more progress over the last 10 years than during the previous 20 years in the systemic treatment of non—small cell lung cancer,” Scagliotti said in an interview with Oncology & Biotech News. “I’ll give you a very straightforward example. Tell me if, 10 years ago, just in 2002, it was possible to imagine a patient wit h stage IV non—small cell lung cancer surviving more t han 2 years. And now that is the case for the vast majority of our patients having a tumor harboring EGFR-sensitizing mutations.”

Scagliotti noted that it has been only 4 years since the first lung cancer genome was “fully codified, fully explored, and fully analyzed,” and that the impact of genetic mutations will come more sharply into focus as the tumors of more patients are sequenced.

The key to making substantial gains in life expectancy for patients with lung cancer is defining “homogenous genetic subgroups of tumors” and developing individualized strategies, Scagliotti indicated in his presentation. The onset of resistance to targeted therapies in patients with an “oncogene addiction” is inevitable, Scagliotti said, and research to overcome mechanisms of resistance is ongoing.

Scagliotti elaborated upon emerging research and treatment strategies in this interview.

OBTN: Please describe the current landscape for targeted therapies in patients with lung cancer?

Dr Scagliotti: Cancer research is getting close to a big roundabout, because we have clear evidence that cancer is a genetic somatic disease in the vast majority of cases and that it is quite likely that it originates in cancer stem cells. For any tumor type, there are genes that are really important in cancer cell initiation and progression. For some of the genes, we are already able to do a molecular diagnosis.

Only when you are able to make a molecular diagnosis and you have an effective targeted therapy for that specific abnormality, are you able to make a difference in the natural history of the disease. In lung cancer, the overall landscape is still incomplete because we have much more information in adenocarcinoma and much less information in squamous cell carcinoma.

In adenocarcinoma, we have at least three or four druggable targets. One, starting in 2004, is the story of the EGFR mutation, with gefitinib in Europe and in Japan, and more recently erlotinib, that are effective agents when you detect the EGFR mutation in the tumor.

Secondly is the ALK translocation story that is quantitatively less relevant than the EGFR mutation, but it is equally important. Crizotinib, the first-in-class agent to hit that molecular diagnosis, is able to extend, significantly, the time to progressive disease. You can improve the symptoms related to the neoplastic disease and you can get, in the vast majority of the cases, a tumor shrinkage.

Now, another piece of information has been added recently, the ROS1 translocation. Those patients with ROS1 translocation are also sensitive to crizotinib. So you have another piece of the story that is consistent with the other two.

But it is an incomplete story because we still don’t know if there is additional room in these oncogene-addicted tumors for the combination of targeted therapies. And that is exactly what we are currently exploring.

What has been the experience in combining a targeted therapy with chemotherapy?

Bevacizumab was the only study positive among 25 or 30 phase III clinical trials that were trying to add on, on top of chemotherapy, one specific targeted agent. Even with bevacizumab, the improvement in survival could be statistically significant, but it’s not, at least in my mind, clinically relevant. Cetuximab was generating another marginally positive or statistically positive study, but that is not enough to convince clinicians to use cetuximab in combination with cisplatin/vinorelbine for patients with stage IV non—small cell lung cancer.

When you are trying to add a targeted agent in a nontargetable way to cytotoxic chemotherapy, you are offering this kind of treatment to all comers. In general, you are not getting any meaningful improvement of most of the clinical outcomes, such as response rate, progression-free survival, and overall survival.

Again, you need the target in the right patient population. I’m not saying that in the future we are not going to use chemotherapy and targeted therapies. Probably we are not going to use, concomitantly, targeted therapies with chemotherapy, but there is still room for a sequential way of administering chemotherapy and targeted therapies. There are, for instance, some data suggesting that patients with the resistance mutation, T790M, are more sensitive to chemotherapy. There are some data showing that the patients with ALK-translocated tumors have a higher sensitivity to pemetrexed. It could be that in the near future, for the molecularly defined patient population, you can envision a scenario in which targeted therapies could be combined in a sequential fashion with cytotoxic chemotherapy.

Evolving Therapeutic Landscape of Stage IV Lung Cancer

Over the past decade, the identification of driver mutations has drastically enhanced the treatment options for patients with lung cancer. Diagram A illustrates the projected histological profile per every 100 patients with stage IV lung cancer diagnosed today. Diagram B identifies patients in this population with mutations for which targeted therapies have been developed or are being investigated.

A. Histology

B. Mutational Status Driving Therapeutic Landscape

Scagliotti, GV. Individualized therapy in lung cancer: where are we in 2012? 13th International Lung Cancer Congress; July 19-22, 2012; Huntington Beach, CA.

Should a targeted therapy be administered before chemotherapy?

When the target is present, the answer is definitely yes because you have much data from clinical trials and meta-analyses favoring this approach for a superior overall response rate and progression-free survival. You can get a significant improvement in quality of life, and you should also consider that 15% of all patients who are treated with chemotherapy are not able to receive a second-line treatment. So, for all these reasons, I believe that the targeted agent, when the molecular diagnosis is done, is much better than cytotoxic chemotherapy.

Which molecular tests should be conducted in patients with advanced non—small cell lung adenocarcinomas?

The minimal amount of mutational testing or genomic testing should include the EGFR mutation testing for exons 19 and 21 and potentially also the resistance mutation, the T790M mutation in exon 20. The second marker that should be explored concurrently and not sequentially is the ALK translocation. Now, it’s quite likely that in the near future we will also have a ROS1 translocation FISH [fluorescence in situ hybridization] assessment in addition to that because of the sensitivity to crizotinib.

In addition to these markers, I would like also to consider the assessment to the mutational status for KRAS. Currently, we are using this information to exclude patients from receiving targeted therapies, because the KRAS-mutated patients are not sensitive to EGFR tyrosine kinase inhibitors [TKIs] and they are not sensitive to crizotinib. At least it’s a way to eliminate 25% of our patients from additional testing. In addition to that, there are preliminary data showing activity of some agents against the KRAS-mutated tumors in at least several phase II studies.

What new research do you find particularly exciting?

The most advanced program is the c-MET program for at least several companies. The c-MET pathway came back into the experimental field because of its association with the mechanisms of resistance to EGFR TKIs.

I believe that c-MET inhibition is much more important and is not limited to a relatively small group of patients showing secondary resistance to the EGFR TKIs. The mesenchymal epithelial transition receptor—that is the original name of c-MET—is probably quite important in generating the metastatic process. Consequently, there is a potential role for c-MET inhibition that is much broader than what we are currently exploring in phase III studies, which are mainly in second-line settings. It could be that the c-MET inhibition is worth exploring also in front-line settings together with chemotherapy. There are also other research areas for c-MET in locally advanced non—small cell lung cancer; for instance, using c-MET inhibition as a sort of maintenance treatment if you believe that the c-MET inhibition can interfere with the metastatic process. We have data from a small phase II study with ARQ 197 [tivantinib] in which there was a clear sign of reduction of time to new metastases.

I believe that the co-inhibition of the EGFR pathway and the c-MET pathway is a nice way to explore the next step concerning the combination of targeted therapies. There are some data in the preclinical setting in cell lines showing that the co-inhibition of the two pathways is much more effective than the single inhibition of one of the two pathways. That is probably the next generation of clinical trial.

There are new agents, for instance, the secondgeneration ALK inhibitors that are currently going through a phase II program. The Hsp90 inhibitors may be explored in EGFR-mutants and the ALK-translocated tumors, again in combination or using an early combination.

Are there any new developments for squamous cell carcinoma?

There are preliminary studies looking at genomic abnormalities in squamous cell carcinoma. The incidence of squamous cell carcinoma is going progressively down, mainly because of changes in tobacco smoking attitudes resulting in the vast majority of consumers using more filtered cigarettes. Now, in newly diagnosed patients, squamous cell carcinoma is no more than 20%. Having said that, we should consider that the mutational load in squamous cell carcinoma is much higher than in adenocarcinoma. There are many more genomic abnormalities than in adenocarcinoma, and you don’t know exactly how many of these genomic abnormalities—that you can find in up to 60% of the cases of squamous cell carcinoma—are really relevant.

So far, we have some genomic changes that are more important or more frequently reported in squamous cell carcinoma than in adenocarcinoma. For instance, the FGFR1 and FGFR2 amplification in some studies is ranging around 20% to 24%. In other studies, it’s only 5% to 6%. We still don’t know if by using specific inhibitors for FGFR, we are able to make significant changes in the natural story of the disease. There are several other genomic abnormalities such as the DDR2 mutations, detected in only 2% of squamous cell carcinoma, that are potentially sensitive to dasatinib and nilotinib. But we don’t have any data, any study, that is currently investigating this tiny subgroup of patients using these two agents. In addition to that, there are 10% to 12% of patients who are PTEN-deleted or they have PI3 kinase mutations. We have agents that potentially are useful in this group, but, again, it’s a matter of future clinical studies.

Are you optimistic that immunotherapy can make a difference in lung cancer?

People are getting excited too early about the latest information. We were extremely disappointed in the past about the role of immunotherapy in lung cancer. The PD-1 data presented at ASCO appear to be quite promising, but we need to get much more information from a formal phase II study.

How promising are heat shock protein (Hsp) inhibitors?

Heat shock protein inhibitors have been around since the 1970s. In the last 10 years, a second generation of Hsp90 inhibitors was synthesized. There are 10 or 15 agents that are currently in clinical development, but we have enough clinical data only for three of them that support the use of Hsp90 inhibitors, mainly in patients with ALK-translocated tumors.