SAN DIEGO – It is equally fair to say that lung cancer treatment has come a long way, and that it has a long way to go.

Speaking at a joint conference by the International Association for the Study of Lung Cancer and the American Association for Cancer Research on lung cancer translational research, William Pao remembered the stark realities of being an oncology fellow at Memorial Sloan-Kettering Cancer Center just 20 years ago, when the main lung cancer “procedure” done by trainees was to get a DNR, or do-not-resuscitate order, from their patients.

Pao, who is now the head of Roche Holding AG’s pharma research and early development unit, has done as much as anyone to change that state of affairs. He was one of the original discoverers of activating EGFR mutations as a lung cancer driver, and led the clinical trials for third-generation EGFR inhibitor Tagrisso (osimertinib, Astrazeneca plc.), which is now approved as a first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutations, as well as for patients who have progressed on other EGFR inhibitors.

The advent of targeted therapy options – along with smokers kicking the habit by the millions – is one reason that lung cancer rates are not just dropping, but dropping at increasing rates, and driving an overall decrease in cancer mortality, according to a report released Jan. 8, 2020, by the American Cancer Society.

That same report noted that lung cancer remains the leading cause of cancer death. While five-year survival rates for individuals diagnosed at early stages are now close to 100% for breast and prostate cancer, for lung cancer the number is around 60%. And because lung cancer is often diagnosed at later stages, the complete overall survival rate is just 23%.

Critically, though treatment with Tagrisso has increased median progression-free survival even compared to other EGFR inhibitors, to slightly more than 38 months, resistance is still near-inevitable.

And when resistance does emerge, mechanisms are more varied and more complex than is the case for Iressa (gefitinib, Astrazeneca plc) or Tarceva (erlotinib, Astellas Pharma Inc.).

A much larger percentage of Iressa- or Tarceva-treated tumors develop resistance through mutations in EGFR itself than those treated with Tagrisso.

In general, John Heymach told the audience, resistance mechanisms can be divided into three broad categories. Heymach is co-chair of the conference and chair of the department of thoracic head and neck medical oncology at the University of Texas MD Anderson Cancer Center.

There are the resistance mechanisms that prevent a given EGFR inhibitor from binding to its target, leaving the dependence on EGFR signaling intact. There is so-called bypass signaling, which circumvents EGFR signaling but activates the same downstream pathways.

In EGFR-dependent resistance, “we don’t see a fundamental rewiring of the downstream signaling – the signaling continues as it was, it’s just that the TKIs are no longer able to block it,” Heymach said. For bypass signaling, too, while there is rewiring at the activation end of the pathway, the downstream molecular landscape remains unchanged.

More challenging are resistance mechanisms where cells switch their cell type, essentially the cellular version of “new year, new you.”

Non-small-cell lung cancer can transform into small-cell or squamous cell carcinoma, both of which have dismal outlooks. Cells can also undergo an epithelial-to-mesenchymal transition (EMT), leaving them in a less differentiated state.

One aspect of the work in Heymach’s lab is to search for targetable alterations for tumor cells that have undergone lineage transformation – an undertaking, he said, that takes “digging into the biology” underlying the resistance, because growth and metastasis “are no longer driven from the same canonical pathways” as during the EGFR-driven phase of such tumors.

Heymach acknowledged that it’s possible to get “a sense of nihilism” when looking at the therapeutic vulnerabilities of lineage-transformed cells. There aren’t many of them to begin with, and in looking at such cells, one thing Heymach and his team have found are that the vulnerabilities they did identify were often specific to a tumor.

Nevertheless, Heymach as well as others have turned up some possible molecular targets for lineage-transformed tumors. There are some hints that inhibiting AXL or Aurora kinases shrink tumors that have undergone EMT.

Speaking earlier in the conference, Kris Wood, assistant professor of pharmacology and cancer biology and biomedical engineering and a member of the Duke Cancer Institute, discussed an alternate method to dealing with resistance.

Wood described a phenomenon he termed “collateral sensitivity” that is part of resistance. In becoming resistant to one drug, tumor cells need to fuel their rapid growth through alternate pathways – and in doing so, they can become hypersensitive to inhibitors of those alternate pathways.

The strength of focusing on alternate pathways is that “there is a possibility that diverse clones that develop resistance through different mechanisms might share collateral sensitivity,” Wood told BioWorld. Targeting such shared collateral sensitivities could resemble a one-two punch more than serial development of inhibitors as resistance mechanisms crop up, a strategy that can start to look more like whack-a-mole.

Collateral sensitivity is in some ways reminiscent of synthetic lethality, though “what we’re doing is not quite synthetic lethality,” because each drug by itself is deadly to the cell, under the right circumstances. And part of the goal of the first drug is to evoke a response that makes cells vulnerable to the second, he said. “We’re laying a trap.”