recent seminal study in the New England Journal of Medicine reported improvement in mortality from non-small cell lung cancer (NSCLC), the leading cancer killer of men and women in the United States.
These advances have been attributed, in no small part, to the more rapid and efficient development of targeted therapeutics and the willingness of medical oncologists to adopt evolving practice paradigms. Less evidently, several convergent developments in the broader community – such as the more widespread availability of broad-based “regulatory caliber” genomic profiling, more nimble and efficient clinical trial design, and a changed regulatory paradigm focused on speeding the subset of clearly active and safe drugs to patients – have contributed to this improvement in mortality from NSCLC.
To understand the impact of these advances for NSCLC and then to extrapolate to other advanced solid tumors, we briefly review the progress in advanced/metastatic ALK-altered NSCLC, a biomarker-defined subset of the NSCLC patient population, which typically is of adenocarcinoma histologic subtype.
The Premise and Progress of Targeted Therapy in NSCLC
Patients whose tumors harbor this predictive biomarker experience markedly prolonged progression-free survival (PFS) when treated with crizotinib, a first-generation ALK tyrosine kinase inhibitor (TKI), compared to chemotherapy treatment as demonstrated in the seminal PROFILE 1014 trial.
Then in 2017 and 2018, respectively, second-generation ALK-TKIs such as brigatinib and alectinib demonstrated superior PFS to crizotinib in head-to-head comparisons via randomized clinical trials. Importantly, beyond superior efficacy as defined by rates and duration of responses, these TKIs commonly carry significantly less toxicity than cytotoxic chemotherapy. For the estimated 55% of patients with metastatic NSCLC who undergo ALK testing, 2-3% are found to have such ALK rearrangement/fusion, but also noting that a higher proportion of those with the adenocarcinoma subtype undergo such testing. Patients treated with one of these newer agents experience median survival of nearly three years, and an estimated 62.5% of patients live five years or more, with some living more than a decade. These lifespans were previously unimaginable in the chemotherapy-only era of NSCLC treatment.
Beyond ALK-altered NSCLC, progress in NSCLC continues apace since Bruce Johnson published his piece in Global Forum in May 2019 when alterations in only four such oncogenic drivers (ALK, EGFR, BRAF, ROS) were linked to available therapies, and two additional druggable biomarkers – METex14 skipping and RET genomic alterations – were tied the approvals of capmatinib and selpercatinib in 2020.
Moreover, development of targeted therapies other than TKIs continues apace, such as sotorasib and adagrasib, which both target the ectopic cysteine of KRAS G12C found in 13% of NSCLC. This target has become the largest druggable oncogenic driver in NSCLC, and mutations in this gene, once deemed “undruggable,” are now an area of rapid drug development and cautious optimism for active targeted treatments on the part of many stakeholders.
While further progress in targeted therapies is still clearly needed, a similarly urgent mandate is to further democratize timely and widespread availability of broad-based genomic profiling, to educate a new generation of medical oncologists to interpret it, and to increase the availability of cognate agents for eligible patients without catastrophic financial consequences to the patient or family.
These are all obligatory components to allow the full benefit from incorporating targeted therapies into the management of patients with NSCLC and other advanced cancers. Broad-based genomic profiling identifies the biomarker in a given tumor that correlates with the sensitivity to a matching targeted therapy. Management of advanced cancer patients with targeted therapy is an evolving paradigm, distinct from histology-paired chemotherapy, and it requires ongoing education of medical oncologists to develop therapeutic hypotheses that incorporate biomarkers and targeted therapy.
A recent study reached the devastating conclusion that, once such agents are approved, the price of TKIs correlates inversely with survival of NSCLC patients. This finding highlights an ongoing and underappreciated difficulty of the financial implications of targeted therapy and the related opportunity for novel drug development strategies to address this challenge.
Progress in Other Tumor Types
Beyond NSCLC, the rising use of comprehensive genomic profiling (CGP) as a broad-based genomic profiling assay in non-NSCLC tumors is intertwined with a growing awareness of a developing therapeutic opportunity across tumor types for targeted and other precision therapies. One prominent attestation to the promise of the above is the recent designation by ASCO of molecular profiling in GI cancers as the Advance of the Year in 2021 based on findings such as the identification of HER2 amplification in gastric and colon cancer.
Arguably, the most notable culmination of this approach has been the recent and remarkable development of “pan-cancer” approvals for therapies such as larotrectinib, the NTRK inhibitor (approved for NTRK rearranged cancers), and pembrolizumab in the second line for all TMB-high (≥ 10 mutations/megabase). Table 1 lists examples of the applicability of targeted therapies to individual non-NSCLC tumor types as well as pan-cancer approvals and the efficacy of these.
Table 1. Examples of targeted therapies and paired biomarkers across tumor types.
NTRK fusion
Larotrectinib
DoR not reached
Hong, D.S. ASCO 2019
Pembrolizumab
Lancet Oncology 2020
Pembrolizumab
PFS in first line setting 16.5 months v. 8.2 months (HR, 0.60; 95% CI, 0.45-0.80; p = .0004).
HER2 amplification
Trastuzumab deruxtecan
Second line (ORR) of 51.3% v. 14.3%
OS: 12.5 months v. 8.4 months (HR, 0.59; 95% CI, 0.39-0.88; p = .0097)
BRCA1/2
Olaparib
Median OS 51 v. 38 months placebo for relapsed BRCA 1/2 platinum sensitive
Lancet Oncology 2017
FGFR2 fusions
Pemigatinib
Lancet Oncology 2020
Table 1. Examples of targeted therapies and paired biomarkers across tumor types.
Tumor Type: Pan-solid tumor
NTRK fusion
Larotrectinib
Hong, D.S. ASCO 2019
Tumor Type: Pan-solid tumor
Pembrolizumab
Lancet Oncology 2020
Tumor Type: Colon cancer
Pembrolizumab
PFS in first line setting 16.5 months v. 8.2 months (HR, 0.60; 95% CI, 0.45-0.80; p = .0004).
Tumor Type: Gastric carcinoma
HER2 amplification
Trastuzumab deruxtecan
Second line (ORR) of 51.3% v. 14.3%
OS: 12.5 months v. 8.4 months (HR, 0.59; 95% CI, 0.39-0.88; p = .0097)
Tumor Type: Ovarian carcinoma
BRCA1/2
Olaparib
Median OS 51 v. 38 months placebo for relapsed BRCA 1/2 platinum sensitive
Lancet Oncology 2017
Tumor Type: Cholangiocarcinoma
FGFR2 fusions
Pemigatinib
Lancet Oncology 2020
To continue to fulfill the promise of patient benefit in non-NSCLC tumor types, CGP as the vehicle of identifying druggable biomarkers and targeted therapy should be widely available and affordable. In concert, consideration of a mechanism-driven, genomically characterized therapeutic clinical trial can often become an earlier consideration in the treatment paradigm. That’s especially the case for tumor types where no true “standard of care” systemic therapy exists (e.g., cholangiocarcinoma) or is of very limited efficacy (e.g., pancreatic cancer). This thesis is also reflected in oncology drug development, as patient stratification by biomarker often goes towards defining a population likely to benefit from an investigational targeted therapy, even as early as in dose-escalation studies.
Trajectory of Targeted Therapies
Since NSCLC has emerged as a paradigm for precision oncology, what do we anticipate is the ceiling for progress in targeted therapy? Combination regimens with a targeted therapy backbone are being vigorously investigated. Currently, the first-line treatment of EGFR-mutant NSCLC is monotherapy with the third-generation EGFR inhibitor osimertinib. To further enhance patient benefit, combination regimens are being investigated with chemotherapy, anti-angiogenic agents, and older EGFR inhibitors assessed as individual partners. Other non-kinase targets such as the previously “undruggable” oncogenes are being actively pursued, and as a prime example, the previously mentioned class of KRAS G12C directed therapies will likely undergo a decade or more of continuous clinical investigation to initially establish one or more class members as approved monotherapy. Then, as with osimertinib, further identification of effective combination regimens to enhance likelihood of response and extend duration will occur, perhaps for compound mutated subclasses such STK11, KEAP1, and TP53.
Beyond the development of new therapies is the extension of indications for existing therapies, in particular a migration of targeted therapies into treatment in earlier-stage cancer looms. The prime example here is again osimertinib, which was recently approved for adjuvant treatment of resectable EGFR mutant lung cancer based on striking data (HR near 0.2) from the ADAURA trial.
In this exciting context, challenges tied to the pace of knowledge dissemination, widespread access to, and affordability of CGP and approved targeted therapies, access to therapeutic clinical trials and the potential for a new therapeutic plateau remain sobering.