We’ve seen that there are a wide range of molecular processes that are associated with acquired resistance in both EGFR and ALK-positive tumors, so we shouldn’t be surprised that we see a range of clinical patterns when patients progress. We may see RECIST-defined progression with a single new focus of disease against a background of still excellent disease control everywhere else. We may see a multifocal process of many lung nodules or other lesions progressing, but still at a very indolent pace, often still with less of a disease burden than the patient had prior to initiation of targeted therapy. Both of these situations suggest that the TKI is still effective in inhibiting a substantial subset of the cancer cell population. And we sometimes do see a more rapid pattern of diffuse progression that might lead us to question whether the targeted therapy is still offering any suppressive effect. These are very different clinical situations, yet thus far we haven’t made a distinction when we refer to the concept of acquired resistance and progression after previously effective targeted therapy.Overall, it’s important to ask what the pace of the disease is, and how extensive is the disease that is setting that pace?
Dr. Oxnard himself provides some of this evidence in his review of outcomes among 42 patients with EGFR mutations who were treated with erlotinib on one of three clinical trials. Though the definition of a need for treatment change was at the discretion of the treating physician, based on their good judgment we say that nearly half did will without clinically significant progression of their disease beyond initial detection of progression, and one in 5 did generally well on ongoing erlotinib for more than a year after that point. In some cases, patients had transient breaks from treatment, and in some cases, patients received local therapy for limited progression, which deserves its own careful consideration.
Investigators from the University of Colorado, including Dr. Doebele, have applied this concept for their own patients, reporting on 51 patients with an EGFR mutation or ALK rearrangement who progressed on TKI therapy. Half of them, those with CNS disease or a limited number of extracranial sites of progression, received local ablative therapy and ongoing TKI therapy, and they found that many continued for several months without further progression, particularly those with initial progression in the CNS, who demonstrated a median time to subsequent progression of 7 more months.
Helena Yu and colleagues from Memorial Sloan-Kettering actually excluded the patients with CNS disease from their analysis of local therapy, because radiation is considered the standard therapy for CNS progression, but they identified 10% of their patients with EGFR mutation-positive disease who were continued on EGFR TKI therapy after progression on the discretion of their oncologist. Though this is a selected subset, they found that this minority of patients went a median of another 10 months before any further progression, a median of 22 months before being felt to need a new systemic therapy, and had a remarkable median survival of over 3 years beyond progression, at 41 months.
That hasn’t been our practice historically, but there is reason to consider it in someone with a driver mutation who has demonstrated a prolonged benefit from a therapy against that specific target. Dr. Greg Riely, Dr. Chaft, and colleagues from Memorial Sloan-Kettering have reported that up to a quarter of the patients with progression on an EGFR TKI can demonstrate a rapid flare of disease, or rebound progression, leading to hospitalization or even death within two weeks of after having this therapy discontinued. Moreover, the TKI can reverse this process when re-introduced. This has also been described for ALK-positive disease treated with crizotinib, then discontinued. This reproducible occurrence argues that bad brakes are still better than no brakes when they’re starting to fail. Slower progression with ongoing TKI therapy may be far preferable to an alternative of faster progression without it.
In fact, we’ve already got a proof of principle in the world of molecular oncology that ongoing targeted therapy can be effective after progression. In the world of CML, targeting the bcl-abl translocation with imatinib is associated with acquired resistance that can be treated effectively with an increase in dose or an alternate therapy against the same target. And in the setting of solid tumors, there’s evidence that continued trastuzumab beyond progression is associated with improved response rate and survival when combined with subsequent chemotherapy in HER2+positive metastatic breast cancer.
So at a time when a change in systemic therapy is needed for acquired resistance, our leading options outside of a clinical trial are chemotherapy with or without ongoing TKI therapy.
We don’t have prospective evidence to guide a recommendation on this question yet, but there is certainly reason to believe this is feasible and perhaps beneficial. Sarah Goldberg and colleagues retrospectively reviewed their experience at Yale treating 78 patients after acquired resistance to EGFR TKI therapy with either chemo alone or chemo and ongoing erlotinib. Though this wasn’t a randomized trial, the numbers are relatively small, and there may have been reasons for favoring ongoing erlotinib in some patients, the response rate was twice as high with the combination, though there was no significant difference in progression-free or overall survival.
I mentioned that Dr. Horn’s trial includes a planned re-treatment with erlotinib after progression on chemo alone, and this remains a viable option as well, as patients may well benefit after having a greater proportion of the cancer cells resensitized to EGFR TKI. Preclinical studies show that the TKI-sensitive cells have a growth advantage over the resistant cells, so without the selective pressure of an ongoing TKI, a significant amount of the cancer may again be found to be sensitive to EGFR TKI therapy after time off of an EGFR TKI.
Drs.Heon and colleagues from Dana Farber and Mass General Hospital looked retrospectively at their experience of retreating 24 patients who had demonstrated prior acquired resistance to either gefitinib or erlotinib. Though the response rate was very low, just 4%, more than half experienced stable disease, with a median progression-free survival of 3.3 months, which is also exactly the progression-free survival seen with afatinib in the LUX Lung-3 trial…highlighting that it’s not clear that afatinib or other EGFR inhibitors given after gefitinib or erlotinib is adding anything more than what you’d get from re-treating such patients with erlotinib. Not surprisingly, patients off of an EGFR TKI for a longer period were the same ones who seemed to benefit most from re-treatment, given the greater potential for resensitization.
One other potential option, though not studied prospectively and not one that I have pursued yet, may be sorafenib, based on a post-hoc analysis of the MISSION study of sorafenib vs. placebo in heavily pretreated patients. Over 80% of the patients had received prior EGFR TKI therapy, and the results revealed that while the overall trial showed no significant benefit with sorafenib, the subset of EGFR mutation-positive patients experienced an improvement in progression-free survival,
….as well as overall survival, that was not seen in patients with EGFR wild type. Though sorafenib isn’t a standard therapy at this point for non-small cell lung cancer, these results suggest that this commercially available agent may potentially be beneficial in previously treated EGFR mutation-positive patients.
Finally, there is the question of whether a repeat biopsy should be performed on progressing disease. We’ve seen reproducible evidence of an immediately actionable result, such as transformation to small cell lung cancer, in a minority of patients, while a much greater proportion have one or more identifiable mutations that may prove to direct treatment decisions soon, but at this point are of greater utility in generating hypotheses and pursuing well-informed research efforts. At the present time, repeat biopsies aren’t a clear standard of care, given the relative infrequency of a clearly actionable result with readily available treatments outside of a trial setting. But it is important to recognize that we have made huge gains in our understanding of molecular oncology that have led directly to some of our best new treatment options based on a greater emphasis on tissue collection and identifying relevant mutations. This is propelling the development of the field, and clinical trials, ideally incorporating tissue collection, are an ideal option to consider in the setting of acquired resistance, especially when patients are prospectively identified for potential future trials long before they actually demonstrate progression.
Overall, then, it’s worth underscoring that patients with acquired resistance demonstrate clinical variability that mirrors their molecular heterogeneity, so we might well imagine that there shouldn’t be one universal approach to such a diverse population. There is a growing recognition that patients may benefit greatly from ongoing treatment with the targeted therapy, and that some progression may be minimal enough that no change is indicated, and some patients may continue to do well and feel well for many months or even more than a year of post-progression treatment with no changes.In those with oligoprogressive disease, local ablative therapy to “get out the lead runner”, and eradicate the pace-setting disease enables a subset of patients to continue to do well on the same systemic therapy with a TKI that controls all of the other disease effectively for a very long time. This approach may be especially appealing for CNS disease, where progression often doesn’t represent resistance as much as a pharmacodynamic limitation of the blood brain barrier.For more diffuse, multifocal progression, there is some suggestive evidence that at least some patients may benefit from ongoing targeted therapy, perhaps just to prevent a “disease flare” from loss of the suppressive effect of still relatively beneficial TKI therapy, and it may well be that the TKI and chemotherapy can be given concurrently to treat different cell populations as effectively as possible. This approach still needs to be compared prospectively to chemotherapy alone, potentially with a benefit from re-treatment with targeted therapy after a period in which the cancer may become re-sensitized to it. We look forward to current and upcoming trials providing answers to these still open questions.
In the meantime, there are also clinical trials with novel agents, as covered by Drs. Oxnard and Doebele, that show promise as well. Though patients may need to travel to find a participating center, some of these agents are demonstrating clinical benefits with such high response rates that they justify the effort to travel to pursue them.Finally, though repeat biopsies of progressing lesions aren’t currently a standard of care, given the relative infrequency of finding an immediately actionable result outside with readily available agents, the greater availability of tissue has been a leading driver in both our understanding of this disease and the growing availability of therapies that have revolutionized the field. We should expect that repeat biopsies will also accelerate the pace of future developments.With that, I’ll thank you for your attention, and I’d like now to open up to questions for any and all of us. Thanks.
West asco clin mgmt acquired resistance tk is
Clinical Perspective on Acquired Resistance:Defining and Overcoming BarriersHoward (Jack) West, MDSwedish Cancer InstituteSeattle, WAASCO Annual MeetingChicago, ILJune 1, 2013
Acquired Resistance to Targeted Therapies InNSCLC: Management in the Clinic Today• Detectable vs. clinically significant progression?• Role of local therapy?• Continue targeted therapy?• Value to re-challenge?• Repeat biopsy?Outline of key questions
Acquired Resistance to Targeted Therapy:Heterogeneous PatternsDiverse molecular mechanisms of resistance diverse clinical patterns of progression• Single focus of progression• Slow, minimal multifocal progression• Rapid, more diffuse progression
Is it clinically significant progression?Questionable/dubious indicatorsMild increase in metabolic activity on PETRising serum tumor markerSlow, slight increase in tumor size(1-2 small new nodules vs. otherwiseexcellent disease control?)
Continued treatment beyond progression,Dana Farber Experience• 42 EGFR mutn-pos pts s/p 1st line erlotinib on one of 3clinical trials• 45% continued without significant progression > 3 months• 21% required no further treatment change for > 12 monthsOxnard, ASCO 2012, A#7524
If significant progression, is it isolatedor more diffuse?Is “oligoprogression” analogous tooligometastatic/precocious metastatic disease?Perhaps especially for CNS disease• Poor CNS penetration of both EGFR TKIs and crizotinib,so brain mets may not represent resistance to drug(Bronischer CCR, 2007; Costa JCO 2011)• T790M seen in 60% of progressing lesions in acquiredresistance, but only 10% of lesions from CNS progression(Hata, ASCO 2012, A#7528)
Local Therapy in Acquired Resistance:University of Colorado Experience• 65 pts (38 ALK+, 27 EGFR mut’n+) of whom 51 (28 ALK, 23 EGFR)progressed• 25 (49%) with CNS (no LMC) or <4 extracranial sites of progressionWeickhardt, J Thorac Oncol 2013
Chen,Oncologist 2012Variability of Molecular Markers Over Timeand Across Disease Sites• Heterogeneity ofmolecular changes acrosslesions• Acquired resistance maybe anatomically isolated
Local Therapy in Acquired Resistance:Extracranial Oligoprogression• 18/184 pts local therapy for extracranial PD(CNS PD excluded)Yu, J Thorac Oncol 2013• Median time to newsystemic Rx: 22 months
Rapid acceleration of PD hospitalization and/or death afterdiscontinuation of EGFR seen in up to ~1/4 of pts in MSKCC series(Chaft, Clin Cancer Res, 2011)Also reported after discontinuation of crizotinib after acquiredresistance in ALK-positive NSCLC (Pop, J Thorac Oncol, 2012)Last day of TKI Off EGFR TKI Resumed TKIDay 0 Day 21 Day 42Rapid Progression with Discontinuation ofEGFR TKI after Prolonged PFS
For Cancers with a Known Driver Mutation, ContinuingInhibition of that Target is Beneficial after Progression• Progression of CML on imatinib increase dose, or dasatinib, ornilotinib lead to consistent response• Solid tumor example: HER2+ breast cancervon Minckwitz, JCO 2009
Treatment Options after AcquiredResistance to EGFR (or other) TKIOxnard, Clin Cancer Res, 2011
Chemo/Erlotinib vs. Chemo Alone atProgression after Acquired Resistance• N = 78 retrospective review ofoutcomes– chemo alone (N = 44) or– chemo/erlotinib (N = 34)• RR 18% (chemo) vs. 41% withchemo/erlotinib)• No differences in PFS or OS betweenthese two strategiesGoldberg, ASCO 2012, A#7524
Chemo with Concurrent TKI• Studies in unselected or clinically selected populations show nobenefit but no signal of increased harm• Combinations of chemo and TKIs are certainly feasible• Little prospective study in setting of acquired resistance yet• ph II trial of pem/EGFR TKI as 3rd line (Yoshimura, JTO 2013)• N = 27; RR 26%, DCR 78%, med PFS 7.0 mo, med OS 11.4 mo• Unclear if they are significantly more favorable thanchemo alone in acquired resistance
Chemotherapy +/- Ongoing EGFR TKI forAcquired Resistance, with RetreatmentPrimary endpoint: progression-free survivalPI: Leora Horn (Vanderbilt)Advanced NSCLCActivating EGFR mutationResp to EGFR TKI>4 moNo prior chemotherapyPS 0/1N = 120RANDCis or Carbo/Pemetrexed+ ongoing erlotinibStratification by:EGFR mut’n exon 19 vs. exon 21Time to progression on EGFR TKI <1 yr vs. >1 yrPS 0 vs. 1Cis or Carbo/PemetrexedErlotinib re-treatment
Chemotherapy +/- Ongoing Crizotinib forAcquired Resistance in ALK-Positive NSCLCCo-primary endpoints:Progression-free survivalResponse rate, pemetrexed aloneALK rearrangementProgression on crizotinibafter response or SD>3 moNo prior pemetrexedN = 114RANDPemetrexed alonePI: D. Ross CamidgePemetrexed + ongoing+ crizotinibSWOG 1300 (in development)
Chemo Without TKI Can BeFollowed by Re-treatmentOxnard, Clin Cancer Res, 2011
EGFR TKI Re-treatment after AcquiredResistance: DFCI/MGH Experience• Retrospective, 24 pts (over 9.5 yrs)with activating EGFR mutation after ARto gefitinib (30%) or erlotinib (70%)• RR 4%, SD 63%• Median interval off EGFR TKI 5 mo(range 2-46 mo)• Greater benefit w/longer interval ofEGFR TKI (PFS 4.4 vs. 1.9 mo for 6mo interval off EGFR TKI)Heon, ASCO 2012, A#7525
MISSION Trial of Sorafenib vs. Placebo:PFS based on EGFR mutation statusBiomarker*treatment interaction analysis: p-value=0.015Patients with EGFR mut (in tumor orplasma)• Sorafenib N=44; Placebo N=45• HR=0.27 (95% CI 0.16,0.46)• P-value<0.001• Sorafenib median PFS= 2.7 mo (83d)• Placebo median PFS= 1.4 mo (42d)Patients with EGFR wild type• Sorafenib N=122; Placebo N=136• HR=0.62 (95% CI 0.48,0.82)• P-value<0.001• Sorafenib median PFS= 2.7 mo (82d)• Placebo median PFS= 1.5 mo (46d)Mok, ESMO 2012
MISSION Trial of Sorafenib vs. Placebo:OS based on EGFR mutation statusPatients with EGFR mut (in tumor or plasma)• Sorafenib N=44; Placebo N=45• HR=0.48 (95% CI 0.3,0.76)• P-value=0.002• Sorafenib median OS= 13.9 mo (423d)• Placebo median OS= 6.5 mo (197d)Patients with EGFR wild type• Sorafenib N=122; Placebo N=136• HR=0.92 (95% CI 0.7,1.21)• P-value=0.559• Sorafenib median OS= 8.3 mo (253d)• Placebo median OS= 8.4 mo (256d)Biomarker*treatment interaction analysis: p-value=0.023Mok, ESMO 2012
Are Repeat Biopsies Mandatory,Desirable, or Neither?Yu, Clin Cancer Res, 2013Not standard of care, relatively low probability of beingimmediately actionable, but repeat biopsies are likely to drive ourunderstanding and future treatments in this setting.• SCLC in 3-15%• Potential insight re: prognosis(+/- value of ongoing TKI?)• Otherwise, uncommon to findactionable result with currentapproved agentsN=155
Conclusions on Clinical Managementof Acquired Resistance (1)• Clinical as well as molecular heterogeneity• No clear evidence-based best approach defined yet• Not all progression merits change in therapy• “Oligoprogressive” acquired resistance– Consider local Rx and continue targeted therapy– CNS as pharmacodynamic issue, not acquired resistance• Diffuse progressive disease– Option of continuing TKI with concurrent chemo to avoid“flare”, treat different cell populations– Option of switching to chemo only, potentially followed byre-treatment
Conclusions on Clinical Managementof Acquired Resistance (2)• Prospective randomized trials are needed– Very real potential for bias in retrospective analyses• Trials of novel agents or combinations– Very attractive option for prospectively identified specialpopulation – consider clinical trials• Role for repeat biopsy?– Uncommon to have actionable result today– Very likely to increase our understanding of the field andidentify future treatment options